Hello Friends 👋
In this engaging Journal Club episode, Ben and Daphna return to explore the latest research in neonatology. They begin with a pivotal clinical report from Pediatrics on updated algorithms for newborn screening of critical congenital heart disease (CCHD), highlighting simplified protocols and their significant impact on infant mortality. The discussion delves into screening challenges in the NICU, high-altitude settings, and for out-of-hospital births.
Next, they discuss the CordSafe study from Australia, a phase 1 trial on the safety of autologous cord blood-derived cell administration for extremely preterm infants, aimed at reducing brain injuries like IVH. Daphna explains the rigorous methodology and promising early findings.
Ben then reviews the STAT trial, which evaluates whether primary anastomosis offers better outcomes than stoma formation in NEC surgery. The results show significant reductions in TPN duration and intestinal complications with primary anastomosis.
The hosts also discuss trends in PDA management and their surprising association with increased rates of BPD over the past decade, along with insights into evolving diagnostic and therapeutic practices.
Finally, they analyze a Spanish study on elective extubation during skin-to-skin care, finding it to be a feasible and safe practice, potentially enhancing neonatal and parental outcomes.
Don’t miss next week’s exciting interview with Dr. Keith Barrington!
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The articles covered on today’s episode of the podcast can be found here 👇
Oster ME, Pinto NM, Pramanik AK, Markowsky A, Schwartz BN, Kemper AR, Hom LA, Martin GR; and the SECTION ON CARDIOLOGY AND CARDIAC SURGERY; SECTION ON HOSPITAL MEDICINE; COMMITTEE ON FETUS AND NEWBORN.Pediatrics. 2025 Jan 1;155(1):e2024069667. doi: 10.1542/peds.2024-069667.PMID: 39679594
Zhou L, McDonald CA, Yawno T, Razak A, Connelly K, Novak I, Miller SL, Jenkin G, Malhotra A.EBioMedicine. 2024 Dec 13;111:105492. doi: 10.1016/j.ebiom.2024.105492. Online ahead of print.PMID: 39674685 Free article.
Eaton S, Ganji N, Thyoka M, Shahroor M, Zani A, Pleasants-Terashita H, Ghazzaoui AE, Sivaraj J, Loukogeorgakis S, De Coppi P, Montedonico S, Sindjic-Antunovic S, Lukac M, Hamill J, Choo CSC, Nah SA, Hulscher J, Emil S, Petersen A, Wijnen R, Sloots C, Sigalet D, Kiely E, Svensson JF, Wester T, Pierro A.Pediatr Surg Int. 2024 Oct 29;40(1):279. doi: 10.1007/s00383-024-05853-3.PMID: 39470842 Free PMC article. Clinical Trial.
Kaluarachchi DC, Rysavy MA, Do B, Chock VY, Laughon MM, Backes CH, Colaizy TT, Bell EF, McNamara PJ.J Pediatr. 2024 Dec 26:114456. doi: 10.1016/j.jpeds.2024.114456. Online ahead of print.PMID: 39732160
Nagy Z, Obeidat M, Máté V, et al. JAMA Pediatr. 2024 Dec.
Morey-Olivé M, Romaní-Franquesa N, Echeverría-Gallart M, Céspedes-Dominguez MC, Camba-Longueira F, Montaner-Ramon A.Acta Paediatr. 2024 Nov 12. doi: 10.1111/apa.17496. Online ahead of print.PMID: 39530316
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The transcript of today's episode can be found below 👇
Ben (00:01.156)
Hello, everybody. Welcome back to the Incubator podcast. We are back in 2025 for the first episode of Journal Club of the New Year. I know. Plus, while the Incubator is always busy, we haven't been on air doing Journal Club in some time. So it's good to be back, good to be presenting some papers. How was your holiday season, Dafna?
Daphna Yasova Barbeau (00:10.167)
Holy smokes!
Daphna Yasova Barbeau (00:18.792)
Yeah.
Daphna Yasova Barbeau (00:25.847)
It was good, lots of celebrating, lots of family. You had to work a lot more than I did, so I can't complain about that.
But it's good, but back to be glad to be on air looking forward to an exciting dynamic 2025
Ben (00:39.641)
Yeah.
Ben (00:44.13)
Yeah, same here, same here, same here. We have a lot of exciting articles for you all today. And I think that without further ado, we should get started, think. What do you think? All right. I wanted maybe to start us off easy with a paper that I think everyone should be aware of. It came out in pediatrics. It created a bit of buzz, mostly because it's an important update.
Daphna Yasova Barbeau (00:56.757)
I so.
Ben (01:13.156)
first author is Matthew Oster, and the paper is called Newborn Screening for Critical Congenital Heart Disease, a New Algorithm and Other Updated Recommendations Clinical Report. So basically the AAP coming out with some updates on the, what you may all know as CCHD screening. I'm going to go over some of these things and then we can talk about that. So.
For the people who are not familiar, obviously in 2011, CCHD screening, critical congenital heart disease screening was added to the US recommended uniform screening panel with an endorsement from the American Academy of Pediatrics. Basically, the idea really is to try to diagnose or to screen for congenital heart disease with a very non-invasive method. And the basis of that testing is basically to have a pulse oximeter
placed on the pre-doctoral limb and one on the post-doctoral limb and just trying to check for any differences between the two, hoping to try to maybe help screen for congenital heart disease that could potentially, and we've seen in the past, present at a couple of weeks of age after the PDA has completely closed and so on and so forth. What's interesting is that obviously this...
the screening tool has been implemented, has been extremely successful. The authors mentioned that the implementation of the CCHD screening using pulse oximetry has been a landmark success in public health and that it has decreased infant mortality, it has been proven to be cost effective and has saved a lot of resources. But the reason for the paper is because they say that there are several opportunities that remain.
to improve the implementation and effectiveness of CCHD screening. So obviously this is a clinical report, so it's not a study, right? So we're just going to go over some of the things that are being recommended. They talk about the development in CCHD screening and it's important I think to...
Ben (03:28.472)
be aware of the updated evidence on the benefits of the screening because I think it's quite staggering. And to be honest with you, I had not suspected that the numbers were this high. They're quoting a study by a book and colleague that said that compared with prior periods and compared with states that did not have screening policies, early infant deaths from CCHD decreased by 33 % after states implemented mandatory CCHD screening. I mean, there are rarely interventions in our field that we can implement and see a decrease in
infant mortality by over 30%. I mean, think about that. They also mentioned a study by Peterson and colleague that found that the estimated time per newborn screening was about nine minutes, that the cost was about like $15 in 2011 US dollars, with costs decreasing with the use of reusable sensors and so on. And that the cost of CCHD screening for life year gained was
$12,000. Now, in terms of the paper, obviously, they're mentioning the issues of diverging algorithms. And they're that although CCHD screening is now universal in the neonates, it has not always been implemented in a uniform matter. And so for that reason, they're going to mention a few special circumstances that
that need to be addressed.
So some of the special circumstances obviously are the babies of the NICU. And what they mentioned is that obviously babies in the NICU often have lower oxygen saturation than healthy newborn infants because of either inherent lung disease or that could be associated with their premature birth or as a result of any underlying conditions.
Ben (05:32.024)
Now, they're proposing a modification to aid in CCHD screening in the NICU. And the proposed modification is that children have to actually be weaned off oxygen before you can actually perform the CCHD screening. And if weaning to room air prior to discharge is not possible, then...
They say that echocardiography is warranted and screening with pulse oximetry is unnecessary unless required by law. I thought that was interesting because to me, if you get an echo, you really don't need to perform a CCHD screening. If you have a detailed overview of the cardiac anatomy, you really don't need to do it. But it was funny to see how sometimes bureaucracy can be so painful because they say if you still have to check that box that you did CCHD screening, then sure, go ahead and do it. But you really don't need it. So I thought that was kind of self-evident.
but it was mentioned there nonetheless. Another interesting situation that they're talking about is high altitude. I have been involved in some conversations within our practice with other units who are actually at high altitude talking about diagnosis of BPD and so on and so forth. And we know that it can be challenging to assess babies at high altitude because again, the PAO2 is lower and so maybe SATs are lower and so on and so forth. And so was really looking forward to see what they had to say, but basically they completely...
copped out and said, well, we can't tell you anything. More studies are needed to determine which modifications are needed at various elevations. So kudos to them for not, like, for basically being honest with their audience and with the audience and just saying that we don't have enough evidence. I was a bit disappointed. I wish there had been new evidence I had missed on that. Another interesting scenario is the one of
Daphna Yasova Barbeau (06:58.91)
my.
Daphna Yasova Barbeau (07:11.276)
Yeah.
Ben (07:24.484)
children who are born outside the hospital setting. And they're talking about the unique CCHD screening challenges regarding the timing, the equipment, the process, and the follow-up testing. They're talking about the cases of successful home birth that undergo CCHD, that have CCHD screening programs, and how it is important to make sure that these babies do not get forgotten. Now, I think that's something that may...
tend to forget. So these are some of the...
these are some of the special circumstances. And I wanted to go maybe over the actual algorithm and see if we can, because the algorithm is, in my opinion, quite simple, even more simple than before. And so they're saying that after more than 10 years of experience and evaluation, this particular report recommends several updates to CCHD screening by simplifying the screening algorithm, as I just said, improving data collection and education. So what are these?
modification. So the first modification to the algorithm is that the lower limit of an acceptable oxygen saturation should be 95 % or more in both the pre and the post-doctoral measurement. So that's modification number one. In terms of the second modification, they're mentioning that there should be only one retest for indeterminate results instead of the usual two.
that could have been done in the past. And I think I'm going to pull up the paper here, but the figure there is figure one. So it's a very straightforward algorithm, something that you can implement right away. So obviously you have birth, making sure you're off oxygen, as we mentioned, the baby has to be above 24 hours of age or pending discharge. You can do the right hand and the one foot for test number one.
Ben (09:29.292)
If the pulse oximetry is less than 90 % in either limb, then it's considered a fail, and you have to do an immediate assessment. Now, if it's not less than 90%, but it is above 95%, you're fine. And the difference between the two sites is 3 % or less, you're fine. But if it is not 95 % or more, or that the difference between the two sites
is not less than 3%, you should retest one hour after the test that you have currently done. And then if you fail, then you have to proceed with an evaluation. So the recommended changes of the algorithm do simplify the screening process. They potentially decrease error rates in the interpretation of the algorithm, reduce the time to conduct a screening by having less repeats.
And there may be a slight increase in false positive rates, but it is balanced by the potential for identifying other clinically important disease. And we'll talk about that in one second. They're saying that these changes are not expected to decrease the sensitivity of the screening because all the infants who would have failed under the previous algorithm will also fail under this new one. so I think that's what, yeah. In terms of, they talk about,
data collection, they talk about how it is important to have a rigorous data collection methods, but they talk about education as well. And it is said that it is important for people to be familiar with the limitations of the screening, with the importance of CCHD screening and the potential that CCHD screening has in identifying non-cardiac disease. And I think that this is something that could be very interesting because...
We tend to think of CCHD screening as really a purely cardiac test, but they're showing that in the context of failed CCHD screening with a drop in the SAT or a difference in the pre and post, if the cardiac condition has been ruled out, then you may be dealing with what they call secondary condition, something that is not related to critical congenital heart disease.
Ben (11:45.164)
These could be hypothermia. These could be infection, lung disease, persistent pulmonary hypertension, other hypoxemic condition, hemoglobinopathies. I think all of these still have to be entertained if you CCHD and you don't really have a cardiac cause. So I thought that table in the paper table one was very interesting because, I mean, I'm going to be very honest. Obviously, we work in the NICU and I tend to think of CCHD as a purely cardiac test.
But in the babies who fail and you don't really have any of these scary cardiac conditions, start exploring these alternative conditions. So I've been talking for a while now, but I'm going to stop here. And I think it was very interesting and very valuable to see the AP making enhanced efforts to use simplified clinical decision tools like this. And I recommend people just check it out and adjust their screening process accordingly based on this newest recommendation.
Daphna Yasova Barbeau (12:19.424)
Yeah.
Daphna Yasova Barbeau (12:45.579)
Totally agree. I think it's neat. I, to your point, I think about these, what else are we picking up? I think is really interesting. Cause sometimes we're like, the echo's normal, move on. But like there's something, there's something going on there, right? So I think that was a really good point to underscore.
Ben (12:57.262)
But then why?
Ben (13:04.281)
Yeah.
Daphna Yasova Barbeau (13:04.947)
You want to keep going? I know you have like a bunch of papers you want to do. Okay, you'll let me go. Okay. Okay. Let me, I got to finish all my papers. Okay. Well, I was really excited to review this paper. Now it is, it's kind of a pilot, a feasibility study, but I always think it's exciting to see what's coming down the pipeline.
Ben (13:08.396)
No, I'll let you go. mean, it's the new year. Let's try to be... I'm going to be polite. I become rude towards the end of the year where I'm like, let me just shovel my papers in.
Daphna Yasova Barbeau (13:32.023)
for our babies. So this was called Feasibility and Safety of Autologous Cord Blood-derived Cell Administration in Extremely Preterm Infants of Single Center Open Label Single Arm Phase 1 Trial. This is the cord safe study coming out of Australia. The lead author, Lindsay Zhao, and senior author, Atul Malhotra. So this was published in eBioMedicine from the Lancet. And I told you the team is out of Australia.
So they're looking at the safety of autologous, so babies own, cord blood administration to infants less than 28 weeks as a potential treatment for neonatal brain injuries like intraventricular hemorrhage. So super exciting stuff. So I told you it was a single center. It was a prospective phase one open label safety and feasibility clinical trial at Monash Medical Center at Monash Children's Hospital in Melbourne. So they consented infants born at...
families with infants born at less than 28 weeks completed gestational age of birth who had adequate availability of the autologous umbilical cord blood cells, which I'll tell you about, available for reinfusion between postnatal days nine and 15. Yes. So basically the process that they took, so they consented these families, most families were consented
Ben (14:46.266)
Can you explain a little bit what you mean by that?
Daphna Yasova Barbeau (14:59.125)
before birth because obviously the umbilical cord blood collection has to happen pretty with some immediacy. So I'll skip a little bit to what they actually did. So babies were delivered. They had delayed cord clamping for 60 seconds. And then they obtained cord blood prior to delivery of the placenta. This was done on vaginal and C-section births. And the goal
this is interesting, was to collect at least seven mls of blood after delayed cord clamping. Now, I think this is quite impressive. We're still struggling to collect admission labs on our umbilical cord blood samples, and they were able to get seven mls of blood on most of their babies, which I thought was really impressive. So then they take the cord blood. I'm not going to get into all the details of the processing, but they basically cryopreserve it.
And then in this select group of babies, they re-infuse it between days nine and 15. So on the day of infusion, they collect kind of baseline vital signs for two hours prior to infusion. They want to make sure the babies are clinically stable. This autologous, umbilical cord blood cells are abused intravenously over 60 minutes. And then again, they're monitored.
very closely for the subsequent 24 hours to look for any adverse events. So that's kind of the process. And the thought is that these stem cells can help with recovery. Again, specifically looking at brain injury and they're targeting the extremely low birth weight infant that are at risk for intravenous, that have intraventricular hemorrhage. Now this has been.
studied preliminary studies for babies with HIE doing the same type of stem cell transfer, but we really never got through the pilot study, the first few phases of the trials.
Ben (17:04.666)
And like you mentioned, if you can get through the collection phase, it might be a very low hanging fruit because you would avoid having to go through the process of isolation and development of stem cells. And it's autologous stem cells. So basically, there's no compatibility issues. So yeah, mean, it sounds like a very low friction. Yeah.
Daphna Yasova Barbeau (17:18.241)
Correct.
That's right.
Super exciting. Yeah. So that's kind of the background detail. So basically, I told you about consenting the exclusion criteria. So they did have some exclusion criteria. Obviously, they couldn't get enough cord blood, less than seven mls. If they had non-GMP grade cells, so I had to do a little bit of work on this. GMP stands for good manufacturing practice. There are obviously a number of guidelines and protocols about
what makes the cells appropriate for use. So if they fell out of that, things like if they had a positive culture, if they had indeterminate ABO blood groups, to your point about, you know, infusing cells that could be at risk for some sort of incompatibility, viability less than 70 % of the cells, and a few other stem cell parameters. They also excluded babies.
So again, the goal is to use this for babies and brain injury, but this is just the phase one trial. So they did exclude severe brain injury on day eight cranial ultrasound. So if you had a grade three or higher, the Papille grading system, or you had cystic PVL already on day eight, you were excluded. If there was culture positive sepsis within 48 hours of the planned reinfusion. So if you're being treated for culture positive sepsis,
Daphna Yasova Barbeau (18:54.287)
You were also excluded. Okay. I told you about cord blood collection. I told you a little bit about the infusion and then they collected prospective data regarding neonatal complications and morbidities until neonatal discharge. They looked at adverse events like infusion site reactions, extravasation, a 30 % increase in baseline cardiorespiratory parameters within 24 hours, the need for cardiopulmonary resuscitation.
new intermittent positive pressure ventilation, escalation of cardiorespiratory support, a bacterial infection within 48 hours of infusion, and death. Okay. So they also looked at this kind of control cohort. So they found demographic and neonatal outcome data for these kind of case controls. These infants were also born at less than 28 weeks.
during the study period and not enrolled in the trial. They had the same exclusion criteria as applied for the babies who received, I'm going to just say from now on, UCBC, so the umbilical cord blood cell infusion. So they had to have abscesses, superior brain injury, and they had to still be alive at the end of the postnatal week too, and they had to not have culture positive sepsis. So they had...
117 eligible infants born during the study period. They were able to consent 51 of those patients prenatally. They did have additional patients consented, but 29 of them delivered after 28 weeks. One withdrew consent, one decided not to continue the pregnancy, and two patients were not approached because they were COVID positive. This was, again, during the height of the COVID pandemic.
So of the 51 patients consented for the study, umbilical cord blood collection was attempted in 44. The other patients kind of urgently, emergently without the availability of somebody to collect the cord blood. So of the 44 patients, they were able to achieve adequate volume in 37. And then after the processing, they had 31 of 37 samples available for
Daphna Yasova Barbeau (21:15.799)
cord blood reinfusion. So they did have to exclude some of those. I told you they only had 31 or 37. So the six that were excluded, three had a positive, the cord blood bacterial culture was positive. So they couldn't infuse that. And three had the indeterminate ABO blood groups. So they were worried about infusing blood that may cause further incompatibility.
Interesting, the latter was determined to be related to maternal red blood cell contamination at the time of the delivery, but regardless. So when a milico cord blood collection was attempted, they had GMP, so appropriate grade cells available for 31 out of the 44. So again, they had a pretty high rate of collection, pretty high rate of acceptable samples, but some were excluded for clinical reasons. Okay.
Ben (22:07.172)
samples.
Daphna Yasova Barbeau (22:12.759)
Then, which babies were excluded? So there were eight infants who had appropriate cells who were excluded from the infusion because of the predefined criteria. They had four infants with high grade hemorrhage, four with culture positive sepsis within 48 hours of the planned infusion. So it was a total of 23 infants who received UCBC infusion. They had a mean gestational age of 26 weeks, a mean birth weight of 761 grams. They were
again, a small group, they did have a high number of neonatal complications and kind of risks for future neuro impairment. 34 % affected by fetal growth restriction, 26 % with chorioamnionitis, 52 % born after prolonged rupture membranes more than 18 hours, 82 % delivered via C-section, but they were able to achieve 70 % receiving at least 60 seconds of deferred cord clamping.
Then I told you they had this control group. So they had 93 extremely preterm infants born during the study period who were alive on day 15 without the clinical exclusion factors who did not receive the stem cell therapy who were again listed as controls. Now the groups were not totally similar. The numbers are small so you can't really make much inference but.
The infused infants were more likely to have been exposed to gestational diabetes, more likely to have been exposed to chorio, the prolonged rupture of membranes, and they were more likely to be growth restricted. But they were also more likely to be exposed to prenatal steroids and mag sulfate. They had a higher C-section rate and more likely to be male. Now regarding the stability of the babies, 15 infants received the infusion on CPAP, three were on conventional mechanical ventilation, and five
on high frequency. Then I told you they looked at all the vital sign parameters. They studied heart rate, respiratory rate, O2 stats, oxygen requirement, temperature and blood pressure. And none were significantly different before, during or for 24 hours after the 60 minute blood cell infusion. There were no extravasation injuries. There was no requirement for the infusion to be paused or stopped. There were no episodes of intermittent positive pressure ventilation.
Daphna Yasova Barbeau (24:34.943)
or CPR for any of the study infants during or within the 48 hours of the infusion. So there were no adverse effects documented related to the infusion. One infant did die within seven days of receiving the infusion and was reported obviously to the data safety monitoring board as a serious adverse event. But after review, the cause was determined to be unrelated to the blood cell infusion. Right.
Ben (25:00.186)
And that's really what matters considering this is a safety and feasibility study.
Daphna Yasova Barbeau (25:03.699)
Exactly. So they documented then a central line associated bloodstream infection with Staph epi for that baby who developed respiratory failure and pulmonary hypertension, a 460 gram infant. But the infused product was tested and was cultured negative. So they don't believe that bacterial infection came from the re-infusion. They did find two cases of post-production positive microbiology. So
One cord blood sample had Enterobacter and one had Bacteroides. But on both occasions, the infant blood cultures were negative and they did result in antibiotic exposure for the study participant, but no other adverse event. Okay. There were no significant differences in neonatal morbidities, but it wasn't powered really to evaluate this again because... Right.
Ben (25:56.974)
That's really not what the... I mean, I know that as neonatologists, we're going to dive right into that table to see like, does it do better? But in truth, you can't really put too much stock into that.
Daphna Yasova Barbeau (26:02.165)
That's right.
Daphna Yasova Barbeau (26:07.703)
So yeah, so they have this table here. I went ahead and calculated all the percentiles and it appears as though there's this trend to greater morbidities in the infusion group. But again, there were only 23 babies, only 93 babies in the control. So major morbidity, 95 % in the infused group versus 85%, death 4 % in the infused group versus 2%, late onset sepsis, 56 % versus 39%.
A NEC requiring surgery 13 versus eight, ROP requiring treatment 18 versus 10, BPD at 36 weeks, 86 versus 81, and the length of stay 108 in the infusion group versus 98 days in the not infused group. However, again, not powered to detect any of these differences. They also did this.
Ben (26:53.486)
Very interesting. Yeah.
Daphna Yasova Barbeau (27:01.999)
a cytokine profile. So they wanted to see like, if we infuse this, do we have any increase or decrease in either anti-inflammatories or pro-inflammatory cytokines? Would this be a problem for babies down the road? So they found no significant difference in either pro or anti-inflammatory cytokine profiles pre and post the infusion. But again, the control group wasn't studied for cytokines. So the babies who got the infusion acted as their own kind of pre and post.
study, but there were no significant differences. So that was the kind of phase one trial. The babies in the cohorts are undergoing developmental follow-up. So hopefully we'll have that information coming out soon in subsequent phases of the trials.
Ben (27:51.342)
Mm-hmm. Yeah. Thank you for doing that review. Atul Malhotra was at Delphi, gave a very interesting talk, and it seems that these guys, especially in Australia and New Zealand, are really at the forefront of stem cell research. mean, they're doing a lot of interesting things, and I guess we'll hear more about that particular type of intervention. Okay. All right, so where I wanted to take you next is a paper that made the rounds, and...
Daphna Yasova Barbeau (27:57.527)
Yeah.
Daphna Yasova Barbeau (28:04.983)
Super exciting.
Ben (28:21.338)
There was a lot of chatter about it. It's the STAT trial, Stoma or Intestinal Anastomosis for Necrotizing Enterocolitis, a multi-center randomized control trial. First author is Simon Eden. It was published in Pediatric Surgery International. I think this is subject that we're all very familiar with. Obviously, we unfortunately deal with necrotizing enterocolitis too often. And when babies do go down for, do go for intestinal...
exploratory laparotomy section, the creation of a stoma allows the distal bowel to rest, to recover, and before any potential reanastamosis. Now, there's additional complications with going through this process, whether it is stenosis, prolapse, excoriation of the skin. And so the concept of primary anastomosis, which means that at the time of the exploratory laparotomy,
the surgical team could actually reconnect the patient right away, the authors do mention correctly that it is a less frequently performed procedure than enterostomy. And they're quoting some data, which is interesting, saying that only 15.8 % of infants receiving a resection for advanced NEC are having a primary anastomosis compared with 84.2 % having stoma formation across the US.
the US network of children's hospital. Now, they're also saying that with this data in mind, there's tremendous inter-hospital variation with 50 % of hospitals performing only stoma, but 18 % of hospital managing at least 50 % of the patient with primary anastomosis. So it's not something that is spread across the board fairly equally. are some centers that are doing it more than others. And national data from the...
data from the UK reflects this with 23 % of patients having a resection for NEC manage with primary anastomosis compared to 71 % with a stoma. So the question of the trial really is trying to understand what is the most effective operations for neonates with NEC requiring intestinal resection? Is it stoma formation or primary anastomosis? This is a big study. It was an international multi-center randomized control trial. It was conducted in 12.
Ben (30:40.064)
neonatal surgical intensive care unit across Europe, Canada, South America, Singapore, and New Zealand. The inclusion criteria is very straightforward. Basically, if you were suspected of having NEC and you needed laparotomy, you were going to be entering this randomization process, which we'll talk about, because it was an interesting randomization process. The exclusion were, there were several, but notably focal intestinal perforation obviously was an exclusion, extensive NEC, like nec totalis,
was an exclusion criteria, NEC affecting the colon that cannot be completely assessed because of the risk of bleeding and the patient's instability during the operation. So the patient underwent enrollment at the time of abdominal exploration. And it is at that point that only those infants in whom the operating surgeon thought that both operations were viable treatment options
that the babies were enrolled and then randomized. So I think it's very interesting that the randomization process happened at the time of the OR and the babies had to be potentially eligible for both operations to then be enrolled. We will talk about that in one second. And they were randomized to either stoma formation or primary reanastamosis. And they did this using
the minimization criteria. Do you know what that is, when you randomize people through minimization? I had no idea what that was. I had to look it up. And it's kind of a non-random way of randomizing. But basically, what it does is that you take a patient, right, and you randomize them. And then you have a selection of criteria. And based on the next patient, you try to make sure that the groups are balanced, basically. The criteria that they were using were
Daphna Yasova Barbeau (32:07.147)
Mm-mm.
Daphna Yasova Barbeau (32:11.287)
Ha!
Daphna Yasova Barbeau (32:25.163)
You're right.
Ben (32:27.95)
the weight at enrollment, the requirement for mechanical ventilation, the inotropic support, the extent of the disease, focal versus multifocal, and the intestine involved. And so basically, every time they randomize, they randomize the baby, and then the next one would be randomized based on these criteria, making sure that the both group were, quote unquote, balanced. And then once the group were balanced and another patient came up, then you randomize again. You just assign them randomly, and then you did these groups.
You adjust the two groups accordingly. I'm sure there's some statistician that are going to say Ben. This is not exactly how but this is the gist of it Trust me. This is the gist of it now That is a big sticking point but I think that we have seen Many trials where it's difficult to randomize and do this assignment so well and the authors are really honest and very upfront about this
saying, and I quote, in designing the current trial, was felt that randomizing patients to stoma versus primary anastomosis before laparotomy would lead to a major bias with surgeons more likely to withdraw patients with extensive disease who had been assigned to primary anastomosis while retaining similar sicker patients assigned to the stoma arm. And I think that's very true. And so they foresaw this potential issue and introduced this sort of.
a novel and innovative randomization process. The primary endpoint was the duration of parenteral nutrition in days. Secondary endpoints included a variety of things including mortality, intestinal complications, anastomosis leak, prolapse, et cetera, et cetera. So let's get into the results, because we've spoken enough about this study already, but basically they ended up having 79 patients. And after some exclusion,
They ended up having 38 patients in the the stomach group and 35 patients in the reanastamosis group. The mean gestational age was 28.7 weeks for the stomach group, 29.2 weeks in the reanastamosis group and the mean birth weight was 1 kilo 264 grams in the stomach group, 1.3 kilos in the anastomosis group. These are relatively, these were not statistically significant to one another, but obviously larger weights than
Ben (34:46.552)
you would expect from a micro preemie. They had extensive description of the disease characteristics, which I'll let you read on your own, but I want to go into the primary endpoint, which is obviously the time to end parenteral nutrition. And basically, there was a significant difference between the group. There was a median of 51 days to actually be off TPN in the stoma group compared to 30 days in the primary anastomosis group. So basically, the kids who ended up getting the primary anastomosis ended up coming off TPN a full 21 days before the stoma group, which obviously is
a very clinically and in this case, statistically significant result. In terms of mortality, there were 12 deaths, 21 % in the stoma group, 11 % in the reanastamosis group. This was not statistically significant. When they're looking at hazards ratio for mortality, for TPN as well, I mean, I think it's pretty clear from looking at the results, I'm going to spare you the details, but that the...
One of the factors that ends up playing a critical role in determining these outcomes is whether babies were receiving inotropes at the time of surgery. And this is something that seems to be showing up for both primary outcome mortality and some of these other outcomes. When it comes to intestinal complications, and these were stoma complications, wound dehiscence, incisional hernia, et cetera, et cetera.
They found that significantly more patients in the stomach group had multiple intestinal complications compared to the reanastamosis group. 12 out of 26 versus 5 out of 31, that was statistically significant. Now the rate of strictures, wound infection, incisional hernia, wound dehiscence and leaks were similar between the two groups. But when they are looking at the number of babies who had more than one, that was more frequent obviously in the stomach group.
And so these are some of the major results I'm going to stop here. The conclusion is that primary anastomosis following rejection of necrotic and or perforated bowel in NEC is associated with an earlier end to parenteral feeding, then stoma formation, reduced risk of intestinal complication with no increased risk of mortality.
Ben (36:51.578)
Primary anastomosis is the procedure of choice at laparotomy for NEC when there is no evidence of NEC distal to anastomosis and should be considered in patients of all weights requiring mechanical ventilation or inotropic support with focal or multifocal disease involving any part of the small and or large intestine. I think it's a very interesting study. I think it's a study that people will be talking about. just wish that maybe while the randomization process was quite novel and innovative, I wish we had a
bit of a clear insight into how did these surgical teams make the call to say, primary reanastamosis is a viable option for this patient. Because that's really the crux of the issue. I'm sure that you could try to come up with criteria, and some surgeons will follow, some others will not. But that's really where it would be interesting to see.
Daphna Yasova Barbeau (37:29.505)
Mm-hmm.
Daphna Yasova Barbeau (37:35.627)
Mm-hmm.
Daphna Yasova Barbeau (37:44.531)
Mm-hmm.
Ben (37:47.77)
how do they make that decision. But it was a very interesting study nonetheless.
Daphna Yasova Barbeau (37:52.215)
Yeah, it seems like we're still not totally sure which babies are candidates, right? So it's hard to make that an arm if we're still not sure. So, totally agree. Very interesting. Okay, well, I have one for you. Hold on. See? I hid it, I'm hiding it on my screen here. This was talking about changes in the...
Ben (37:56.217)
No? Yeah.
Ben (38:02.35)
Yeah.
Daphna Yasova Barbeau (38:20.439)
the patent ductus arteriosus management and outcomes in infants born at 26 to 28 weeks gestation. Lead author Dinushan C. Kaluarachchi and senior author Patrick McNamara. So obviously quite a team for talking about the PDA management. This was published in the Journal of Pediatrics. And so they basically wanted to look at the outcomes in infants born at 26 and 0 to 28 and six sevens weeks.
Over this time period in neonatal history here, where rates of PDA treatment have been decreasing. So we've been talking about the PDA a lot in the last 10 to 15 years. And over that time, treatment for the PDA has decreased because the pendulum has swung quite a bit. So they wanted to look at, well, during this timeframe, what happened to neonatal outcomes?
The study design, it's a retrospective cohort study. It includes infants born between 2012 and 2021 in participating hospitals from the NICHD neonatal research network. The primary composite outcome they were looking at was defined as surgical NEC, grade two to three BPD, severe intraventricular hemorrhage or death. So any one of those...
bad outcomes. And then they wanted to look at relationships of temporal trends in the PDA treatment with this primary composite outcome. And they wanted to look at the components also on kind of an individual level. So they used this multi-level model to account for patient level factors. And they did a separate analysis looking at these relationships stratified by hospital changes in PDA treatment.
How did they decide on the PDA? So basically it was a PDA diagnosis of yes or no. It was defined as documentation of clinical or echocardiographic evidence of left to right PDA physiology determined by the clinical team in routine care. So I think that's interesting point. Obviously there's a lot of discussion in the community that not all PDAs are the same. And maybe it depends on which PDA we treat that we have changes in outcomes.
Daphna Yasova Barbeau (40:45.045)
So just remember, this is PDA, yes or no.
Ben (40:47.736)
Yeah, I think that for any PDA study, no matter what the diagnosis method is, somebody will come and say, well, that's not really the right way to do it. I think that the fact that it was a yes or no classifier is okay. But I think some people might get hung up on the fact that it was defined as documentation of clinical or echocardiographic evidence because
Daphna Yasova Barbeau (40:56.587)
That's it.
Daphna Yasova Barbeau (41:15.595)
That's right. So what was clinical,
Ben (41:18.134)
Yeah, yeah, I'm sure.
Daphna Yasova Barbeau (41:21.687)
So that's that, keep that in mind. And then what was PDA treatment? So medical PDA treatment was defined as any medication used specifically to induce PDA closure. So indomethacin, ibuprofen, or acetaminophen. And of note, this was regardless of the timing, the duration, or the dose. So that data is not included. They did include prophylactic indomethacin for intraventricular hemorrhage prevention.
as basically, sorry, this was administration of indomethacin within the first 24 hours after birth, but they did include it as medical PDA treatment for this study because we know that in the studies it did have the effect of closing many, many PDAs. Now, procedural PDA closure included catheter and trans-thoracic surgical closure, but notably,
Data on the use of acetaminophen and the transcatheter PDA closure were not collected prior to 2016. Obviously, they were not used as frequently during that time period, but just of note, those are absent from the data as well. So what were the results? A total of 7,800, uh-huh.
Ben (42:33.412)
So I'm so sorry. So that means that because it was not recorded before that date, it was excluded altogether or they collected it afterwards.
Daphna Yasova Barbeau (42:43.895)
Well, I think it just wasn't documented for that individual baby is what I, is my understanding of it. We'll have to ask, but, um, but they couldn't say yes or no. If the baby had gotten acetaminophen prior to 2016, because it wasn't being recorded. Correct. Yeah. Same thing for the transcatheter PDA closure, which again was not as
Ben (42:51.394)
I see. I see. Got it.
Ben (43:03.714)
It wasn't just in the database. Fair enough. Okay, and then it was collected afterwards. it.
Daphna Yasova Barbeau (43:13.655)
was not as happening as often in that time period, but still it's of note. So they included 7,864 infants. The mean gestational age was 27 and a half weeks and the mean birth weight was 977 grams. For the entire cohort, there was a decrease in any PDA treatment from 21 % in 2012 to 16 % in 2021. This was statistically significant.
Ben (43:17.208)
Mm-hmm.
Daphna Yasova Barbeau (43:42.327)
PDA treatment was relatively stable from 2012 to 2018, but treatment did decrease during the last three years. So what were the trends and outcomes? So incidents of the primary composite outcome increased from 24 % in 2012 to 36 % in 2021. This was statistically significant. The increase of grade 2-3 BPD was really responsible for the majority of this increase.
It increased from 13 % to 26 % during the study period, also statistically significant, while the incidence of the other components of the primary outcome, death, surgical NEC, and severe IVH, remained unchanged during the study period. So then they looked at this multivariable model comparing grade 2 to 3 BPD in 2019 to 2021 compared to 2016 to 2018, and it showed an increased odds of grade 2 to 3 BPD
So the adjusted odds ratio of 1.38, so higher in 2019 to 2021 than 2016 to 2018. Then they wanted to look further into this. So they did this sensitivity analysis that looked at grade 3 BPD in the primary outcome instead of grade 2 to 3 BPD. And there was no significant temporal change in the modified primary composite outcome during the study period. 15 % to 18 % was not statistically significant. But the incidence of grade 3
And the incidence of grade 3 BPD did not significantly change during the study period, 3 % to 4%. However, the incidence of grade 1 BPD decreased from 32 to 27%, and this was statistically significant. And underscoring, it was the incidence of grade 2 BPD that increased from 10 % to 22%. That really, I think, was the primary underlying factor for this change.
Ben (45:41.498)
And grade two BPD and the way they are defining it is not benign. mean, it's a pretty significant amount of respiratory support at 36 weeks.
Daphna Yasova Barbeau (45:45.622)
No.
Daphna Yasova Barbeau (45:50.763)
That's right. So they're using the Jensen criteria. I didn't mention that. Trends in characteristics and treatments. So what else was going on? So gestational age, birth weight, and sex actually remained unchanged during the study period, which is interesting because it's a decade of neonatology. Infants that were born small for gestational age did increase from 8 to 11%. Receipt of mechanical ventilation, late onset sepsis decreased.
But on the converse, there was an increase in use of postnatal steroids, vitamin A injections, and antenatal steroids. There was a trend towards decreased administration of surfactant. Time to surfactant replacement wasn't changed. And duration, not surprising, of invasive mechanical ventilation was unchanged, but duration of the noninvasive respiratory support increased from 48 days to 59 days. And this was also significant.
Then they wanted to look at this PDA treatment trends versus kind of an individual outcome. So they looked at the data using a multi-level model that clustered them by birth year. So decreases in annual PDA treatment were associated with increases in the primary outcome in grade two to three BPD, even after controlling for patient level risk factors. They observed no relationship between death, surgical NEC, severe IVH or grade three BPD.
and yearly PDA treatment after accounting for those potential confounders. The following variables were associated with grade two to three BPD in the model. Any invasive mechanical ventilation, gestational age, male sex, grade two, three IVH, late onset sepsis, grade two, three NEC, postnatal steroids, small for gestational age, and yearly PDA treatment. So then they wanted to look at what did it look like at an individual hospital level?
So they looked at hospitals and what were their changes in PDA treatment from 2016 to 2018 compared to 2019 to 2021. And hospitals were labeled as having large or no to small decreases in PDA treatment or as having increases in PDA treatment during the period. And these hospitals ranged from having decreases of nearly 18 % to increases of 8%.
Daphna Yasova Barbeau (48:12.161)
So some hospitals are still having an increase in treatment. Increases in the primary outcome, three to 8 % and grade two, three BPD, three to 8 % were seen in all three groups with no clear relationship to changes in PDA treatment. There was no significant difference in the increase in the primary outcome or grade two to three BPD between centers with increases or decreases.
and PDA treatment. So I thought that was an interesting analysis. think it makes all the data a little bit more confusing, but because some hospitals, while there was a temporal kind of population community-based decrease in PDA treatment, that wasn't true at the individual hospital level. And there was this overall increase in grade two BPD that drove the composite outcome.
But that wasn't necessarily shown at the individual hospital level either. So, interesting.
Ben (49:12.686)
Yeah, yeah. Yeah, I think there's a lot to say about this paper. I think that there's some criticism of how people might want to interpret the data. I think that we are putting on equal footing the treatment of PDA and the evolution of BPD. And I think that some people might say, well, there are other components. Based on the paper, you cannot let your brain automatically associate the two as a direct and unique
causational link where you say, because of the PDA, then that's what happened to grade two. I think they're making an observation. And there are several things, in my opinion, that could explain this a little bit. Also, like you said, the fact that some hospitals changed dramatically their approach to PDA, but in various directions, but different outcomes also may show that this potentially is not the only reason for affecting the development of BPD. It is important to say that historical evidence has demonstrated
Daphna Yasova Barbeau (49:59.895)
Great.
Daphna Yasova Barbeau (50:04.513)
Mm-hmm.
Ben (50:11.962)
clearly that the presence of a PDA increases the risk of BPD. So that is known and that is not in question here. But I think what's interesting too is that you have to look at definitions and the fact that they used the Jensen criteria I think is critical here because of the time span they decided to cover. They covered 2012 and the question becomes, are we using more high flow nasal cannulas today than we used back in 2011, for example, because then suddenly,
Daphna Yasova Barbeau (50:14.945)
Mm-hmm. Mm-hmm.
Daphna Yasova Barbeau (50:29.559)
Hmm.
Ben (50:40.396)
If you have a baby on high flow three, that's a, that's a grade two BPD, according to Jensen. And maybe that was not really available before then. And you might have been even more aggressive. So I think it's interesting. I would recommend people listen to the short interview we did with Dr. Ben Kalari at Hot Topics, where he mentions that sometimes these babies and, also Cindy McEvoy. So these two interviews that we did where people do talk about these infants that are quote unquote, often forgotten on their high flow nasal cannula, because they're doing well and we're leaving them there.
Daphna Yasova Barbeau (50:43.639)
Mm-hmm.
Daphna Yasova Barbeau (50:54.591)
Mm-hmm.
Daphna Yasova Barbeau (51:07.786)
Mm-hmm.
Ben (51:10.276)
But if you leave a baby on three liters high flow nasal cannula at 37 weeks, you have a grade two BPD. If that had not been available in 2010 in your institution, you might have pushed at that time to win. So who knows? Who knows? But it's definitely something interesting. And the last point I'm going to make is that whenever we see these studies looking at temporal trends, we tend to think, but the babies are sicker today. That is not true. I think it's important to highlight what you said. They put the cutoff at 26 weeks. So this study,
Daphna Yasova Barbeau (51:34.955)
Right.
Daphna Yasova Barbeau (51:39.777)
Don't include the right, that's right.
Ben (51:40.314)
Don't include our 22-weekers. You no, the 22-weekers are mixed in. it's, no, that's not true. These are 26, 28 weeks that we, there's no, there's not, the 22-weekers cannot be blamed on this one. So, yeah. So, very interesting, very interesting. And I think it's going to lead to interesting discussion.
Daphna Yasova Barbeau (51:50.465)
That's right. Yeah. And, and I think they tried to parse it out, but like, there were like a lot of things happening with BPD management and other types of management in this particular decade. Right. So they talked about vitamin A, they talked about pre and postnatal steroids, but we didn't really have a standardized approach to any of that across the community. So, but it was, it was an interesting look, I think.
Ben (52:19.066)
Mm-hmm.
Daphna Yasova Barbeau (52:20.471)
to see what they could find.
Ben (52:22.584)
All right, we're already at an hour, so I could keep going. However, I'm going to have to pick a paper and I'm going to let you choose. We can either do a paper on IVH or on iron supplementation.
Daphna Yasova Barbeau (52:24.405)
Yes.
Daphna Yasova Barbeau (52:31.863)
gosh, I love both those topics.
Ben (52:37.549)
I know, take one.
Daphna Yasova Barbeau (52:41.537)
IVH.
Ben (52:42.486)
Okay, all right. So stay tuned for Iron Supplementation paper next week or two weeks from now on the next journal club. So IVH, there's a very interesting paper that came out in JAMA-PEDS called Occurrence and Time of Onset of IVH in Preterm Neonates, a systematic review and meta-analysis of individual patient data. First author is Susanna Nagy, and this is coming from Hungary. We're running out of time. I'm not going to talk to you about
what is IVH and intraventricular hemorrhage. I think we all know this pathology, unfortunately. I'm going to go straight into the study. The primary aim of the study that we're talking about was to explore the temporal distribution of the onset of IVH in preterm infants using a systematic review and mid-analysis of previous studies.
They had a secondary aim, which was to test the hypothesis that recent improvements in neonatal care were associated with a reduction in the prevalence of IVH and or the delayed onset of IVH. They did something very interesting. So they obviously conducted their mid analysis and they looked at the articles that were selected. They had to have at least two cranial ultrasound examinations in the first week of life to diagnose IVH.
studies with only out born preterms were excluded because of these potential issues with transport, think. There were three reviewers that extracted the data and they followed the Prisma reporting guideline. And they basically said something which I thought was interesting. They basically used 2007, the year 2007 as a cutoff. And they said, as there were no single therapeutic breakthrough innovation in neonatal medicine in recent years that would have provided clearly identifiable time boundaries.
They said 2007 was used as the cutoff date for their time analysis. And so basically what they're going to do is contrast all the different findings that they have from this mid analysis and say, what was it like prior to 2007? And what is it now post 2007? So the search methodology and everything else I think is fairly standard. It was well done. Please go read it.
Ben (54:59.404)
in further detail if you must, but I'm going to go into the results. In total, they had 9,633 infants that were included, mainly from Europe and North America. Most of the studies presented and analyzed were cohort studies. 12 studies were retrospective, and 40 studies were prospective.
So let's talk a little bit about some of the data. And Daphne, you're going to be interested in this. What is the proportion of any grade and severe IVH? So data from 61 included studies of 9,218 infants were used to calculate the overall occurrence of IVH among preterm neonates. The overall occurrence of IVH in preterm neonates was 33%, and severe IVH was 10%. They're saying that neither
the occurrence of IVH nor the occurrence of severe IVH was different between the different groups before and after 2007. So the total occurrence of IVH was 36 % prior, 31 % after 2007, and for severe IVH it was 10 and 11%. Obviously not statistically significant. So that's already interesting, right? You would say, well, but aren't we
Daphna Yasova Barbeau (56:18.518)
Mm-hmm.
Daphna Yasova Barbeau (56:23.207)
It's really kind of a bummer.
Ben (56:25.338)
I know, right? So you're like, what about all this pain in the butt neuro bundles and like all the things that we're doing, but they're going to go into more details and try to tease that apart. And that's going to be very interesting. So in terms of general, all grades IVH, they categorize things by subgroups and they found some difference. So for babies that are less than 28 weeks, they found that before 2007, the rates were 33%.
Daphna Yasova Barbeau (56:30.603)
Mm-hmm. Mm-hmm.
Ben (56:53.274)
And after 2007, they were 41%. So they had gone up. For babies that are less than 32 weeks, then those numbers are gone down 32 % before 2007, 27 % after 2007. They have this other category, which is where if the gestational age were non-categorized, and that was 38 % IVH in...
before 2007 and 28 % after. So I think that for us, a lot of times we worry specifically about severe IVH. And so we have data for that as well. For babies that are less than 28 weeks before 2007, the rates were 18 % and after 17%. And for severe IVH and babies less than 32 weeks, it was 7 % before 2007 and 8 % after 2007.
pretty much unchanged. So what they did then is to say, well, let's take a look at the proportions of either IVH in preterm infants, but by postnatal age. And so what they found was that the proportion of very early presenting IVH, which they define as anything up to six hours of life after 2007, was significantly lower than before 2007. So it was 5%.
compared to 13 % before 2007. IVH up to 24 hours was 18 % before 2007 and is now 22 % after 2007. IVH up to 48 hours of life is 28 % before 2007 and is now 18 % after 2007. And then when they looked at a similar pattern, looking at the proportion of IVH,
Among all different IVH events by postnatal age, what they found was that up to six hours of life, the rates were 35 % before, 9 % today. The striking difference that is also statistically significant. Up to 24 hours of life was 44 % before 07 and 25 % after. And less than 48 hours, 82 % before 07, 50 % after 2007. And everything else took place after 72 hours of life.
Ben (59:17.326)
And so what they're finding basically is that the overall prevalence of IVH did not change significantly over the past 20 to 40 years. However, what this highlights is that the very early presenting form of IVH declined substantially. Less than 10 % of all IVH in preterm infants occurred before six hours of life. And this data, they say, suggests that recently implemented preventive measures have the potential to postpone
rather than reduce IVH in preterm infants. And obviously, the first thing I thought was like, we deserve the credit because we're doing all this neuro bundle, delayed cord clamping, but it also goes on the OB side, right? I mean, they were mentioning in the discussion, I'm going to not go into too much detail right now, but an IVH that happens at one hour of life could be the result of an insult in utero. So I think that we have to look at this in the form of a continuum.
Daphna Yasova Barbeau (01:00:00.129)
Mm-hmm.
Daphna Yasova Barbeau (01:00:06.162)
Mm-hmm
Ben (01:00:11.93)
looking at this from OB and NEO, but showing that with the interventions, we've been able to stave off IVH for some time. But in the end, it doesn't change the IVH rates significantly. And I want to show you this graph because it's kind of interesting. This is figure four. And you can basically see that when they are looking at the trends before 2007, after 2007, you can see that in the first few hours of life,
Daphna Yasova Barbeau (01:00:12.267)
Yeah.
Daphna Yasova Barbeau (01:00:37.686)
Mm-hmm.
Ben (01:00:38.766)
the yellow line, is us today, are doing much better, but eventually both lines converge when we're looking at closer to 72 hours. And that's kind of depressing, but opportunistic from the standpoint of like, this is what we have to focus on right now.
Daphna Yasova Barbeau (01:00:49.911)
Yeah.
Daphna Yasova Barbeau (01:00:56.023)
I mean, I'll say one thing. think unless you're doing every six hour head ultrasounds, it's hard to write. Some babies are diagnosed at six hours. Some babies are diagnosed at 24 hours, but most of us are still waiting for 72 or seven days to get the first head ultrasound.
Ben (01:01:12.376)
And that's a question that they're asking you, guess, in the paper saying, should we do an early head ultrasound to try to track and identify the development of the IVH? Also trying to get better information on what is the status of our patient? Meaning a baby that's doing well but has an IVH diagnosed at seven days, you wonder, did it happen after birth? Did it happen before birth? Was it there at six hours? And I think that they're not, I don't think they're doing this formally.
Daphna Yasova Barbeau (01:01:15.852)
Yeah.
Daphna Yasova Barbeau (01:01:19.991)
Mm-hmm.
Okay.
Ben (01:01:41.732)
But they're kind of asking the question, should we just change our policy on how, on when we do ultrasounds? They do mention the recommendations that an ultrasound has to be done within, like you said, seven days of life. But they said, maybe that should change. Maybe we should do a bit more frequently. I don't know what your thoughts are on that.
Daphna Yasova Barbeau (01:01:54.751)
Yeah, and it's, well, it's hard to, think, because parents have that question, right? Why are you doing the head ultrasound at seven days? But like, I want to know at three days if my baby has an IVH. And if it wasn't present at three days, what happened between days three and seven that a night or whatever the timeframe is that something occurred? And then I think it goes down to like,
Did something happen or were some babies just predisposed and they had a second hit of hyponatremia or a blood pressure spike? I mean, some things we can, we try really hard to avoid and we still can't seem to avoid sometimes. I don't know. But I think that this information is both promising and a little bit of a bummer still.
Ben (01:02:47.546)
A little bit of a bummer. that's why I want to...
Daphna Yasova Barbeau (01:02:49.591)
But to your point, maybe there's something we can still do. If you can make it through the first 24 hours, maybe we can do something differently. Because that's not how we used to think about it. We used to think about it that the majority happened in the first 24 hours and then almost all happened in the first 48 to 72 hours.
Ben (01:03:00.826)
Mm-hmm.
Ben (01:03:13.076)
Yeah, maybe we've moved the target now.
Daphna Yasova Barbeau (01:03:16.895)
Yeah. And so maybe we're so careful in that golden hour, but we become too lax in the subsequent few days. I don't know.
Ben (01:03:25.176)
Yeah, but we want parents to hold and we want to be able to do some of these things. it's tough questions for sure.
Daphna Yasova Barbeau (01:03:32.151)
for sure. Very interesting. Okay, speaking of parents holding, I'm going to do one quick paper. I'm going to be fast, I think. Okay, this paper is, elective extubation during skin-to-skin care and preterm newborns is safe and well tolerated. What a punchline. Lead author, Moray Olive and senior author, Montaner Ramon. This is coming from Barcelona, Spain.
Ben (01:03:34.51)
Mm-hmm.
Let's do it.
Did you? Okay.
Daphna Yasova Barbeau (01:04:00.863)
It's an act of pediatrica. So basically what they were looking at is they have a practice already in their unit of some people extubating babies that are less than 32 weeks with a birth weight less than 1,500 grams during the first two months of life, either in the incubator or during skin-to-skin with parents. So they wanted to look at this retrospective data to see
Did they have more extubation failures with one method or another? So that's basically what they looked at. I told you it was retrospective. It's all done at one hospital in Barcelona between January, 2022 and December, 2023. The inclusion criteria was less than 32 weeks and or weight less than 1500 grams at birth who required intubation and mechanical ventilation during their hospitalization.
And like I said, those babies were electively extubated during the period, some of which, this was not a randomized trial, this is retrospective data. Some of those were extubated during skin to skin, and some were extubated directly in the incubator. The exclusion criteria, okay.
Ben (01:05:15.898)
Hold on, hold on, hold on, hold on, hold on, hold So can we just clarify that what you're saying is what you're saying? So basically, they knew they were going to do skin to skin. So like we're not talking about unplanned extubation during skin to skin.
Daphna Yasova Barbeau (01:05:26.647)
Correct, that's the exclusion criteria, that it was not an accidental extubation. They put the babies in skin-to-skin care with plans to extubate on the mother or father. 70 % were on the mother.
Ben (01:05:31.62)
So the...
Ben (01:05:39.578)
Okay, so to be clear, the babies they thought were ready for extubation, and so they said, we will perform the procedure of extubation on the mother. Okay, it's not like they're extubating for the purpose of skin to skin. My post-call brain somehow.
Daphna Yasova Barbeau (01:05:44.417)
Correct.
Daphna Yasova Barbeau (01:05:49.045)
Wow, skin to skin, yeah.
Daphna Yasova Barbeau (01:05:54.601)
No, that was an interesting take. Definitely not. No, maybe I was unclear, but no, you've got it right. So these were babies that they felt were ready for extubation. They didn't tell us what their extubation readiness criteria was, but somebody thought the baby was ready to extubate and they either did it in the incubator, which I think is pretty routine practice, or they put the baby skin to skin with the purpose to extubate.
Ben (01:06:02.98)
No, no, no, no, no.
Ben (01:06:10.479)
Fine.
Daphna Yasova Barbeau (01:06:24.469)
You still don't follow? Okay.
Ben (01:06:24.536)
Yeah. I follow. No, no, I follow. I follow. And I think the key here is the fact that positioning of the baby, suctioning, doing a lot of different interventions at the time of extubation is sometimes the recipe for a successful extubation. So if skin-to-skin could be that added secret sauce, maybe, why not?
Daphna Yasova Barbeau (01:06:35.595)
Mmm.
Absolutely.
Daphna Yasova Barbeau (01:06:44.297)
Right, that's right. There were some exclusion criteria. So you were excluded if your first extubation performed was after the first eight weeks of life. So you were already two months old, you were excluded. You were not included if it was an accidental extubation, for example, if you were doing skin-to-skin care and you were accidentally extubated. If extubation performed outside of the neonatology unit or extubation in the context of an end-of-life situation, obviously.
So, okay, let me tell you a little bit about how they, it's a little confusing how they wrote it, but I think my understanding is that they had, if you were going to extubate during skin to skin, you had three people, you needed nurses, nursing assistants, and or neonatologist. So they transferred the baby from the incubator to the chest of the parents, preferably the baby was in the prone position. So, uh, face down on the chest while the newborn is connected to mechanical ventilation.
They made sure the baby was stable for about 15 to 30 minutes. They put on the nasal interface and then they extubated and they attempted at least to maintain skin to skin care for at least 30 more minutes. Okay. Now it looks like skin to skin care.
very common in their unit, though they are a referral center. So they did mention that like they either had lots of skin to skin care or some parents were rarely at bedside because of the need for transportation. looking at their skin to skin data, the first skin to skin care in these babies less than 32 weeks or less than 1500 grams was performed at a median of 39 hours and 33 % of skin to skin care.
was within the first 24 hours of life and 66 % within the first 72 hours of life. So this is a unit that does a lot of skin-to-skin care. They did look at a bunch of clinical data. They wanted to look at what is extubation tolerance. So they collected FIO2 heart rate data 30, 60 minutes, three hours and 24 hours after extubation. And then they looked at post-extubation respiratory support.
Daphna Yasova Barbeau (01:08:54.049)
kind of adverse events during extubation and then the time and reason for reintubation. So we'll look at the patient characteristics.
Ben (01:09:02.202)
And they looked at these kids up to 72 hours to see if they were going to, I mean, I think they used 72 hours as their ultimate sort of time point of like successful extubation, which, yeah, which I think is reasonable.
Daphna Yasova Barbeau (01:09:11.543)
for stability, yeah. Now, the two groups were not totally the same. So I think that's important to talk about for a number of reasons. So during this two-year study period, 257 patients were admitted to the NICU. They had 142 elective intubations in 93,
patients. Does that make sense? So they had 93 infants. They had 142 elective extubations. So more elective extubations. So more extubations than infants. So 60 were done in skin-to-skin care in 45 patients and 82 were done into the incubator, 69 patients. Okay.
What did I want to tell you here about the excavation criteria?
Daphna Yasova Barbeau (01:10:17.975)
Okay. Um, there's a lot of information here, but we're short on time. So I want to give you the, biggest, the biggest data. The mean gestational age was 25 weeks in the skin to skin group versus 26 weeks in the incubator group. The median birth weight was 700 grams in the skin to skin group and 880 grams in the incubator group. So the babies who were actually extubated to skin to skin tended to be smaller and they tended to be, um,
earlier gestation. There were also some other differences. So the postnatal age at extubation into the incubator group was six days. So they were more likely to extubate to the incubator in the early days of life. The postnatal age at extubation median day was 16 days in the skin-to-skin care. The postmenstrual age of extubation was 29 to the incubator, 28 skin-to-skin, but this was not statistically significant.
Ben (01:11:05.358)
Mm-hmm.
Daphna Yasova Barbeau (01:11:16.535)
Now, had they had previous skin to skin prior to extubation? So 80 % of the skin to skin group and 40 % in the incubator group. And they talk about this. So if you had done skin to skin care before, you were more likely to get skin to extubated to skin to skin care. Had they had previous extubation failure? So it was 14 % in babies extubated to the incubator. It was actually 35 % of babies extubated to skin to skin care had previous extubation failure.
you have an umbilical venous catheter? Well, I told you the babies extubated to the incubator were early, day six. So 48 % had an umbilical venous catheter, only 23 % and those were skin to skin.
Ben (01:11:58.308)
There's still some reluctance to do skin to skin when you have these catheters in,
Daphna Yasova Barbeau (01:12:00.439)
with a catheter, absolutely. But that doesn't seem to totally be a problem for this unit. Do they have sedation? So continuous infusion of sedation, 30 % in the incubator group, 53 % in those babies who went to skin to skin. And that was statistically significant. Did you get dexamethasone prior to extubation? This was significant. So 13 % in the incubator group.
48 % in the skin-to-skin group. Did you actually get the DART protocol? 10 % in the incubator group, 40 % in the skin-to-skin group. And the FIO2 needs were different. 0.09 % in the incubator group, 0.13 % in the skin-to-skin group, but that was statistically significant. So the babies who got extubated in the skin-to-skin care,
tended to be higher risk babies, but they did get more steroids. So that's just something to consider. They also were extubated later in their course. Okay, so let's just get into extubation tolerance. So most patients, they used a type of BiPAP. They call it DuoPAP support initiated after extubation. 85 % of those in skin to skin. And sorry, I just want to reiterate one thing.
Ben (01:13:04.857)
Mm-hmm.
Daphna Yasova Barbeau (01:13:26.775)
This was not a randomized control trial. So this was retrospective. Some babies did get skin to skin. Some babies were extubated in the incubator. And then they looked back at this group of babies. 85 % were extubated to this duopap in skin to skin and 50 % into the incubator. Who got CPAP? 11.7 % in the skin to skin, 40 % in the incubator group. And 5 % of cases got high flow. There were no severe incidents related to extubation in either cohorts.
There were no differences in the FIO2 requirement or heart rate compared to baseline during the 24 hours following extubation in both groups. The reintubation rate during the first 72 hours after extubation was 20.4%. This was an N of 29. There were no differences between both groups. Most failures occurred between three and 24 hours and immediate failures were rare.
Not surprisingly, patients with lower gestational age, lower birth weight, lower postnatal age, and lower weight at extubation had higher rates of extubation failure. The use of DART protocol was not significantly associated with the rate of extubation failure or success. And among those under 28 weeks and N of 54, 21 patients were extubated into skin to skin and 33 into the incubator. Extubation failure rates among those extremely preterm
were 33 % in the skin-to-skin versus 45 % in the incubator, but this was not statistically significant. Then they looked at a birth weight adjusted analysis to compare success rates. And while birth weight was a significant predictor of success, skin-to-skin extubation did not show statistical significance when they analyzed looking at this compounder.
The main causes of extubation failure were respiratory insufficiency, 44%, apnea is 24%, intercurrent illness is 10%. And in 13 % of cases, respiratory support had to be escalated without the need for reintubation within the first 24 hours. But this was not statistically significant difference between the cohorts. And during the study period, there were no adverse events recorded during extubation and skin-to-skin care. So.
Daphna Yasova Barbeau (01:15:46.199)
Basically, what they found is that skin-to-skin care or extubating to skin-to-skin care was not inferior, I guess you could say, to extubating into the incubator. They didn't find that it was better necessarily, but again, the groups were not totally similar.
Ben (01:16:03.47)
Yeah, sometimes, yeah, I think you're right. I think that's exactly the takeaway that I have, which is that, yes, this may not, this paper clearly doesn't tell you that you should do it in the skin-to-skin setting rather than in the incubator, that it's not outrageously superior, but it probably shows that it's very much feasible. And maybe as we start studying this a bit more, maybe we'll find some benefits or specific benefits for a population. And it's kind of the things you and Gabriel sometimes say the same things, which is like,
Daphna Yasova Barbeau (01:16:26.039)
for
Ben (01:16:33.56)
What's the harm of the... There's some interventions that you're like, we could maximize what we do in skin-to-skin, if we could maximize certain things, how much evidence do you need before you can actually roll them out? And I think that extubation failure is really the critical point. I know some people might say 72 hours is not long enough. You want to maybe look at extubation failure for five, seven days. All right, but give me a break. 72 hours is pretty good. And there are other factors that play a role. So yeah, I think this is very interesting.
Daphna Yasova Barbeau (01:16:35.009)
Yeah.
Daphna Yasova Barbeau (01:16:57.943)
Pretty good. Yeah.
Daphna Yasova Barbeau (01:17:03.765)
Yeah, I mean, I'll just say in most of the units where I've worked, if a baby gets extubated, everybody's like, don't even look at the baby. Like don't touch the baby. And maybe we don't have to do that to this baby who's undergoing this critical transition in life. Maybe they could be held by their parents.
Ben (01:17:17.316)
What's interesting about it is that we had reviewed a paper about extubation, I forget when it was, and it was mentioning how basically proning the baby right after extubation really maximized the areas of ventilation of the lung. And if you have a mother that's leaning back that gets a baby placed on their chest, you're kind of doing this in a roundabout way because it's not exactly prone, but you might be at an angle. And so you might end up being in that position through skin to skin.
Daphna Yasova Barbeau (01:17:25.953)
That's right.
Daphna Yasova Barbeau (01:17:33.463)
For sure.
Daphna Yasova Barbeau (01:17:44.299)
Yeah, and opening up those apices
Ben (01:17:46.842)
Yeah, yeah. So I think that was interesting. That's interesting to think about it also in those terms because yeah, there's likely a benefit there as well. Very cool. Well, this was a fun Journal Club. We will see you guys next week. Is there anything, Daphne, that you want to mention before we say goodbye to the audience?
Daphna Yasova Barbeau (01:17:56.439)
Okay.
Daphna Yasova Barbeau (01:18:09.783)
Do you want to tell people about our interview next week?
Ben (01:18:12.31)
Absolutely. so number one, on Wednesday, January 8th, we will have a new episode of the Global Neonatal Podcast with Shelly Ann Dakarai and Mbozu Sipalo. They've been doing a phenomenal job. So check them out. And then on Sunday, Daphne and I will be back and we have a special interview with Dr. Keith Barrington from Montreal, Canada. If you
Neonatal Research Blog, I'm sure you've read some of his commentaries. He is a fascinating individual, so it's an interview you should definitely not miss. Please continue to send us your feedback. Please continue to share your thoughts and comments with us, suggestions, and we'll be happy to listen, reply, and implement those into the show. All right, Daphna, have a good rest of your day. Bye-bye. Thanks.
Daphna Yasova Barbeau (01:18:43.666)
Mm-hmm.
Daphna Yasova Barbeau (01:18:49.271)
Mm-hmm.
Daphna Yasova Barbeau (01:19:04.789)
All right, have a good one. Get some rest.