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#103 - 📑 Journal Club 41

Hello Friends 👋

We were fortunate this week to have so many publications available for review on Journal Club. We reviewed the data just published from the BeNeDuctus trial, the EpoRepair trial and many other articles looking at Late Onset Sepsis, transpyloric feeds, antibiotic duration and NEC and more. This week we are also introducing a few new things. First we are releasing Journal Club Shorts, short podcast episodes for the main articles Daphna and I reviewed on the podcast this week. I have also decided to make available to you all my journal club notes, in case these little research summaries could be value to you on your journey to keep up with the literature. Don't forget to secure your seat for the Delphi conference coming in March 2023. Have a good sunday!


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

Srivatsa B, Wesolowski A, Srivatsa KR, Bennett MM, Clark RH, Kupke KG.J Pediatr. 2023 Apr;255:175-180.e1. doi: 10.1016/j.jpeds.2022.11.025. Epub 2022 Dec 1.

Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, de Vries WB, Dijkman KP, van Kaam AH, Villamor E, Kroon AA, Visser R, Mulder-de Tollenaer SM, De Bisschop B, Dijk PH, Avino D, Hocq C, Zecic A, Meeus M, de Baat T, Derriks F, Henriksen TB, Kyng KJ, Donders R, Nuytemans DHGM, Van Overmeire B, Mulder AL, de Boode WP; BeNeDuctus Trial Investigators.N Engl J Med. 2023 Mar 16;388(11):980-990. doi: 10.1056/NEJMoa2207418. Epub 2022 Dec 6.

Wellmann S, Hagmann CF, von Felten S, Held L, Klebermass-Schrehof K, Truttmann AC, Knöpfli C, Fauchère JC, Bührer C, Bucher HU, Rüegger CM; Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair) Investigators.JAMA Netw Open. 2022 Dec 1;5(12):e2244744. doi: 10.1001/jamanetworkopen.2022.44744.

Flannery DD, Edwards EM, Coggins SA, Horbar JD, Puopolo KM.Pediatrics. 2022 Dec 1;150(6):e2022058813. doi: 10.1542/peds.2022-058813.

Ahmad I, Premkumar MH, Hair AB, Sullivan KM, Zaniletti I, Sharma J, Nayak SP, Reber KM, Padula M, Brozanski B, DiGeronimo R, Yanowitz TD; Children’s Hospitals Neonatal Consortium NEC Focus Group.J Perinatol. 2022 Nov;42(11):1458-1464. doi: 10.1038/s41372-022-01433-2. Epub 2022 Jun 27.

Thivierge E, Luu TM, Bourque CJ, Duquette LA, Pearce R, Jaworski M, Barrington KJ, Synnes A, Janvier A.J Pediatr. 2023 Jun;257:113268. doi: 10.1016/j.jpeds.2022.10.042. Epub 2022 Dec 1

Suarez EA, Huybrechts KF, Straub L, Hernández-Díaz S, Jones HE, Connery HS, Davis JM, Gray KJ, Lester B, Terplan M, Mogun H, Bateman BT.N Engl J Med. 2022 Dec 1;387(22):2033-2044. doi: 10.1056/NEJMoa2203318.

El-Khuffash A, McNamara PJ, Breatnach C, Bussmann N, Smith A, Feeney O, Tully E, Griffin J, de Boode WP, Cleary B, Franklin O, Dempsey E.Matern Health Neonatol Perinatol. 2018 Dec 3;4:24. doi: 10.1186/s40748-018-0093-1. eCollection 2018.

Lin M, Sayeed S, DeCourcey DD, Wolfe J, Cummings C.Pediatrics. 2022 Dec 1;150(6):e2022057824. doi: 10.1542/peds.2022-057824.

Find Ben's Notes Here:

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

Ben 1:01

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

Speaker 1 1:05

I'm good. But I didn't expect you to open the show, though.

Ben 1:12

I decided, well, it's

Unknown Speaker 1:12

been a long week.

Ben 1:14

It's been tough. It's been tough this week. We're pushing off neonatology review by a week because it's been we've been on service. You're on service next week. And we've been somehow, why did it fall on us to cover the unit during December the whole week?

Speaker 1 1:29

Yeah. It does feel like that the whole month, every other every other?

Ben 1:34

Yeah. That's messed up.

Unknown Speaker 1:38

Yeah, here we are. Here we are.

Ben 1:42

All right, a couple of housekeeping announcements. We released the episode on the Delphi conference, and the tickets are on sale. There's limited space. So please make sure you you reserve your seat before they're gone. And next week, we'll announce the first set of speakers. The speakers by the way, we're not completely clueless, like we the speakers are booked. But we're gonna announce them.

Speaker 1 2:07

No, I thought about that. I was wondering the people, the people think we haven't released the names because we don't know who's coming. We don't

Ben 2:16

know what's coming. And

Daphna 2:20

we're able to book we were able to book more speakers, then we're making more, we're making more spots for speaker.

Ben 2:29

That's correct. That's correct. And then we're going to start doing something a little bit different. This starting this week, where on the podcast feed, we will try to we will release the episode as usual. And we'll start having small highlights for each individual article this way, if you want to just listen for like 10 minutes, then you can just listen and make it easier for yourself. So you don't have to scroll and so on and so forth. And that's all the announcement as I have so many papers are read, I probably read like 12 papers this week. And they're all very good. And I had to drop a few because there's no way I'm gonna get around to all of them. No. Okay, so then I'm not gonna get let's go. Let's get into it. So as I was done, and I had read so many papers yesterday, the paper called The expected management for expectant management or early ibuprofen for patent ductus arteriosus, the New England Journal of Medicine came out. First author is hunchy, ID and colleague. And it's a fascinating paper. So let me let me tell you some of the notes that I that I wrote down. So I laughed a little bit, because the first like one of the first line of the introduction stated that like the first line, stated that like PDA management is subject to debate. That's like no kidding. That about sums it up. Yeah. But then there's some good stuff in the introduction, some some board review and high yield stuff, that the PDA is associated with neonatal mortality, morbidity, including BPD, neck ivh. And that meta analyses of or randomized control trials showed that pharmacologic treatment with cyclooxygenase inhibitors induced PDA closure but had no beneficial effect on clinical outcomes. Felt like some of these things really could have come up on boards. Now the question that the trial that is called the Early treatment versus expected active management of PDA in preterm infants, the Benedict the bene ductus, So, B E and E D U CT, US beanie Drs. I'm giving this a five out of 10. On the show, I

Unknown Speaker 4:35

think it's cute.

Ben 4:38

Too complicated. But the bene

Daphna 4:42

feel like it's it sounds like the duct is a good thing. Right then Ben? Yeah.

Ben 4:49

Which we'll see. I mean, that's a good point. So it was performed in extremely preterm infants with a PDA confirmed on echocardiography to assess whether expected management would be non inferior to early ibuprofin treatment with respect to specifically three outcomes necrotizing enterocolitis, moderate to severe BPD, or death, and all that assessed at a time point selected at 36 weeks postmenstrual age. This was an international multicenter, randomized, controlled, non inferior trial conducted at 17, neonatal intensive care units in the Netherlands, Belgium and Denmark. So the babies who were included were infants with a with a gestational age at birth of less than 28 weeks, they have to have a confirmed PDA on echo cardiogram with a diameter of superior to 1.5 millimeter at the smallest point and who had a trans ductal left to right shunt between 24 and 72 hours postnatal age, I thought it was either Gabrielle altered, or Phil levy during the new heart that had this great slide about like PDA architecture and saying, like obviously, the PDA is a three dimensional structure. And so there are points where it could be larger than others. So that's why the SE superior to 1.5 millimeters at the smallest point. So at the very, very least 1.5 millimeter exclusion criteria were contraindication to ibuprofen, the use of any cyclooxygenase inhibitor before randomization, persistent pulmonary hypertension, a congenital heart defect life threatening congenital defect or chromosomal abnormality. And the intervention was interesting, it was ibuprofen, but they didn't really specify a dose and it says it was the dosage according to local protocol. So most people will see ended up using standard doses but there was no news or there's no nothing specifically established right in the in the methodology. And then echocardiogram was done. After about 12 hours or more after the last dose of the regimen. The control got no treatment aimed no can no treatment aimed at causing the PDA basically right. So really nothing. So the definition of PDA closure was either that the duct had completely closed or that the size had gone below 0.5 millimeter on echo. If closure was not achieved, there was an option to give a second course of ibuprofen. If it still wasn't closed after two courses, then the options included either third course or Dr. ligation. The primary outcome was the composite outcome of neck moderate to severe BPD defined as the 2001 definition plus a new oxygen challenge or death associated assessed at 36 weeks postmenstrual age. The non inferiority of this intervention was defined as an absolute risk difference with an upper boundary of the one sided 95% confidence interval of less than 10%. And so we'll see we'll see if the material right the performance both an intention to treat and a per protocol analysis that included infants in the expected group that received open label treatment after meeting the criteria. The bottom line is in that case, they had the option of doing echoes on the babies who were in the control group. And if there were significant findings on echo, they were able to give medication in an open label fashion to these babies. And so we'll find out that there was not much deviation from the protocol but that this was given as an option obviously for for ethical and safety reasons. So they were able to consent 442 families and infants 273 underwent randomization 136 in the expectant group 137 In the early ibuprofen group. And we'll talk about that because they didn't meet the number that they wanted to actually enroll. They didn't meet the number of patients they wanted to enroll based on their power calculation. The median gestational age was 26 weeks, the median birth weight was 145 grams. Ibuprofen was started at a median of 63 hours of life with a median dose of 10. Meg's per kilo for Windows, followed by two doses of five mils per kilo, which is sort of what right that's not what you and I use. But obviously there's discussions about higher ibuprofen doses and so but that was the medium that was that was the most commonly seen dosage. The baseline characteristics were similar between the two groups except that in the control arm more babies were born to mothers who developed help syndrome. Okay, but the primary outcome, so the primary outcome of neck moderate to severe BPD, or death at 36 weeks occurred in 46% in the expectant management group, and 63% in the early ibuprofin group with an absolute risk difference of minus 17 percentage points. And mostly and so the thing that's interesting is that because they use this composite outcome of neck moderate to severe BPD, or death, it's important to note that this difference of, of 1717 percentage points was mostly driven by BPD, actually. So the babies who got the early ibuprofen were more, much more likely to develop BPD. And I have the table right here. And for BPD, specifically, it was 39% versus 57%. And when it came to neck, it was 24 versus 21%. Death was 19 versus 25% 25%. Still in the in the early ibuprofen group, so but that was not really statistically significant, as opposed to BPD. The distribution of reported causes of death were similar between the two groups. And as we just said, moderate to severe BPD was diagnosed in 33.3% of infants in the expectant group versus 51%. In the early ibuprofen group. The frequencies of adverse events and serious adverse events were similar between the two groups. And the results of subgroup analysis, were consistent with the overall finding, with the exception of a potential difference according to sex that suggested maybe better outcome for expectant management and male infants. Compared to female infants. I thought that was interesting, they didn't really go into much more details. Now, I usually. So the conclusion of the article is that infants with a gestational age below 28 weeks expected management for PDA, measuring more than 1.5 millimeter was non inferior to early ibuprofen treatment with regards to neck moderate to severe BPD, or death. And results suggest a lower risk of this outcome in the expectant management group. Now, I don't usually read too much into the discussion, because I say it's always the opportunity for the authors to make their numbers look good. But the discussion was fascinating in this paper. So even though I sort of skipped on the discussion on the podcast, I do read through all of it. And in this case, it was really interesting. So obviously, they mentioned that the main limitation of the paper is that they didn't meet the goal for enrollment. And, and that goes to show how difficult it is to design these PDF files, because they say that they recruited infants in 17 centers for almost four years and only reached 48% of the planned sample size, to undergo randomization. So I mean, this is this is extremely difficult. And and that's, that's a big deal. They also did a very nice job in trying to explain and and review some of the data. So they mentioned that, like a recent prospective study showed that should so the big question is, could we explain why some of these findings and that's the main thing that I was interested in reading, through the discussion that they're saying that the recent prospective study showed decreased vascular growth factors in preterm infants with PDA after exposure to ibuprofen, which something I was not familiar with, and previous randomised trials have not shown increased risk of bronchopulmonary dysplasia with ibuprofen treatment. And so they're saying it's possible that this discrepancy can be explained by the high percentage of infants who received open label treatment in the expectant management group in these trials. And that's something that's been a play for all the PDA studies where there's a lot of crossover. But in this specific trial, in the Binney doctors trial, there wasn't very much of that. And so maybe we're seeing something for the first time that we were not able to see because of that, that adherence. They also mentioned, rightfully so that the results of the trial should not be interpreted to suggest that there's no causal relationship between PDA and neonatal morbidity in extremely preterm infants. It's possible, it's plausible that an attempt to close the PDA with ibuprofen may be more harmful than the condition itself, safer and more effective treatments for PDA with a high left to right shunt volume, one study. So leaving us really questioning what else are we going to be able to do? But fascinating study fascinating outcomes. And I'm going to try I mean, I have I keep talking about like, I'm reading through my notes, obviously, but I'm going to try to post my notes on the website page. So if you guys want to read through and make it easier for people to read, because I use little emojis to make it easy for myself and stuff, you'll be able to find that.

Daphna 14:43

I think the authors were very measured in their in their conclusions, which I appreciate, you know, PDAs are there. It's a it's a rivalry, right? people's thoughts on the PDAs so I think that they

Ben 14:58

if you're interested in the PDA You should follow on Twitter, Professor Felco, fresh Dr. Schulich Mitra, who discuss PDA and who are involved in PDA research at a very high level. And it's interesting, because the comment that always comes back from from them too, is it's so hard to design the proper study and conduct the proper PDA study. So I was not truly surprised to see the results of this study in from that standpoint.

Daphna 15:23

Yeah. And there are other PDA trials underway. So we'll see the results of that right

Ben 15:29

there to present them when they come out.

Unknown Speaker 15:33

Okay, my turn,

Ben 15:36

yeah. All yours.

Daphna 15:38

Okay. I thought this, this is a totally different kind of paper on the other end of the BPD spectrum, but I thought this was a very interesting article, something we discuss in our unit all well, almost every unit I've worked. So all the time, trans Pyloric feeding is associated with improved oxygenation compared with gastric feeding among non intubated, extremely low birth weight infants. I mean, they really give you the punch line here in this title. I appreciated that. Lead author, broth served Bazza. This is in the Journal of Pediatrics coming to us from Atlanta, Georgia. Some big names in PDA BPD. So that's good also. So the question was really does placement of transpiler feeds change the oxygenation and very low birth weight infants. And I thought the I thought there, I'll get, let me just get into the the definitions of what they what they use, because I think what they used was really valuable they were using, and we reviewed the paper that presented the pulse oximetry tool in 2021. But as a measure of oxygen lability. So basically, across the design, the background information you need to know is that they were taking simultaneous measurements of the FY O two, and the SPO, two, and they create this ratio of the SPO, two over the FY oh two. So that's the first number you need to know, they also have a titration.

Ben 17:30

And you would love that number, I guess to be very high, right? Because you would want your yourself correct

Daphna 17:34

to higher saturation with lower and lower requirement, right?

Ben 17:40

Just finished my daughter in six, six planets. Very helpful

Daphna 17:45

for very, very timely, the titration index looks at manual titrations per hour by like the bedside staff. And they're also interested in this intermittent hypoxic episodes, which I think is very valuable because it's really looking at saturations like less than 80%, or greater than one minute. So is your baby. Does your baby decide a little bit? Or does your baby decide a lot. And they also calculate this hypoxia severity score, which is really how low is the D saturation from the lower baseline limit. So that's another way to look at how severe are these episodes of hypoxia. And so basically, what they were trying to do is looking at measurements before and after transpiled work tube placement. The unit standard for feeding was bolus feeds, but the time like how, like over how long was the bolus feed wasn't really specified, but feeding every three hours. And just some other parameters for information in this unit target saturations are 90 to 95. With alarm set at 88, and 95. But let's get back to the beginning. So their study design, which is was actually a retrospective chart review, to find infants who had transpiler work tubes placed. The inclusion criteria were infants that weighed less than 1000 grams of birth were born between January 1 2017 and December 31 2020. And admitted to this single level three ICU. In addition, part of the inclusion criteria was that infants had had an indwelling transpiler to feeding to placed and who had both, you know these oxygenation parameters. So simultaneous serial oxygen saturations and FY oh two data for this eight day observation period around the time of the Transpolar tube placement exclusion criteria, infants who didn't get the tube placed, or who lacked this oxygenation data in addition, and I thought This was useful. They looked for other potential confounding clinical conditions that might affect oxygenation. And they would exclude babies for example, who had who went from non invasive to invasive respiratory support who had a transfusion of packed red blood cells initiation of steroid therapy, initiation of caffeine therapy or a greater than 20% change in dose of either steroids or caffeine treatment of a PDA or culture positive sepsis. So, any of those things that might drastically change your oxygenation status also was a criteria for exclusion. And the other thing that definition to note because they do split the group by this Paramor is what is the positive pressure respiratory support. So that included mechanical ventilation CPAP nasal IMV, or nasal cannula greater than two liters. So, basically what they did is they looked at this period of time before and after transpiler tube placement. Again, it wasn't randomized. It was a retrospective study. So, you know, the indication was not always clear for why they put in the transplant work feeds. But, in general, it was felt that it was to help with this oxygenation status in these babies. So the baseline characteristics were that they had 14 intubated and 42 non intubated infants. So admittedly a very small study. The mean birth weight of the non intubated patients was 737 grams, and the non intubated patients had a greater weight than that of the intubated patients an average of 594 grams. The mean transpiler work feeding duration was significantly longer among the intubated versus non intubated patients. So the intubated patients had transpiler kids for longer 75 versus 2060s. And I thought this was interesting that they pulled from the chart data clinicians reported clinical improvement in 64% of the non intubated patients, compared with 14% of the intubated patients. In terms of adverse events, he had one patient with hemorrhagic gastritis. Obviously, there's always concerned that Trump could transpiler needs to be associated with additional adverse events. So for the primary outcome, there was no significant improvement in any respiratory measures among the intubated patients. Again, this was a small group of 14 patients after transpiler to placement, which was consistent with this low rate of perceived clinical benefit by the clinicians that was reported. Of note. That ratio, the oxygen saturation over fit requirement ratio showed a trend toward an improvement based on the change in slope post transpiler to placement. But what was really interesting was the non intubated infants showed significant improvement improvement in several respiratory measures following the change from gastric to Transpolar. Exceeding the median SPO to over fit ratios remain stable prior to the placement and demonstrated a steady increase during transpiler feeding indicative of improved oxygenation. The titration index, and average number of hypoxemia episodes should steadily rise in levels prior to transpiler feeds consistent with like a worsening respiratory status, but fell after trans Pyloric tube placement indicative of significant improvement. They have toxemia severity score likewise for this group of infants showed a steady rise before transpiler to placement but fell after trans Pyloric tube placement and remained stable there after. So I thought this was interesting. I thought it was particularly useful that they distinguished the intubated babies from the non intubated babies. I think that may give an indication of why it's even potentially useful. I think a lot of people try this with intubated babies, right? Just do what can what can we do to get this baby excavated? Right. So they tried it but they did not see a major difference in the small group of intubated babies. But they saw a significant difference in the in the non invasive group. I'm sure you have some I'm sure. I'm sure you have something to say about this. I like transplanter.

Ben 24:49

I was gonna say no, it was a great paper. And yes, and I suggest people take a look at the graphs because while Yeah, so some of the things like, for example, the hypoxemia severity score over time, like, it's true that it was rising before transpiler refeeds. And then it fell, but it's sort of sort of plateaued more than failed. And that's not you. I mean, you were reading off the paper. So I'm just saying, but but they are are the metrics. So for example, the ratio that we were mentioning the SATs over fit to like, that's quite impressive. The jump that you see, after the initiation transpiler is, I think, it's a great paper, because it's something that we're we've been doing in our unit, and that theoretically makes a lot of sense, especially if you have a bit of reflux, that could be impacting your respiratory system. It's nice to have evidence that supports the use of transplant, low fees. So that paper is saved. So that when I want to highlight refeeds, and somebody's gonna say, Well, there it is.

Daphna 25:49

Well, you know, I think sometimes it's difficult to quantify, for me for a lot of the things we do right, quantify what is improvement? And so I mean, I thought that was useful if you have higher saturations with lower fit requirements or higher saturations on the same fit requirement, then, then that's an improvement to

Ben 26:11

be devil's advocate here, just because I can I can imagine people think, like, it's funny how you said, like, it's almost like an ongoing conversation we have everyday in the unit, right. And I was surprised, considering Rhys Clark is on that paper, and that they have access to these large databases, that it was only like 14 intubated patients and 42 non intubated patients, which is not very

Daphna 26:32

well, I think it's because I think it's because they really needed all of that data. Right, basically, continuous data of FAO tos and oxygen saturation. So obviously, this would be a great study to do on a on a big database. We just need

Ben 26:49

Yeah, I'm not sure. I'm not sure how feasible it is. But it is the one thing where you can say, well, it was like I could see people making the case for the fact that it was a small study. And there's nothing wrong with small studies, but they have inherent limitations. So and I think if I remember correctly, the authors do acknowledge that somewhere. But yeah, yeah, otherwise. Yeah, that's it first, first relatively small, small sample size. So it's first first line of delimitations. So but it's a solid waste study saved on my on my folder. This episode is proudly sponsored by racket me Johnson. Recommend Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive Enfamil portfolio for premature and low birth weight infants learn more at HCP dot meet Okay, so my next paper today, is there also a paper that came out not too long ago, in The JAMA Network open, it's called safety and short term outcomes of high dose erythropoietin in preterm infants with intraventricular hemorrhage, the equal repair randomized clinical trial. So it's kind of cool because this is a trial that we said we were expecting the results when we covered EBO and erythropoietin stimulating agents in our neonatology review podcast, right. So the results are out. And so it's was quite cool to finally get the results not too far after we spoke about it. So think that with the background is very important. And I think that we're equal, there's a lot of confusions. And the background mentioned that observational studies on babies with ivh treated with erythropoietin showed better and neurodevelopmental outcomes compared to control observational studies. And there's always been this lingering data that seemed to hint at the fact that high dose erythropoietin for ivh could have potentially better outcome. And they also mentioned something in the background that I saved because it could be like a board review question, dimension that these these this data is is taking place in cases where it's pointing is given several days or weeks after the after the brain insult the neurological insult, and its proposed mode of action is thought to be the facilitation of repair, sustaining of neuronal growth and differentiation after brain injury rather than protection against damage itself. I thought that was very, very interesting. Now the equal repair trial is investigating the safety and efficacy of high dose EPO after the diagnosis of moderate to severe ivh in preterm infants. They included babies who were born at 32 weeks of gestation or less or weighed 1500 grams or less. And they had to have a diagnosis of ivh within the first eight days of life and it had to be grade two or higher. So all these grade ones are not gone. We're not looking at them in this study. They had a bunch of exclusion criteria. That's fine. They randomized the baby to either One to One either to EPO or placebo and This is where I think Dr. Oz on the podcast came and explained that to us but the dose of EPO is not the dose we use for for prevention of transfusion, this was 2000 units per kilo per dose, given every 24 hours for three day course, then followed by an additional dose at day 10. And another additional dose at day 17. And just to give you an idea when we talk about ar, ar, I'm using my words because it's late at night, but our dosage for for hematocrit boost, right, we're talking about like a couple 100 units. So it's usually like what two to 500 units per kilo, given like three times a week. This is 2000 units per kilo given every day for three days. Significantly, significantly, not the same at all. The primary outcome was the intelligence quotient at five years of age using the Kauffman assessment battery for children. And they had secondary outcome global brain abnormality the GBA score, and white and gray matter injury score assessed on T one and T two weighted MRI images at term equivalent age. They also had some mini clinical secondary outcomes that were collected that you can find in the paper. So 121 infants were randomized from eight study centers in Switzerland and Austria and 15 out of those 121 died before term equivalent. So so the could not be imaged and assessed. 100 infants underwent MRI a term equivalent. And interestingly enough, the one of the most shocking findings is that they found a higher mortality rate in the EBO group 16.7% versus 8.2% In controls. So almost double. This difference, however, was not statistically significant. P equals 0.15. Sorry, so I know. I know. That's because it's not statistically significant. It still, it's still give me a little bit of made me uncomfortable. There was no statistically significant differences observed between the groups with respect to infections or P BPD, neck or intestinal perforation, medically treated PDA or length of stay. There were also no significant differences between groups for there were also no significant differences between groups for ivh complications, including post hemorrhagic hydrocephalus need for transient or permanent cerebral fluid drainage or diffuse and cystic PVL. They did find that they did find that babies who they did find that babies who had received depo actually had a higher hematocrit.

Unknown Speaker 33:00

That makes sense.

Ben 33:04

There were no statistically significant differences in MRI outcomes between groups. Even if the empirical cumulative distribution of GPA score the global the global brain abnormality score indicated a trend toward less brain abnormality in the erythropoietin group. So the conclusion is that the equal repair trial done in preterm infants demonstrated that moderate to severe with moderate to severe ivh confirms the absence of treatment effect on brain imaging, and clinical endpoints are term equivalent, whether that will translate into better outcomes at five years that remains to be published. And the authors seem to be a bit skeptical as to whether this will hold true. Now, this is another paper where the discussion is again, excellent. And so I'm going to walk you through some of the things because it's sometimes hard to make heads or tails of like all these trials that are coming out with like, what's the evidence showing? And so they actually go over the four omegas, the three trials that came before them, and their trial included. So they're saying how the Swiss cohort is Swiss, a quartet of Switzerland and a quarter of China. Looking at the use of erythropoietin reported slightly lower mortality rates in their EPO group, right. The peanut trial done in the US reported mortality rates of 13% in the EPO group versus 10.9% in the placebo group. Now, they're saying that the mortality rates in the equal repair trial, the one we're reviewing today was 16.4% in the program versus 8%. In the placebo group. What they're suggesting is that the higher mortality in the peanut and the equal repair trial may reflect the inclusion of more immature infant the mean gestational age was 25.9 weeks in the peanut trial, and 26.6 weeks in the equal repair trial. When you compare that to the Swiss cohort that was the healthiest age From age of 29 weeks, and the Chinese cohort, they had gestational age of 30 weeks. And so again, including babies who are more immature me under may may uncover an association between the use of Hippo that could not be seen previously in more mature infants. Now, what they did is that they aggregated their data with the one from the peanut trial. So I thought that was really cool to do that in the discussion. And they're saying that the aggregate peanut and equal repair data shows no significant difference in mortality 13% in the upper group versus 10.6%, in the placebo group, with a P value of point one, three. So I have to say this is a bit more reassuring when you when you even though it's still higher in the epoch group. It's not like double. So it made me feel a little bit better. But I thought that was really nice that they sort of summarize some of the previous trials and sort of aggregated some of the US data together the US data with their data. So I thought that was really good. So yeah, I chose Evo is not, is not here to stay.

Daphna 36:01

I know I'm so disappointed. I'm so disappointed. I two things that I wanted to say I love how many studies are really looking at starting to look at, okay, we weren't able to prevent some of these things. So how do we rehabilitate, right? These these babies, instead of saying like, Okay, well, we've that happened in the first 24 to 72 hours. And now we're just stuck with it. So, I mean, I think it's it we have, we have to be looking to see what we can do for these infants. And then I wanted to just second what you said, I think, when I was a trainee, they said like you just, you know, skip, skip the background, skip the discussion, go right to the methods, and then you decide like, what kind of paper you have. And I think that's a mistake, I think that our trainees can learn. For us, all of us can learn so much from the Background section, you read a really good well written Background section. And you learned so much, regardless of the what what happened in the try. And it's

Ben 37:09

and it's a testament to the authors, because I think, yeah, we could, you could technically use the discussion to wrap up your loose ends and try to make make it fit, a nice bow tie on everything. But some others are very, like some others are attacking. Yes, some of the discrepancies between their data and other data head on like they did in this trial and saying, Well, here's, here's what we think, right? This is what could be. And, and that's kind of nice, because it kind of gets tiring, like, oh, it's the first trial of its kind to do it's like

Daphna 37:43

think I've asked I think that just shows like how accessible information is and you know, if you put it out there that somebody's going to be talking about it, you know, on near Twitter, so you might as well, you as well. broach that topic before it gets. Okay, you're next I wanted to review this paper late onset sepsis among very preterm infants, lead author, Dustin Flannery, and senior author, Dr. Karen poop, hello. So obviously the big team for

Ben 38:22

they're always they're always publishing together and they're becoming like this. Become this duo now do Dustin and Karen Yeah, right.

Daphna 38:30

Yeah. But if they write it, you gotta read. Ya gotta do. This is in pediatrics coming to us out of chop. And I like these papers, these epidemiologic papers to determine the epidemiology, microbiology and associated outcomes of late onset sepsis among very preterm infants using the von database. So obviously, this is a very large database 774 participating senators from 49 US states. So, the design this prospective observational study included infants born between 401 to 1500 grams and or 22 to 29 weeks gestational age, between January 1 2018 to December 31 2020. And data was collected from birth until hospital discharge, death, or first birthday, whichever came first. And then definitions are always useful in general, if you're part of a Vaughn participating hospital that's the those are the definitions that they used. But late onset sepsis was defined as isolation of a bacterial or fungal pathogen from blood and or bacterial pathogen from cerebral spinal fluid cultures obtained greater than three days after birth. And they wanted to discuss specifically cons so coagul Release negative staphylococcus. So if these were isolated from blood or CSF, they were considered a true case of late on successes as there were signs of generalized infection. And the patient received greater than five days of antibiotics. So the primary outcome was survival to hospital discharge and the secondary outcomes among survivors included home oxygen tracheostomy, and gastrostomy or GG and ostomy. So they had 124,497 infants, of which 118,650 infants survived greater than three days, the median birthdate was 1.11 kilos and a median gestational age of 28 weeks, half of the cohort were male, and the median length of stay among survivors was 66 days. So to the data so overall, I'm 10,501 infants are 8.9% of the cohort had late onset sepsis for an overall incidence rate of 88.5 per 1000. Eligible, very preterm infants. Not entirely surprising the incidence was highest for infants born less than 23 completed weeks gestational age, and then pathogen specific incidence rates were similar across all three study years, which I also thought was interesting. I think it's useful for us to know how pathogens are changing over time, and late onset sepsis increased with decreasing gestational age. Incidence of the composite late onset sepsis or death was 135.1 per 1000 infants and was highest for infants born less than or equal to 23 weeks gestational age. And they told us a little bit more about the pathogens, we had 12,117 isolates and 34 pathogens were identified. Gram positive bacteria accounted for 62.9% of isolates and gram negatives, or 32%. Cons was number 120 9%, Staph aureus 23%. They didn't distinguish between MSSA and MRSA, E. coli 12%, of CLL 8% Enterococcus 5%. And then when they look

Ben 42:19

at the positives, the gram positives are much more common, though.

Daphna 42:22

Yeah. Hi, Lee outway. But then they wanted to look at the pathogens by gestational age because we know from previous data, that that can be different. So the distribution of pathogen types by gestational age demonstrated a higher proportion of gram negative and fungal infections and lower proportions of GBS and other gram positive infections among infants at lower gestational age compared with those at higher gestational age. And that's been shown in previous data that gram negative infections are more common in our earliest babies. proportions of cons infections were similar across gestational age categories. So some of the other demographic kind of data infants with late onset sepsis were more often born vaginally 33% versus 24.5%. Or more often born to mothers with chorioamnionitis 17.8% versus 12.2%. I actually thought that was not so different. It's gonna be a bigger difference there. And they were more often born to mothers without hypertension, 30.2% versus 40.3%. Infected infants had lower birth weights median of 760 versus 1140 grams. They also had a lower gestational ages median 25 weeks versus 29 weeks compared with uninfected infants. Infected infants also have longer length of stay compared with uninfected infants 102 versus 62 days much longer length of stay, and length of stay was longer among surviving infants with late onset sepsis, compared with uninfected surviving infants. The median length of stay for infants with late onset sepsis who died was 21 days. And then they wanted to look at the outcomes associated with late onset sepsis. So infected infants had lower overall survival 78.2% versus 94.9%. And adjusted risk ratio of point eight nine. And infants with late onset sepsis who survived to discharge had significantly increased adjusted risks for home oxygen, with adjusted risk ratio of 1.32. They had higher increased risks for tracheostomy adjusted risk ratio of 2.88 and higher risk of need for gastrostomy adjusted risk ratio 2.09 When compared with survivors without late onset sepsis. So I mean, I think I think this is valuable work. We have to know refer for pathogens are changing over time. I think it's useful to know what you're looking for based by gestational age and that I mean, sepsis is not just, you know, treat the infection, it's it predisposes to significant additional morbidity. So

Ben 45:21

yeah, no, I have nothing to add. What? No, yeah, it's I mean, that's really Dustin's paper are always that good. I mean, there's no straightforward Yeah, very straightforward, very well, it's

Daphna 45:33

easy to read. So there's so I love it so easy to read. They give you the data you're looking for. So I'm grateful for this paper.

Ben 45:44

Okay, I can take your next to either mer unknown, or antibiotic duration. And in any see which ones you want to hear about,

Unknown Speaker 45:51

I want to know it biotic duration.

Ben 45:53

Let's do it. So this, this paper is published in the Journal of parasitology. It's called variability in antibiotic duration for necrotizing enterocolitis, and outcomes in a large multicenter cohort, first authors, your fun, Ahmed and colleagues. This is data from the US. The background is not earth shattering, but it does highlight the fact that there is a lack of consensus regarding the duration of antibiotic courses for infants with medical or surgical NEC. And having worked in multiple institutions, we all know that this is the case. And so this, this group used the CH and C database, the Children's Hospital National Consortium database, and the goal was to assess the variability and duration of antibiotic treatment for medical and surgical neck. The second question they had was whether longer antibiotic duration would be associated with issues or changes in time to reach for feed and length of stay. So they searched this agency database for infants with any gestational age or birth weight admitted within two days of neck diagnosis, to see agency unit for the people who are not familiar, and I'm going to go on and then but I'm pretty sure that the Children's Hospital National Consortium tend to get their babies referred to them. So that's why that's why they included babies who were admitted with a diagnosis of neck. And and so that could be confusing when you read it. But I think if you know how the consortium works, then it makes sense. The infants had to reach for feeds so that they could assess how long it took, obviously, they excluded babies who received antibiotics for less than five days, if they only had just a SIP or immune deficiencies, or any type of renal disease that required sort of antibiotic prophylaxis, so they could have confounded the duration. The primary outcome was the variability in the duration of antibiotics, secondary outcome, the time to full feeds and hospital length of stay. So the database includes 126,000 infants, so huge 44,712 infants, so 3.7% are were diagnosed with NEC, after all, the exclusion criteria is 315 infants with medical neck, and 276 infants with surgical neck were analyzed. The median antibiotic duration was 12 days for medical neck and 17 days for surgical neck and the interquartile range are quite high, like 12 days with a range of nine to 17 and 17 days for surgical with a range of 14 to 22. So sometimes, you know, sometimes I think we give too much antibiotics, but I thought I thought I was gonna see lower numbers, to be honest. I'm surprised we still give that much antibiotic. And I'm not saying

Daphna 48:42

anything. Like you said, we just don't know what's the right.

Ben 48:45

Yeah. And I'm not saying anything bad about the but you know, like, sometimes you think, oh, you know, we're probably giving too much. But then you get? Yeah. And then you look at data like this, and you're like, well, actually, we're not giving that much of the right

Daphna 48:58

one, I think just like all of the other infections, right? We're learning that probably shorter curse, horses are reasonably effective. Right? We're just pushing the lower limits, but you know, it's, so you feel like surely we could treat less.

Ben 49:19

So there were there was wide intra and inter center differences among the 22 centers reporting to this agency and duration of Antibiotics for Medical and for surgical neck. So variability across centers makes sense but even within the center, so even within a center, there was often variability. So that's, that's quite fascinating. In terms of feeding fees, were started that a median of 11 days for medical and 18 days for surgical neck from the time of neck diagnosis. So about 11 days is medical 18 days for surgical neck. Time to full feed median was 11 days for me Medical and 24.5 days for surgical neck. So it takes a long time. Right? I mean, if you consider that feeds are started 18 days after surgical and it takes 24 days to get back to full feeds, it's crazy. overall 13% of infants with neck developed stricture, and this included 15% of infants with medical neck versus 10%, with surgical neck and we were talking about that, obviously the other day, that babies with medical neck obviously, are at higher risk of developing those strictures, because they don't get that those segments removed, I guess. In terms of let's go over some of the data for medical and surgical neck and then we'll we'll close out this this paper. But for medical infants in the lengthier antibiotic categories took longer to reach for feeds and had a longer length of stay. There was no difference in survival among the antibiotic duration categories, but infants with medical neck in the lengthier antibiotic course categories had a higher incidence of post neck stricture. And I'm not sure if it's like a chicken or the egg situation there. But that was very interesting. So they have a higher incidence of post neck stricture, the longer they get antibiotics, so it's like it because yeah, because you know, initially you think like, Could it be the inflammation? But it's like if you get more antibiotic, technically information should be reduced, more annual, it's very difficult to know, or are they giving? The reason why I'm singing chicken or the egg is are they giving longer antibiotics because the baby was really sick, you know, and may Yeah. surgical neck infant in the lengthier antibiotic categories took longer to reach for feeds and had longer length of stay, survival to discharge and the incidence of post neck stricture did not differ significantly among the three surgical antibiotic duration categories. For surgical neck, the duration of antibiotic treatment remained significantly related to time to four feet, for instance, in both medical and surgical neck, so the longer you you need an antibiotic, the longer it took you to get back to four feet, and the duration of antibiotic therapy was also related to length of stay for both medical and surgical neck. So the conclusion on that there is large variation in the duration of antibiotic therapy for medical and surgical neck both within and between centers. Longer courses of antibiotics are associated with prolonged intestinal recovery and vent of hospitalization. And then they wrote in the conclusion that the authors speculate that evidence based guidelines or consensus based guideline where evidence is lacking. And quality initiatives to enhance the degree of adherence to these guidelines will decrease exposure to prolonged antibiotic courses and help infants achieve enteral autonomy earlier during recovery from medical and surgical neck. Meaning, since we don't know we might as well agree on a number so that we minimize

Speaker 1 52:51

or at least get rid of the the outliers. Right? The

Ben 52:57

unfortunate situation was you're getting 13 days.

Daphna 53:02

I like to I like that. What do they call that? enteral? autonomy? Yes.

Okay, I had a paper I'm was really excited to talk about. This is coming to us from the Journal of Pediatrics. It's called guilt and regret experienced by parents of children born extremely preterm and lead author, Emily, the years.

Unknown Speaker 53:33

I think I wasn't.

Daphna 53:38

And the SR app is anti jam beer. Yeah. So their objective was to explore decisional regret of parents of extremely preterm babies and analyze the factors associated with regret. And I thought this was super cool. I think it's gonna surprise but I think the answers will surprise some people. So play along. They have this cool project called the parents voices project. And they survey parents who come back to their follow up clinic, and more about their follow up clinic. All infants, less than 29 weeks gestational age, treated at their institution are eligible for neonatal follow up and then they're invited for follow up at 18 months, 36 months, and then at five years and seven years if they have ongoing developmental issues. So they have this neat group of families that they see for potentially a very long time. So the study design for this particular study was that between July 2018 And July 2019, parents of these infants between 18 months and seven years, who were attending the follow up, clinic were enrolled, and they did have access to the hospital records. So they looked at morbidities and they can They apparently do great documentation of their family meetings. And so they had some information regarding conversations with parents about levels of care. And so they asked parents this one question, knowing what they asked parents lots of questions, but this is the question they're they're talking about in this paper, knowing what you know, now, is there anything you would have done differently, and then they really took kind of a qualitative approach to looking at the data. So during the study period, they had at least one parent for each of the 258 children scheduled for follow up, were contacted 213 children came to follow up was amazing. And 248 parents participated so 98% participation rate of parents who came to follow up, they provided 285 individual responses 71 children had both parents respond for individual apparent responses most were mothers, among responding mothers and fathers. Let's see 63% of mothers and 82% of fathers respectively, self identified as white 25% of mothers and 10% of fathers self identified as black 82% of mothers and 87% of fathers reported having at least a high school diploma, none of the parents declined to participate due to language barrier. of their group the 230 children were born and a mean gestational age of 26.6, a mean birth weight of 907 grams. 55% met criteria for no neurodevelopmental impairment, 25% had mild to moderate neurodevelopmental impairment, and 20% of their group had severe neurodevelopmental impairment. And they also talked about this group, about 21% of the children, discussions about withholding or withdrawing life sustaining interventions had occurred, they were able to find that through documentation, and in the group that had had these conversations about withholding or withdrawing life sustaining interventions. The Children's are born earlier in gestation and mean gestational age of 25 weeks had more neonatal complications. For example, retinopathy of prematurity, 30% versus 9%. They had moderate, more moderate to severe bronchopulmonary dysplasia 95% versus 55% more likely to have late onset sepsis. 71% versus 24%, more likely to have grade three to four IV H, or cystic PVL, 57% versus 15%. And after the discussions for families opted for redic, redirection of care. And a lot of these parents were parents of multiples, so I think that's where some of the data is coming from. So for one child, parents opted for comfort care, and for three children, parents opted to limit interventions. For 11 Children, parents chose to continue all in for interventions. And for another 11 Children, physicians described a conversation with errands, explaining that maximal support was being used their child may die and how to prepare for this possible death and described a care plan of comfort care if the child deteriorated further, I'm just impressed that they had all of that in the documentation. I think that's wonderful. I think that's the first thing we can learn from the paper. So of the 248 parents who participated 53% did not report regret at all. And the majority 94 of the parents expressed this without any additional details. For example, I have no regrets. 22 parents specified that they felt they could have done their that they had done their best and said things like I did the best that I could 15 parents added comments explaining the absence of regret, for example, I would change nothing simply because all of this changed me and my life are the best or no regrets we consider we did everything we could and we're very proud of all the support we gave. Or parents linked their lack of regret to the idea that they had followed the advice of nurses and doctors saying For example, we did what we could and what we were told to do. So then they wanted obviously to look at the families who did report regrets, and I hope people are paying attention. So 113 parents reported having regrets, but the following themes were interesting, the most frequent theme invoked was guilt about preterm birth and focusing on self blame and thinking that they could have prevented prematurity and so I wanted to highlight some of the

Ben 59:40

you have to read that quote quotes from from that segment that one that's that's sort of highlighted that the at the end of this paragraph because it's like all in one

Daphna 59:48

yes. So this mom Hold on I now and now what you want me to

Ben 59:53

own the one that starts with asking for support sooner?

Daphna 59:56

All right, you read it you have a right there. Yeah, that that one so we're gonna read but go ahead read that one. Yeah, that

Ben 1:00:03

was that one was very good many parents invoked more than one theme, for example, this quote saying, ask for support sooner when she was in the hospital. I waited too long because I thought I was bothering them. Two pregnancies close to each other. And this causes prematurity, normalized prematurity, because I hated myself for so long, I should have stopped comparing her evolution to the evolution of a child born a term. I think there's a lot to unpack from this from this, but it definitely shows

Daphna 1:00:28

their parent, their parent, I think, describe the entire NICU admission, right, like guilt and regret and every kind of every stage, but mostly based on not on decisions that they made. But on, you know, things that happened. So a lot of quotes again about things that they thought led to a preterm delivery. For example, I should have pushed for the abstractions obstetrics team to keep me in the hospital when they saw the membranes were fragile. We could have had several weeks for the birth, I should have listened to my spouse when she said something was wrong, we should have done a better follow up during pregnancy, I should not have traveled. Because I was not followed by a doctor that time I should have stopped working as soon as I learned about my pregnancy, I should have avoided kayaking. Because this will always stay in my head is the cause of the birth too early. In addition, they had regrets about neglecting self care. This is so valuable. Many parents described having been so involved in the NICU that they forgot about their own well being neglected their relationships did not take adequate care of their own physical or mental health. And many parents regretted not seeking psychological support, or help the help of social workers or other services offered, for example, I should have slept a lot more while she was in the hospital, the return to home was a catastrophe. I should have listened to the nurses who told us to go and sleep, I should have asked the individual psychological support for me and dad and also support from our families, I should have taken better care of me my health, my couple, I should have created more ties with other moms having a support group should be compulsory. I should have consulted the unit psychologist instead of consulting one, five years after birth. In addition, they had regrets about the choices they made specifically related to their parental role in the NICU. And when describing the regrets they have about their parental role. Parents generally described how it took time to understand how the Nikki worked to understand what their role was, or how they could participate in their child's care to communicate with a team grasp the next step, and how this could change their involvement or communication style. I should have been less concerned I should have had more confidence had more trust, I missed so many good moments because of that. I shouldn't. Let's see, explain the routine where and how the parent can get involved, know better and in advance what the Nick use day would be like.

Ben 1:03:00

So what are you what are your What are your What are your takeaways from from my,

Daphna 1:03:05

obviously, my my takeaways that I think everybody can take to the bedside literally, Today Tonight, if you're on call is that every family should hear from somebody at least once that like, this isn't their fault. And there's nothing they could have done differently. And I think so many families, the moms, the parents, they won't ask us, was this my fault? Some of them do very brave ones do but they're all thinking it. And so we should just go out there and say whether they say it or not that it wasn't their fault. There isn't anything we could have done differently. Obviously, this begs for increased structure and resources for mental health. For sure. 100% sure, for sure. Yeah. I wanted to say one more part. I know you're trying to move us along, because we got a lot to do. But I think what we

Ben 1:04:02

know it's not trying to move us along. No, but I know. I know. You can read those quotes, like at the end of the night, so

Daphna 1:04:07

I know. But I think everybody says okay, well what about the babies who are really sick or medically complex? Now, what did those parents say? So interestingly, parents of older children were less likely to report guilt about their preterm birth compared with parents of younger children. And then, interestingly, parents of children who had severe abnormalities on head ultrasounds were less likely to report regret 68% versus 32%, but they were more likely to regret report regret about self care decisions 47 versus 23%, but less likely to have regrets about their parental role in the NICU 16 versus 42%. There is no difference in the proportion reporting regret when comparing parents of children born before or after 25 weeks or Those who lived with a child with neurodevelopmental impairment and those without parents who participated in discussions or decisions related to withholding or withdrawing life sustaining interventions were not more likely to report regret or guilt feelings. So I think I think those that was important data.

Ben 1:05:22

Your turn honest. Yeah, um, I'm gonna give you a few. Like, I may have like, two brief papers I want to cover but very briefly, because we're already over time, there was this interesting paper in the New England called blueprint, buprenorphine versus methadone for opioid use disorder for opioid use disorder in pregnancy. As you can see, I'm slurring my words, it's getting terrible. Others are Suarez and colleagues, it's from the US. The Background section is very interesting. It really highlights a lot of the opioid epidemic that we're seeing in the US. They're saying that like 8.2 per 1000 deliveries are affected by opioid use nationwide, and that in patients who are insured with Medicaid, which is public insurance, that goes up to like 14.6 per 1000. So we clearly see a discrepancy there in our societal makeup. Now, what's interesting is that they actually go into the differences between buprenorphine and methadone. And they're mentioning and that's something that I had added, because I think it's high yield. Methadone is a full agonist with a high intrinsic activity at the mu opioid receptors. It's given in persons who have to go to a clinic and you get your methadone. Now, buprenorphine has a high affinity, but is a partial agonist with low intrinsic activity. So methadone is a full agonist with high intrinsic activity. Buprenorphine is a high affinity partial agonist with a low intrinsic activity, and that can be taken at home that you can get your prescription, get your medications and take them at home. Now, they compared mothers who were either on buprenorphine during pregnancy or methadone. And the results are quite fascinating. Especially I mean, we could go into the maternal outcomes, but again, we're short on time, but they showed that the neonatal abstinence syndrome occurred in 69% of infants exposed to methadone versus 52%. In those exposed to buprenorphine in the 30 days prior to delivery, meaning the mothers receiving that before delivery. There was also inverse association between buprenorphine exposure and SGA and low birth weight. So the use of buprenorphine in pregnancy is associated with lower risk of adverse neonatal outcomes and methadone. So that was, I think, very interesting, because it might mean that we'll see a shift on our end of mothers who are being maintained, more commonly on buprenorphine rather than methadone. I thought that was a very interesting, very interesting paper. Not much for us to take to the bedside right now. But I thought that was that was an interesting paper. And then the last one I wanted to mention was this Milburn own paper, it's actually quite quick. And it's, it's, you know, when FIFA Kuvasz publishes something about pulmonary hypertension in Melbourne, and you sort of want to pay attention. This is published. Yeah,

Daphna 1:08:11

we're gonna do that one. I thought either. I thought you were gonna do that one last time.

Ben 1:08:16

Yeah, but I mean, I'll tell you, you'll see very quickly why it's not really something that it's more of a methodology paper than anything else. So the paper is called the use of Marinol in neonates with persistent pulmonary hypertension of the newborn, a randomized control, trial pilot study. It's the mint one study. Obviously, as we know, melanin is a selective phosphodiesterase three inhibitor with pharmacological effects including relaxation of the vascular smooth muscle, enhanced myocardial contractility, so it's an isotope and improve myocardial relaxation, which is Lucy Tropi. So the question they're trying to ask is, Does the use of IV melanin used in conjunction with I know reduces the time on nitric and the time spent on invasive ventilation in Infants who are born after 34 weeks of gestation with a diagnosis of pulmonary hypertension? I'm gonna so the the interesting thing that you may want to know everything is sort of very well outlined, but the intervention is milrinone is given at a loading dose of 50 mics per kilo and followed by a maintenance dose of point 375 2.75 Mike per kilo per minute. So that's arranged on the on the infusion continued until the nitric oxide is either taken off or to a max of 35 hours. And they basically had babies on Marinoni, nitric oxide and measured hemodynamic monitoring 612 and 24 hours after marinara administration. It's very exhaustive all the things that they looked at the primary outcome was the duration of a no treatment in ours. The secondary outcomes were time on invasive ventilation, oxygen supplementation and duration of hospital stay. What else rate of hypotension you is a bedroom the Niner tropes need for ECMO and mortality. And so the study was conducted to determine the fifth the feasibility of patient recruitment, instituting the study protocol, randomizing and blinding, blinding application, collecting outcome data, and contributing to determining to determine the sample size necessary for a definitive multicenter trial. Right. So that's not so yeah. And so they assessed 30 infants, and were able to enroll only nine infants, four went into the Millionen, group five went into the placebo group. And there were no differences in the duration of no ventilation, or oxygen administration between the two groups. And I'm going to skip the rest. But the bottom line is that a fifth in his in his conclusion, it's so well written because it's in conducting an intervention trial of a vasoactive agent in the setting of acute pulmonary hypertension in term infants is challenging using the current approach, the apparent fall in the incidence of severe pulmonary hypertension and the difficulty in approaching parents during a critical treatment window have led to very slow recruitment, right, which is like how do you how do you consent these parents in those situations, future endeavors aimed at assessing the impact of vasoactive medication clinically important. For clinically important unit or cardiovascular condition should consider alternative methods of investigation. Those should include cluster randomization by center to facilitate comparison, meaning, like you basically assign an intervention to a center. So like, that's it if you if a baby is born in that center, they get this intervention, the use of well designed registries or the implementation of standardized clinical assessment and management plans. Clinical Trial lists should engage with hemodynamic physiologists to determine strategies to enhance patient recruitment and trial conductance taking into account the increased recognition of the variable pathophysiological underpinnings of the clinical phenotype of current and potential. So a very depressing paper about how we're gonna have a hard time studying this in the future. But yeah,

Daphna 1:12:03

but what I love about the discussion, is that like, you can tell he feels so strongly about finding the answer that is to say, he's basically saying, like, Let's collaborate, let's figure it out together, how we can answer the question. So

Ben 1:12:19

that's cool. And that's all I have for tonight. Do you have anything?

Daphna 1:12:24

I have one more thing, I lightning round kind of thing. I wanted to draw people's attention to this paper that you hear that the case for advanced care planning in the NICU. It's in pediatrics, obviously, this month, but I think for anybody who was going to say it's interested in palliative care, but that should be all of us, right? It affects all of our work, whether or not it's something you, quote, unquote, enjoy doing, or, or not. Um, and I think what it does is it, it gives a good background, it gives two cases about where advanced care planning went really well. And advanced care planning went not so well, but I think not uncommonly. And so I think that can help people maybe see where they may have their units practice around advanced care planning might have some deficiencies. And I'd especially like to draw people to the figure one, one, which I think is a great, it's called a pediatric serious illness conversation guide. And I think, especially if you're new to managing these conversations, it basically gives you a template, including some of the verbiage you could use verbatim, to conduct these meetings. And I think that's valuable. I think some people say like, I just don't know what to say. You can literally say these things and conduct a very effective family meeting. So I just wanted to get

Ben 1:13:58

we can put that figure one on Twitter this week.

Daphna 1:14:01

Sounds good. All right. Get some rest. I know you gotta go back tomorrow.

Ben 1:14:05

Have to go back tomorrow. Yep. Thank you, everybody, for listening. And, yeah, well, we'll see you next time. Thank you. Bye. Thank you for listening to the incubator podcast. If you'd like this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcast, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address, Nicu You can also message the show on Instagram or Twitter, at NICU podcast or through our website at WWW dot d dash This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice if you have any medical concerns Please see your primary care professional Thank you

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