Hello friends 👋
In our latest Journal Club episode, we review several important recent studies in neonatology. We begin by discussing a paper on the changing trends in Apgar scoring, noting a shift from scores of 10 to 9, likely due to increased recognition of normal transitional acrocyanosis.
Next, we examine a study on using ChatGPT and Google Translate for pediatric discharge instructions, finding mixed results across different languages. We then review new transfusion guidelines for very preterm neonates, featuring an interview with co-author Dr. Ravi Patel who provides insights on the guideline development process and implementation considerations.
We also discuss an observational study from Sweden on early skin-to-skin contact and its potential benefits for reducing intraventricular hemorrhage and sepsis in preterm infants, though we note limitations in the study design.
Additionally, we review a pilot randomized trial comparing whole-body hypothermia to targeted normothermia for neonates with mild hypoxic-ischemic encephalopathy. The study found no clear benefits to cooling in mild cases and highlighted the need for further research.
Finally, we highlight an op-ed emphasizing the importance of addressing mental health needs of new fathers, especially those with infants in the NICU. We note that while screening all NICU parents for postpartum depression is recommended, it is often overlooked, particularly for fathers.
Throughout the episode, we provide thoughtful analysis of the studies' methodologies, findings, and clinical implications, offering valuable insights for neonatology practitioners. We hope this Journal Club helps keep our listeners up-to-date on the latest research and encourages critical thinking about how to apply these findings in clinical practice.
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The articles covered on today’s episode of the podcast can be found here 👇
Deschmann E, Dame C, Sola-Visner MC, Fustolo-Gunnink SF, Guyatt GH, Patel RM, Stanworth SJ; Neonatal Transfusion Network.JAMA Netw Open. 2024 Jun 3;7(6):e2417431. doi: 10.1001/jamanetworkopen.2024.17431.PMID: 38874929 Free article.
Everett SS, Bomback M, Roth P, Goldshtrom N, Polin RA, Lyford A, Hays T.J Pediatr. 2024 Jun 14:114150. doi: 10.1016/j.jpeds.2024.114150. Online ahead of print.PMID: 38880381
Brewster RCL, Gonzalez P, Khazanchi R, Butler A, Selcer R, Chu D, Aires BP, Luercio M, Hron JD.Pediatrics. 2024 Jun 11:e2023065573. doi: 10.1542/peds.2023-065573. Online ahead of print.PMID: 38860299
Montaldo P, Cirillo M, Burgod C, Caredda E, Ascione S, Carpentieri M, Puzone S, D'Amico A, Garegrat R, Lanza M, Moreno Morales M, Atreja G, Shivamurthappa V, Kariholu U, Aladangady N, Fleming P, Mathews A, Palanisami B, Windrow J, Harvey K, Soe A, Pattnayak S, Sashikumar P, Harigopal S, Pressler R, Wilson M, De Vita E, Shankaran S, Thayyil S; COMET Trial Group.JAMA Netw Open. 2024 May 1;7(5):e249119. doi: 10.1001/jamanetworkopen.2024.9119.PMID: 38709535 Free PMC article. Clinical Trial.
Johansson MW, Lilliesköld S, Jonas W, Thernström Blomqvist Y, Skiöld B, Linnér A.Acta Paediatr. 2024 May 27. doi: 10.1111/apa.17302. Online ahead of print.PMID: 38803030
Fairchild KD, Petroni GR, Varhegyi NE, Strand ML, Josephsen JB, Niermeyer S, Barry JS, Warren JB, Rincon M, Fang JL, Thomas SP, Travers CP, Kane AF, Carlo WA, Byrne BJ, Underwood MA, Poulain FR, Law BH, Gorman TE, Leone TA, Bulas DI, Epelman M, Kline-Fath BM, Chisholm CA, Kattwinkel J; VentFirst Consortium.JAMA Netw Open. 2024 May 1;7(5):e2411140. doi: 10.1001/jamanetworkopen.2024.11140.PMID: 38758557 Free PMC article. Clinical Trial.
Badurdeen S, Blank DA, Hoq M, Wong FY, Roberts CT, Hooper SB, Polglase GR, Davis PG.Pediatr Res. 2024 Apr 26. doi: 10.1038/s41390-024-03131-5. Online ahead of print.PMID: 38671085
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The transcript of today's episode can be found below 👇
The Incubator (00:01.646)
Hello everybody, welcome back to the Incubator podcast. It is Sunday, we're back with an episode of Journal Club, which is overdue, as far as I can tell, right, Daphna? Well, we had a special event on Sunday for Father's Day. Father's Day, I think that was a good thing. And it was a great episode, so hopefully people have taken listen to it. That's right, that is right. All right, we need to do a few housekeeping stuff because we put out this survey.
and to celebrate our three anniversary. And many people have filled out the survey to enter the giveaway. Thank you, everybody, for that. The question that I have for you, Daphna, is at some point we're going to say that's it. So it's as of this recording, we are June 23rd. I guess what we will tell people is that we will close the forum next week.
I think that makes sense. So you have a week. If you're listening to this, you have a week you can enter. We will put the link on the episode web page. You can go. It's a very quick feedback form. It helps us a lot to understand where to go in the future. And then we will close the form and then we will select winners for this massive giveaway. There's tons of stuff. Basically, we decided that instead of having one prize, we'll have like tons of little like Amazon gift cards, AirPods, all sorts of stuff.
So yeah, so that's going to be that. Then the Delphi conference is coming along. We have a completely updated website. Everything is on there. If you haven't registered, we have limited seating. So just make sure to reserve your spot. And then we're all very excited to see you then. Is that it for housekeeping? I think so. OK, that's good. Should we get on with Journal Club then?
And we must, we must. We must. I'm going to start with an easy one. Please do.
The Incubator (02:03.662)
Get everybody warmed up. Yeah, it's a good paper because it does it serves a lot of different purposes. Number one, it's coming out of the team at Columbia and we are going to be in New York at the end of the month of July for NeoHeart. So the podcast booth will be there. Very excited to collaborate with the NeoHeart team. And so if you are attending NeoHeart July 30th in New York City, we'll be there.
Around July 30th. Yeah, July 30th, August 1st. 28th to the 1st. No, no, no. 30 to the 2nd. No, you're right. The 30th to the 2nd. Obviously, as you can tell, we have not booked our plane tickets. But we'll be there. One way or another, we'll get there. Hopefully on the right day. That's right. But the team at Columbia, on this paper by Everett and Colleague.
And on this paper, there are a few of our friends, Richard Pullen, Nim Goldstrom, Tom Hayes. And the title of the paper is, Nine is the New 10 Apgar Score, an observational retrospective cohort study. And so obviously we're going to talk about why we're giving nine Apgars, but not tens anymore. And so in the background, I thought it was interesting that they went back to the original papers of Virginia Apgar to find that she assigned.
a score of 10 out of 10 at 10 minutes of birth in only 14 % of cases. But 14%. But 14%. And they're saying in our experience, they say 10 is rarely a sign because there's acrocyanosis. And so usually give a nine, rarely give a 10. I've tried to give a 10 once. Everybody. The nurse said no, she's like, no, I was a I was a pediatric resident.
I was trying to be a hot shot and I said, 10, 10. And they're like, no. But it is an interesting thought because if the nine is an acrocyanosis is normal, quote unquote, is anticipated, expected. We'll talk about that. So it's not going to be a long paper, obviously, but what they want to find out is how have APGAR scores of 10 been assigned over time. So they collected five minute APGAR scores and some demographic characteristics for babies that are born.
The Incubator (04:32.558)
term like 37 to 40 weeks from this database called the National Vital Statistics System maintained by the National Center for Health Statistics. It basically includes all US birth certificates from 1985 onwards. Yeah. And basically they had to use the five minute Apgar because that's what was available starting in 1978. And then in 1994, they stopped using the one minute Apgar. So that's why they couldn't include that. But so that's the reason.
And the other thing too is that in the database, they don't know how the Apgar was broken down. So they won't be able to tell us where the baby lost points basically.
So they looked at 99 million births, 493 ,809 infants. This is a tiny cohort. Exactly. And they looked at the proportion of infants receiving a five -minute Apgar score of 10 has decreased from 40 % in 1978 to 2 % in 2021. Wow. We've been doing it wrong, maybe. Well, I think we'll talk about it. I think the discussion of the paper is very interesting. And they're saying that obviously this is accompanied...
by a comparable increase in scores of nine from about 50 % in 1978 to 84 % in 2021. When it comes to looking at the infant birth weight, the gestational age, the sex, the maternal age, whatever, most of the stuff was relatively similar. Nothing major that jumped at them. And so that's really it for this paper. But the discussion is very interesting because they're basically...
delving into the question as to why are we doing this? And when was the change? Yeah. And they're saying that is this change going from 10 to 9 reflecting a gradual change in clinical practice driven by improved understanding of transitional circulation and by the establishment of other technological tools like pulse oximetry that now allow us to say, well, you know, it's not we know we're transitioning and
The Incubator (06:39.95)
And they're saying that diffusion of this knowledge may have led to an increased recognition of acrocyanosis following birth. And consequently, babies were deducted one point from their APGAR scores, usually for color, because I mean, it's usually for color, and the scores of nine were replaced by 10. To which your follow -up question would be a good one, which is, if we know that's sort of transitional and it's OK, then why not giving them 10? So I think that's interesting. But no solutions, huh? No, just...
Everybody gives 10, no, they give us nines, I'm sorry. Well, you know, I think it's interesting because the lay public doesn't seem to understand that. They all want to know like, why wasn't my kid a 10? That's right. It's just the way it is. But nine is great. Nine is optimal. It's a very European thing, in my opinion. In France, when you are in high school, like you do not get the 100 on your exams. Nobody gets 100. No one gets 100. You're not allowed. Like this is like what you can strive for is like a 95 or something. And...
in Europe for the baccalaureate, if you give people a perfect score, the teacher has to write a report as to why they give a perfect score. So they're definitely not handing out perfect scores. No, very, very rarely. Anyway, so that's the first paper. Since we're having a good time, then I'm going to continue with another fun paper. Don't take away all the fun stuff. No, no, no, no.
But I read this other paper in pediatrics called the performance of chat GPT and Google Translate for pediatric discharge instruction translation. I think that's a potentially great utilization of chat. Well, we'll see. You'll tell us, I guess. First off, I'm going to be disappointed if Brewster and colleagues published in pediatrics. And I have been tempted. I have been thinking about doing it, taking some very well crafted discharge instruction, put it in chat GPT.
get the translation and give it to my Spanish speaking patient. Well, so that's exactly the question they're asking. They're saying, how does the accuracy and acceptability of discharge instruction generated by professional translation, Google Translate and Chad GPT compare across three languages? In this case, it is Spanish, Brazilian, Portuguese, and Haitian Creole. These languages obviously were picked because...
The Incubator (08:55.406)
these guys were from Boston, they did it in their health system and that's the languages that they needed to have translated to most commonly. There was no particular reason. Notably, that would work great for us. That would work great for us. And what's interesting is that they're not just comparing chat GPT, but they actually hired professional translators to use that as sort of a reference. And the study design is fairly straightforward. They took basically the discharge instruction that are standardized and that are...
provided by their healthcare system. The material I never really realized is developed at a sixth to eighth grade literacy level. And they follow recommendations based on clinical guidelines, systematic reviews and peer review publications. And they took basically 20 set of instructions about from 16 topics for like common clinical diagnoses. Remember, this is a pediatric study. So it has like it's not neonatology specific. Then.
The content includes precautions, some explanation about the disease process, some interventions, instructions for medications, prevention, supportive care, et cetera. And they took the instructions and they were translated from English into Spanish, Brazilian, Portuguese, which they just call Portuguese for. Like in the beginning, they tell you it's Brazilian Portuguese, but they call it Portuguese the rest of the paper, and Creole. And like we said, they use these three modalities, professional translation, child GPT, and Google Translate. Then they recruited eight clinician evaluators.
who hold credentials, I think that's very important, from their hospital to practice as certified bilingual providers. They were all practicing pediatricians in academic medical center and they were the ones who evaluated the translations. And they were all, all the Raiders were native speakers with formal education in the target language and proficient in English, obviously. Yeah, so that's really what they did. All right, so let's take a look at some of the data.
So for Spanish, Google Translate and ChatGPT scored higher than professional translation. So I was like, whoa. And they looked at that on. So you can go into the you can go into the methods. They basically had a rubric where they basically scored all these translations. So Spanish did better in terms of adequacy. It did better in terms of ChatGPT and Google Translate did better in terms of adequacy, in terms of fluency, in terms of meaning.
The Incubator (11:20.014)
And they said that a total of 38 % of responses preferred the Google Translate version, followed by the ChatGPT in 31 % of cases. So I read this and I was like, phenomenal. But that means almost 30 % preferred the...
translators. Yeah, it ends up being a little bit less than that. Exactly. What is interesting is that when it comes to these other languages, the trend did not continue. So for Portuguese, only adequacy rating were higher for chat GPT. Otherwise, there was no significant differences in fluency in terms of meaning or...
the severity across translation sources. When they talk about severity, they talk about the potential for errors and so on. And the professional translations were most commonly preferred in 43 % of cases. When it comes to Haitian Creole, the professional translation consistently outscored both Google Translate and ChatGPT for adequacy, fluency, meaning, and severity. And the professional...
Haitian Creole translations were more frequently preferred in about 50 % of cases. In terms of discrepancies, I think that was interesting that they noted discrepancies across language in the potential for translations to result in clinical harm or delay in care. And compared with 8 .3 % for professional Haitian Creole,
23 % of Google Translate and 33 % of Chad GPT translation were reported as containing clinically meaningful errors. Whether it was a poor description. They have like in the addendum, they have some examples and talks about like how they describe cyanosis, not using the proper color terms. So the parents may not be able to recognize this in time. And Chad GPT translations were reported as containing clinically meaningful error and the proportion of potentially harmful translations were overall lower.
The Incubator (13:25.678)
in the Spanish and the Portuguese compared to the Haitian Creole. And I think it goes back to maybe, again, I am not a specialist here, but like how these models were built. Maybe there's more ability for these models to learn more in Spanish than in other languages. And so I think that's interesting. So I think you can take that data as you wish. And the conclusion is that the authors say that their study provides key insights into the promise.
and limitations of using machine translation for clinical documents provided to families who speak other languages. And the utility of low cost and user -friendly translation tool is expensive and may enhance access to language -concordant care and health system without interpreter or translation services. However, unbalanced multilingual performance raises concern that machine translation system may not yet be a suitable alternative to professional translation, especially for languages of limited diffusion, as we just said, like Haitian Creole.
And by extension, even favorable performance for Spanish and Portuguese should be interpreted with caution and require further validation. And I think they're very, very correct in saying that amid the rapidly evolving landscape of AI in healthcare, their work reiterates the need for pragmatic patient -centered research, updates to clinical education, targeted regulatory oversight, and continuous quality improvement to ensure novel technologies are applied equitably across patient care. It's interesting. I'm...
I'm quite optimistic actually because I think optimally everybody would have a human that speaks their language sitting beside them as part of the translation and the discharge teaching. But like we know that that is not happening, right? Hospitals are not paying for that. At best this translator line, which is fraught with not always not always not optimal. And that doesn't help you with the discharge.
paperwork. So there are tons of units and hospitals where people are leaving with no discharge paperwork in their language. Right. It's a big problem. People take the discharge paper. They nod yes to everything because they just want to get out of there. And then once they're home, they're like, what do I do? What was I supposed to do? So I don't know. In my opinion, I think the question should be.
The Incubator (15:41.07)
Is it better than nothing? Which is what is still happening at plenty of hospitals? I must say that if that's your question, when you look at the example of potentially clinically significant errors, you will look at them and you'll say, that's fine. I'll tolerate that. Right. Because, for example, maybe you'll appreciate that. They are saying that there was an error in the terms of terminology. And they said that at some point, the word levar was used, meaning to physically move or transport.
which is used in the instruction for how to take inhaled asthma medication in Portuguese. And I'm like, all right, big deal. Yeah, and I think, for example, if I was going to read something that was translated into English, I think I would get it. Right. That's the question. Right. I mean, that leap is kind of difficult to make sometimes, depending on the level of education of the family. And sometimes people will.
get instructions from the doctors. They're going to follow to a T and right. I wonder. There's this famous French joke of the doctor runs into his patients and he sees that the pills are hung around his neck and the necklace. And he says, what's understood? And he says, what are you doing? It's like you said to suspend the treatment. Well, I wonder. I mean, communication is so interesting, right? Even when we're talking to English speakers, speaking to English speakers or writing things in English.
I wonder if AI can help us with visual discharge instructions. yeah. I don't think personally, I would say definitely not there yet. But yeah, that's a promise that should be something to be accountable. And I think that may help us even with English speakers, because I think so much is lost in this, both our verbal and written communication. Absolutely. Anyways, we could talk about this all day. We do not have the time for that. But that was a good introduction. Where are you taking us next? OK, I'm going to take you to these two articles that we've been trying to...
cover. This one in the Society for Pediatric Research. It is blood pressure and cerebral oxygenation with physiologically based cord clamping, a sub -study of the baby duck trial. The lead author, Shiraz Badr -Deen. So I'm going to be quick about this because I want to spend some time on the other paper. But again, this is a kind of a sub -study of the baby duck.
The Incubator (18:04.206)
So what they were really looking for is looking at delayed umbilical cord clamping and just some background. So this is, like I said, a sub -study nested trial. Infants were eligible for participation in baby duck if they were greater than or equal to 32 and zero weeks gestation at birth. They had a handful of exclusion criteria.
And then basically what they were looking at in the BB -Duck randomized control trial is resuscitation following initial stim was randomly allocated one -to -one within one minute of birth to either the standard of care where you had cord clamping occurred quote unquote early, and I'll talk about that prior to resuscitation or the physiologically based cord clamping where...
It was defined as ongoing vigorous stimulation and or respiratory support commenced prior to umbilical cord clamping. So infants in the PBCC or that physiologically based cord clamping group received positive pressure ventilation and had umbilical cord clamping deferred until greater than or equal to two minutes after birth and until greater than or equal to 60 seconds.
of exhaled carbon dioxide was detected on like a disposable CO2 detector. So basically what they were doing is ensuring that the pulmonary circulation was established prior to cord clamping in the intervention group. And infants in the early cord clamping group had umbilical cord clamping immediately after randomization and they were transferred to kind of the resuscitation table.
prior to commencing their resuscitation. Infants who were vigorous immediately after birth were not randomized and received two minutes of the deferred cord clamping. So it was just clamped after two minutes with kind of just routine observation. Okay, so that's kind of the background. So what this nested study really wanted to look at was in this group of babies, kind of the immediate...
The Incubator (20:22.702)
So they wanted to look at how did it modify blood pressure and how did it modify cerebral tissue oxygen saturation immediately after birth. So I'm going to just kind of get to the punch line. So among late preterm and full term infants receiving these varying levels of resuscitation, the blood pressure.
at three to four minutes and six minutes, and the cerebral tissue oxygen saturation are not influenced by timing of cord clamping in relation to establishment of ventilation. So they really didn't see changes in either, so no real difference. And then they provide us with some reference ranges for both of these markers in the late preterm and full term infants who are receiving delayed cord clamping. So.
I thought that was interesting just to basically set us up for the next paper, which is a randomized clinical trial. So ventilatory assistance before umbilical cord clamping in extremely preterm infants. This is in GMN Network Open. The lead author is Karen Fairchild, and this is from the Vent First Consortium. So they wanted to look at whether assisted ventilation in extremely preterm infants, so 23 and O.
to 28 and sixth, seventh week gestation, followed by cord clamping, reduces IVH or early death. So Vent -First is a kind of one -to -one parallel stratified randomized clinical trial. It's conducted at 12 centers in the US and Canada. The primary outcome was any grade of IVH on a head ulcer sound at day seven, but then they said day seven to 10 or death before day seven.
So basically the intervention is similar to what they were doing in Baby Duck, but after birth, all infants receive stimulation and suctioning if needed. And then from 30 to 120 seconds, infants were randomized to the intervention, received continuous positive airway pressure if breathing well, or PPV if not breathing well, with cord clamping at 120 seconds or two minutes.
The Incubator (22:38.254)
And then the control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. They also pre -specified two analysis cohorts. This group of babies who were quote unquote not breathing well within 30 seconds after birth and those who quote unquote were breathing well within 30 seconds after birth. They enrolled singleton pregnancies initially but over time as the...
study teams became more comfortable. They did begin enrolling twin pregnancies. They enrolled between 2016 and 2023, enrolling women who were expected to deliver prematurely at, like I said, 23 and 0 to 28 and 6, 7th gestation. Other exclusions, higher order pregnancies, medical emergencies requiring immediate delivery, which is interesting because a lot of our, a lot of this cohort.
May fall into that category known major fetal anomalies severe fetal anemia high drops or decision not to pursue intensive care for the infant So basically I kind of gave you the basis of protocol but at each delivery a facilitator read the protocol script like at delivery they asked for assessment of breathing at 30 seconds so then that Put the baby into one of two groups the breathing well or the not breathing well group And then they announced the cord clamping time based on the study group
and then documented the infant status and interventions. So they had basically like, they split their cohort into one that was breathing well and one that was not breathing well. That's right. Interesting. So basically in both groups, just like a baby duck, initial steps of resuscitation are the same, tactile stimulation, suctioning the airway if needed.
for infants randomized to the intervention arm, one or two neonatology clinicians trained in the protocol were assigned to perform the intervention. And to be clear, the breathing well had nothing to do with the intervention. Correct. Meaning you were randomized into intervention or control. Right. And then once you were in that group, then they also looked at after you were born, did you breathe well, did you not breathe well? Exactly. Yeah. Yes. I think, I mean, they talk about this in discussion. They were particularly interested in these babies who are not breathing well.
The Incubator (25:00.91)
as opposed to the entire cohort. Might they do better if we could delay cord clamping and intervene, provide respiratory interventions at the same time? Yeah, I mean, that's something that if you haven't read some of the work from Anup Katheria, where he really is trying to make that difference between the vigorous versus the non -vigorous child. So I think that makes sense that you would look at these babies differently. Right, because the baby who's breathing well probably will tolerate some time without any immediate intervention.
But it's that group where we're like, well, they're not doing great. Should we tolerate delayed cord clamping? So this makes sense. The ones that give you some anxiety. That's right. And then I felt like people might be interested, OK, where are they resuscitating these babies for the especially the delayed cord clamping? So immediately after delivery, infants were placed near the perineum for the vaginal birth on sterile wrapped trays across the mother's thighs and for cesarean birth or sorry.
on sterile -wrapped trays for cesarean birth, or on freestanding platforms that were like right adjacent to the mom's bed for the initial steps of stabilization. They did use warming pads and plastic wrap to minimize heat loss. I thought that was interesting, especially based on the findings that I will tell you about. 30 seconds after birth, the infant received CPAP if breathing well, or PPV if not breathing well. They checked heart rate at 60 and 90 seconds.
And of course, if less than 100 beats per minute, ventilation corrective actions were performed based on NRP. To clarify, for infants randomized to the control group, the umbilical cord was clamped 30 seconds after birth if the infant was not breathing well or delayed up until 60 seconds if the infant was breathing well. After umbilical cord clamping, infants in both arms were transferred to the radiant warmer for continued stabilization and...
of other routine care in the NICU. Okay? The outcome assessment was any IVH, and I thought this was important. They were read first by the local radiologist, and they were read by one of three external radiologists. So they had to be validated by at least two radiologists, IVH. And I think this is really important. Yeah, because I think, actually...
The Incubator (27:18.862)
We see this a lot, that their discrepancies in the way that ultrasounds are read, there's still some objectivity to it. And actually, this is probably something that should be done in every study that is using IVH as an outcome measure. And if they did not agree, then it was read by a third radiologist. So they needed two radiologists to confirm the grade of IVH.
Secondary outcomes included Apgar scores less than five at five minutes, a lowest hematocrit in the first 24 hours, medication for low blood pressure, number of red blood cell transfusions in the first 10 days, death prior to 36 weeks post -menstrual aid, and severe brain injury, defined as grade three or four IVH, cerebellar hemorrhage, or cystic PVL on the seven to 10 day, or the 36 week head ultrasound.
They also included a number of kind of other 24 -hour outcomes, which you can discuss in a moment. So they had 570 eligible infants from 548 randomized mothers who delivered at less than 29 weeks. Notably, the median gestational age was about 26 .6, and that was pretty true for both groups. And they had 47 % female, 52 % male.
What else did I want to tell you? They had 526 singleton, 22 twin births, zero still births. And so in total, 570 infants were included in the analysis. So interestingly, they had assumed that 37 % kind of at the outset of the study design would be this group of not breathing well at 30 seconds. But actually they found that it was 47 and a half, almost.
almost half of enrolled infants were assessed as not breathing well at 30 seconds after birth. And they did a number of evaluations, calculations, and the results indicated that in the best case scenario, there was less than a 10 % probability of rejecting the Nell hypothesis. And so they recommended closure of the study at that point. But they did give us data for the cohort of infants.
The Incubator (29:36.942)
I told you the cohort of infants assessed as not breathing well at 30 seconds represented 47 % of the total cohort. They had a median gestational age of 26 and 43 % female. And those assessed as breathing well represented 52%, a median gestational age of 27 weeks, 51 % female and other pregnancy and maternal related.
information did not differ between the two groups. They had reasonable protocol adherence. So the protocol was initiated in 83%, 78 % in the intervention group and 88 in the control group. The most common reasons for inability to initiate included placental emergencies, 6 .3%, pretty similar between the two groups and precipitous deliveries within an adequate time for preparation in 8 .3%.
of infants in the intervention group and 3 .1 % in the control group. The median cord clamping time, including cases where the protocol was not initiated, was 120 seconds in the intervention group and 60 seconds in the control group. They had similar rates of immediate cord clamping where they decided to clamp right away, so less than 15 seconds. So in all, 570 infants, IVH on the seven to 10 day head ultrasound or death prior to day seven,
occurred in 34, almost 35 % of infants in the intervention group and 32 .5 in the control group. The adjusted risk ratio is 1 .02 and the confidence interval does cross one. So no significant difference between the two groups. And then split by breathing and not breathing.
In the not breathing well cohort, IVH or death occurred in 38 .7 % of infants in the intervention group. So you weren't breathing well and you were in the delayed clamping group and 43 % in the control group or risk ratio of 0 .91. No statistically significant difference in the group that was not breathing well.
The Incubator (31:54.126)
And then in the breathing well cohort, IVH or death occurred in 30 % of infants in the intervention group and 25 in the control group. Again, no statistically significant difference. There was a difference in the median lowest hematocrit in the first 24 hours after birth between the intervention and control groups. In the not breathing well cohort, it was 43 % compared to 39%.
And then in the breathing well cohort, the lowest hematocrit within 24 hours of birth was not significant between the two groups. Interestingly, there was no difference in blood transfusions in the first 10 days despite that difference in lowest hematocrit. Compared with the control group, infants randomized to the intervention group and assessed as not breathing well at 30 seconds had higher.
One -minute APGAR scores and were less likely to require endotracheal intubation in the delivery room. The median NICU admission temperature was 0 .2 degrees centigrade lower in the intervention group as compared to the control group in the not breathing well cohort. There was no difference in admission temperature in the breathing well cohort. Finally, for the intervention group compared with the control group, the
risk ratios of APGAR score less than five at one minute and hematocrit less than 40 % in the first 24 hours were less than one. They had no statistically significant difference in those measures as well. So their overall conclusion is providing assisted ventilation starting 30 seconds after delivery and clamping the umbilical cord at 120 seconds compared with 30 to 60 seconds of delayed clamping followed by assisted ventilation did not reduce the primary outcome of IVH.
at age seven to 10 days or death prior to day seven. There were no discernible differences in mortality, severe brain injury, or common morbidities of prematurity through 36 weeks post -menstrual age. So that's kind of a bummer. Makes it easier though. That's true. Because it's a lot of work. It's a lot of work. To resuscitate with the clamp open. That's right. 100 % very difficult. So yeah.
The Incubator (34:17.646)
I think this is interesting and I think that we will find out more about how to optimally manage these babies right after delivery. I think it's interesting to see some of these secondary outcomes where you can see that like in the not breathing well cohort of this last paper that you reviewed, sort of the rates of intubation in the delivery room favoring, some things are favoring the intervention, you know.
some less so and you're like, is this just noise, signal? It's hard to tell. But it's good because it helps us keep focused on just 60 seconds of delayed chord clamping. And we're still having, let's be frank, we're still having trouble getting there at our institution. It's so funny because as we are trying to get to 60 seconds, the OBs now are like, isn't it supposed to be 30 seconds? And it's like,
I know. Meeting after meeting after meeting. So we're working on it. Yeah. And I think there's room for growth there. But I guess it's not so bad if it doesn't if it doesn't come out to be more effective. Right. Because it is a lot of a lot of work. But we'll see. Lots of people are working on this. So we hope we will be reviewing more of these papers. All right. In terms of.
segueing into this. I don't really have a good segue. I'm going to talk about blood transfusions. There's a very important paper that's coming out in JAMA Network Open, lots of good articles in that journal this past few weeks. This article is called Clinical Practice Guideline for Red Blood Cell Transfusion Thresholds in Very Preterm Neonates. First author is Emoki Deshman, probably pronouncing this wrong, from the Neonatal Transfusion Network. And it's kind of rare that you get a group that...
puts out a paper that says, here are some transfusion guidelines. It's delightful. For a group to say, we've studied it, have enough data, let's be brave enough to put out some guidelines and standardize what we do. And they're introducing this by saying that in 2020, as we reviewed on the paper on the podcast, the two largest randomized trials comparing high versus low RBC transfusion thresholds in very preterm neonates were published. We're talking about the top trial and the ETTNO trial.
The Incubator (36:41.678)
And we have some idea as to how these recommendations align. They are not far off from one another. And the question they're asking is that when should RBC transfusion be given to preterm neonates with anemia to improve clinical outcome, including survival and long -term development? Now, this was an international steering committee that was established, which basically included members from the neonatal transfusion network in Europe and in the US. And these guys had...
expertise in the field of neonatology, in the field of hematology or transfusion medicine, and in epidemiology. Interestingly enough, parental values and preferences were provided by a group of parents representative set up by the European Foundation for the Care of Newborn Infants. And the PICO question that they asked with a list of potentially relevant outcomes were developed, prioritized, and agreed upon by the steering committee.
The critical outcomes for decision -makings were survival, short -term morbidity, like BPD, IVH, PVL, ROP, and NIC, and major neurodevelopmental disability at two years corrected age and at school age. They looked at weight gain and adverse outcomes, and they defined two PICO questions, and they were based on short versus long -term outcomes. So the first PICO question was,
in preterm neonates less than 30 weeks of gestation, what are the implications of using a high transfusion threshold intervention compared with a low transfusion threshold during their hospitalization for survival, short -term morbidity, and transfusion -related events, and looking at weight gain at term post -menstrual age? Then they had a second PICO question, was that for the same babies less than 30 weeks, what are the implications of high versus low transfusion threshold?
for mortality and major Neurodevelopmental disability at two years, corrected age, and for social and behavioral problem at school age. They're very clear that they were not able to make recommendations when it comes to volume of transfusion and rate of transfusion. They put the steering committee and the broader stakeholders, including parents, it's very interesting, placed a high value on avoiding exposure to RBC transfusion if there was no clear evidence of benefit.
The Incubator (38:51.15)
And I think we tend to forget that parents would like, most parents that I've spoken to, would like to avoid blood transfusions at all costs if that's possible. Moving forward with the evidence to recommendation, the group considered criteria in the grades evidence to decision framework, and they came to a consensus on every recommendation. These recommendations that we're going to talk about may not apply to patients with acute decompensation or acute bleeding. Very important to remember that. Your critically ill patient may not be the one you want to...
look at when we're talking about this. Clinicians should also consider higher threshold for patients with sepsis or NEC, neonates requiring vasopressor or inotropic support, patients with previous intrauterine or postnatal exchange transfusion. The recommendations are also not applicable to babies receiving ESAs, erythropoiesis simulating agents like EPO and DARB EPO, since they were excluded in the evaluated RCTs. So now.
done all this then we can go into some of the recommendations. They looked at a systematic review of six randomized control trials involving basically 3 ,500 participants and these trials compared high versus low hemoglobin based and hematocrit based threshold for transfusion. In preterm neonates with less than 30 weeks of gestation we see that the authors recommended a restrictive PRBC transfusion strategy and in
it's outlined basically in table two of the paper. And it's done in a way where you have, they give you both the hemoglobin and the hematocrit, so you can use both. And then they give it to you based on how old the baby is, so whether it's postnatal week one, week two, week three, or more, and then whether the baby is on respiratory support or not. I'm going to go through this so that we all can talk about the same language. So in terms of looking at the hematocrit, if you are on respiratory support, the transfusion threshold,
is 33 in week one, 30 in week two, 27 in week three. If you are on no or minimal respiratory support, then the thresholds are 30 in week one, 25 in week two, 21 in week three. Brace yourselves. But it's interesting because I'll tell you an example that we had in the unit this week where this can be very valuable.
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They recommended hemoglobin threshold at different age of different time points in the baby's life. And when they looked at respiratory support, which is nasal cannula flow rate of one liter per minute or any form of, or more, or any form of positive airway pressure, that's when the recommendation changed.
So in terms of the PICO questions that they ask. So before I guess I get into some of these answers, it's interesting, right? I mean, I had a baby recently that was week three, right? And you see based on the hematocrit, like it makes a huge difference. Like if you're able to take this baby on room air, then your threshold for intrusion is 21. If you're on any form of respiratory support, it's 27. So big difference. If you have a crit of 25,
then that's the deciding factor. How will they do on Romare? So for the PICO question regarding the short -term outcomes, a low threshold compared with a high threshold had little or no association with survival at any time point based on five trials. Similarly, there was little to no association with survival up to two years, BPD, severe IVH, severe ROP or NEC.
And for the outcome of PVL, a low threshold compared with a high threshold probably had little or no association, they write. For death and neurodevelopmental impairment at two years corrected age, there was little or no difference between the low and the high threshold based on three trials, looking at about 3 ,000 patients. And studies reporting on outcomes at school age are ongoing from the NICHD, Neonatal Research Network. Several small RCTs have...
assessed the association of transfusion volume with various clinical outcomes. However, none of these trials was powered to assess relevant clinical outcomes such as mortality, long -term neurodevelopmental outcomes, or substantial morbidities. The rationale for the recommendations, the recommendation for the low threshold was based on consistent evidence from multiple randomized controlled trials addressing both PICO questions that showed little or no benefits of a high threshold on the short term and the two -year outcomes reported.
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And so for that reason, there's really no reason to expose the baby to more transfusions. And they do acknowledge, however, that the school age children studies are ongoing. And so Lord knows, maybe those studies are going to come back and suddenly we're going to revert all the way. But for now, at least that's the best evidence available. And so the conclusion are that the consensus statement reports on the development of a guideline by an international steering committee. I will add to the words of the author.
that include parents, I think that's very important, and that the steering committee recognizes the important additional clinical consideration, including clinical status, comorbid conditions, we mentioned that, don't forget, and parental values and preferences. The recommendation is conditional based on moderate certainty of evidence, and the parents should properly be informed about the complexity of neonatal transfusion medicine, including the known benefits and the remaining uncertainties and unanswered questions. Given the uncertainties, parental views and preferences should be considered in the decision -making process.
very well done paper. Ravi Patel is on there. There's a bunch of people that we know. But yeah. It can take some getting used to. It's funny because I mean, we've certainly shifted our transfusion parameters based on the evidence a number of times. Thanks. Thanks to you. That's the first thing. The first thing I did, I went back and I was like, my God, like how far off am I? And we're not that far off. But I mean, the
I mean, at the end of the day, whatever we used to draft our own local guidelines were based on the same trials they were looking at. So we're not that far off. Yeah. So I don't go to 21. And I was like, I'm going to be honest. It makes me very nervous to go to 21. You know, so we're very excited today because not only do we get to review this paper, but we also have the pleasure of having on with us Dr. Ravi Patel, who's one of the authors of these new transfusion guideline.
Ravi, thank you so much for making time today to be on the show with us. Thanks, that is Daphne. And I know Melki Deshmand, who led this, was disappointed at all on holiday, so I'm glad I could join in. It's the blessing and the curse of what we're doing, trying to always review papers relatively quickly, that sometimes the turnaround is a little bit quick for us to get on the phone with the authors. Daphne and I wanted to maybe start off by asking you that,
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What your thoughts are on this consensus statement because it is pretty unique and rare for a group to come out with almost like a transfusion protocol. I mean, as a resident, I remember I was looking far and wide for it and everybody's always on the fence about publishing their transfusion protocol. But for the first time ever, we have a protocol being published in a major peer review journal. What was the impetus for doing that?
Yeah, that's a great question. You know, I think clinicians often are looking for guidance and this happens sometimes at the hospital level. You know, it's an opportunity to make it easier for those that are practicing in the NICU. If you think about, you know, your last time rounding decisions about transfusions and, you know, any week on rounds, it's a pretty common thing. But when we do that guidance, I think there is a formal process to think about the evidence, consider it, read how certain it is, then from there,
engage kind of the values and preferences of clinicians, of parents, of various stakeholders, and then come considering all of that come to recommendations that they can help guide care and make it easier for the practicing clinician to provide evidence -based care. So we've reviewed the article, but tell us a little bit about, you know, why you thought, like, why did we have to review it so quickly? Why do you think people need to start using
and the guidelines right away. So, you know, guidelines are only as good as people if people are aware of it. And one of the challenges is evidence implementation gap. And I think you're the incubator does a great job of getting the evidence to people. And so that's part of the impetus is, you know, we want people to be aware of these guidelines. So if they're either they don't have red, so again, transfusion guidelines, and then if you this is a great way to start if you do and you're reconsidering it or you want to think about revising it, we hope that this can be useful.
It is a common decision. And one of the values of these guidelines is we have evidence from a number of trials that we can consider. So this is something where there is all this evidence out there. And our goal is to help translate that evidence into practice. And I think these guidelines can help with that. Let me ask you a question, Ravi. In many of these trials, we talk about hemoglobin. Even though everywhere I've worked in the NICU, we use hematocrit. Can you tell us a little bit why?
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Hemoglobin is making a stand in all these papers on transfusion. Now there's a little bit of a preference towards Hemoglobin. I think either is okay. You know, we ended up actually discussing this and decided to report both because some places like hematocrit, others like Hemoglobin. And we want this to be implemented, you know, not people to change the way they measure either, but really to be able to use this. So that was more of a...
Just to align with people's focus. More to remain inclusive. Fine. So there's no, because I was legitimately wondering this at some point. I was like, is there a benefit to just tracking hemoglobin instead of hematocrit? Or, I mean, I know they're kind of the proxy of one another, but I was like, maybe there is a benefit. I don't know. But so I thought, you know what, since we're having you on, I was going to ask you. They're pretty well correlated. And so in the range of the decisions you're going to make, they're pretty close to one another.
Now, our unit, for example, has been following the data. We've been kind of making adjustments to our protocol. We've talked about this a little bit, but for people who might say, you know, this is a far from our current standard or transfusion practice, you know, who may still feel weary about making such a big change. And I think you're the right person to ask this question to, obviously, with your huge involvement in the study of...
let's say NEC. So when people are saying, well, I'm still concerned about NEC and the association of anemia. Can you speak to that and how we can feel more comfortable using the guidelines? Yeah, and we can maybe just briefly talk about the guidelines. These are for preterm infants less than 30 weeks of station and the recommendations are conditional recommendation for use of a lower threshold. And we try to make it simple. So for babies, our rest of your support in this is defining the guidelines.
11 10 9. So that's kind of the way the memory tool during rounds is 11 10 9 11 in the first week, 10 grams per deciliter second week, nine grams per deciliter third week, that's kind of the general guidance for these guidelines for thresholds for routine transfusion. How you know, we had a lot of kind of preferences elicited and most parents and clinicians would say if there's not a clear benefit of using a higher threshold, that we would prefer to avoid transfusion. And that was the general
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general kind of consensus among the group. And that's what came out of the data. It wasn't clear that there was really any clinical benefit with regards to the important outcomes we assessed with being more liberal or using a higher hemoglobin or hematocrit threshold. And that kind of led to the recommendations. They are conditional. And so there's moderate certainty of evidence. So, you know, with conditional recommendations, I do think these might apply to every patient and clinicians need to use their expertise and judgment for patients where they think that, you know, that that
might need to be transfused differently than the guidelines recommend. But this at least can provide guidance and can reassure also when we synthesize the evidence, I think to your point, Daphna, if there are people that are concerned, you know, you can look at the evidence and really this shows that if you follow these guidelines, the best available evidence says that at least with these algorithms, the risk of NEC, for example, doesn't seem to be increased with the use of a lower threshold.
Now, if you use lower than these guidelines and you're more, you know, if you're more restrictive, then that's a little bit uncertain. And so for some NICUs, this might be that they're actually even lower than these using hemoglobin wrap, which is lower than these guidelines. They may actually have to increase their thresholds. And so that depends on kind of where people started off with.
Thank you for that review. And you did mention briefly, and we've talked about it in our review about the parent involvement in these guidelines. And that's really quite novel. I mean, we talk about families being integrated into the decisions and shared decision making, but it's rare for patients to be involved in guidelines. Can you talk a little bit about that? Yeah, so the EFC &I is this wonderful organization in Europe and their involvement was supported by the New Neal Transfusion Network and really our colleagues in Europe that
that provided this. And so they actually were really central to help give input on what were the most important outcomes we should consider when making these transfusion decisions. So the importance of the outcomes that we assess and then what the values and preferences would be regarding the approaches and weighing in on the recommendations. And so this was important. They were part of our stakeholder panels and really provided input and multiple steps along the way and really a credit to our
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colleagues in Europe who, including Amoky Deshvan and others, that really helped to engage this group. And I think it's important when we're thinking of conditional recommendations versus strong and when we have recommendations that might vary, the variance might be because we should elicit the values and preferences of families in terms of decisions regarding transfusions, but this applies broadly to other clinical dimensions.
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Yeah, that's very interesting. I'm just curious also as we conclude this Q &A of what are your thoughts on the numbers? You said 11, 10, and 9. I mean, I found that the numbers in the first week of life have gotten, I guess, higher than we tended to think before the ETTNO and the top trial came out, where we often let babies really go much below. I thought to me that was the biggest...
change that we've seen coming from the data and obviously as a secondary measure from the transfusion guideline that in that first week, we really have to be careful about the hematocrit and the hemoglobin for these babies. Yeah, the depots of respiratory support, if babies are on no respiratory support, it is a little lower. So 10, 8 .5 and 7 over the first, second and third week. But that is important. And I think one of the emphasis is, these are the thresholds that were tested. So we have to be a little cautious about saying,
we can just avoid transfusions altogether without risks. I think that needs to be shown to be safe, but at least we feel that with the data that we have for these thresholds, if clinicians follow that, that doesn't increase the risk outcomes. And conversely, also, if clinicians use a higher threshold, that actually didn't seem to worsen outcomes either. So I think it's important to, when we look at that data,
the use of a higher threshold did lead to worse outcomes, but most people would say, you know, if there's not a benefit to giving more red cell transfusions, then why do it? And I think that's where we, that's kind of the rationale for use of a lower hemoglobin threshold in that recommendation. Last question. How hard was it to come up with the sentences around adjusting these thresholds for patients with NEC?
Yeah, that, you know, that is, there's always unique circumstances. And so, you know, these guidelines are for the general patient, but, you know, we want to, you know, clinicians should use their judgment and say, this patient is really sick. Maybe we think they need to be transfused differently. I think that as centers implement the guidelines, and there might be people resistant to this, I think it's always important to think about.
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that this isn't a strict, rigid protocol, but this is guidance for the clinician. And in general, this can be used, but they can always use their judgment if they need to transverse differently.
Ravi, thank you so much for making the time to come on the podcast and discuss this great article. Congratulations again on your really making such a difference in this field, in the field of neonatal transfusion medicine and also all the work you're doing in the field of NEXT. So we are very thankful for all the time you're spending helping us move along. Thanks to both of you. And I really wanted to give a big shout out. I know that they can enjoy, but the authors who led this effort, as well as the people who joined in the stick -hole panel and to the...
people listening, this is open access, go take a look at it, download it, maybe this can help stimulate some changes in your group and really appreciate the opportunity to be on. Thanks, Ravi.
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I have one more paper, I think, and then one more, one op -ed I want to share. So this is entitled Early Skin to Skin Contact on the Risk of Interventricular Hemorrhage and Substance and Preterm Infants. Lead author Maria Johansson. This is an act of pediatrica and it's coming from Sweden. So notably, it's an observational study with data from 2015 to 2021 extracted from the
SNQ, that is the Swedish Neonatal Quality Register, and all neonatal units in Sweden report to the SNQ, featuring 98 % completeness of data for preterm infants. So that's pretty good. So they really wanted to look at the groups of babies who were getting kind of immediate skin -to -skin care, early skin -to -skin care. They looked at a number of variables and...
including cumulative hours in skin -to -skin care per calendar day and mean hours per day in skin -to -skin care during the hospital stay. So these are things that the SNQ already collects. They have all of these variables included, which I think is a great place to start. So they really wanted to look at the exposure they were looking for as skin -to -skin care on day zero.
and or day one after birth. So they got the like full 24 hours compared to no skin to skin care on day zero and or day one. Again, so they didn't miss anybody regardless of the time of birth. And their outcomes were all IVH and all sepsis in the extremely preterm infant and the very preterm infants. You're presenting a lot of papers with IVH as a primary outcome today, huh? That's true.
I didn't recognize that, but that is true. A reminder of our verbiage where we are, very preterm infants are those born between 28 and 0 and 31 and 6, and the extremely preterm infants are those born before 28 and 0 weeks. But as we know, that is becoming a much bigger group. I will mention...
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I'll mention just right off the bat, one of the major limitations is obviously missing data in the register. So if there was no documentation of skin -to -skin care, that baby was coded as not having skin -to -skin care. If there was no documentation of IVH or sepsis, they were coded as not having those things. So of the extremely preterm population, those born before 28 and zero weeks, 20 % were exposed to early skin -to -skin care.
And of the very preterm infants, those between 28 and 0 and 31 and 6, 58 % received the early skin -to -skin care. This was a pretty healthy group, the mean birth weight of infants exposed and not exposed to early skin -to -skin care. So those exposed was 1 .3 kilos, those not exposed 1 .0 kilos.
The proportion of infants exposed and not exposed to early skin to skin care that later died, 5 % in exposed and 17 % and not exposed. So very interesting. And sorry, I wanted to talk about, so we talked about the median gestational age, but we talked about the birth weight, but I wanted people to know the median gestational age, so.
In the no skin -to -skin care group, the gestational age was 27 .3, and the early skin -to -skin care group, 29 .4. So a bigger, older group of babies. And then they wanted again to IVH. So for IVH, all IVH in the exposed to early skin -to -skin group was 11%, and the not exposed,
was 27%. This corresponds to an adjusted odds ratio of .67, and this was statistically significant. There was no statistically significant difference in the proportion of the extremely preterm infants with IVH in the exposed and not exposed to early skin care, though there was a difference in the very preterm group. The proportion of IVH in infants exposed was 8 % as compared to not exposed.
The Incubator (01:01:16.462)
13%. The proportion of all infants with IVH grade three to four was 3 .4 % in early skin to skin and 9 .9 in the not exposed group, but this was not statistically significant. Then they wanted to look at sepsis. The proportion of infants with sepsis in the exposed group was 16 % and not exposed was 30%, respectively. This corresponded to an odds ratio of 0 .47 and this was statistically significant.
significant. However, the adjusted odds ratio was not statistically significant for sepsis. For extremely preterm infants, those exposed 29%, not exposed 44%, this was statistically significant. And the proportion of extremely preterm infants with verified sepsis,
The Incubator (01:02:12.462)
Sorry, hold on a second.
The Incubator (01:02:17.582)
Okay, sorry, that was sepsis in the extremely preterm. There was no difference in proportion of sepsis in the very preterm group. So, there are some differences between the groups that received early skin to skin care versus those that did not. Obviously the main limitation of the study is that this is a register study design. There are some differences in the two groups.
Infants exposed to early skin -to -skin care had a higher mean birth weight, lower proportion that later died. This was kind of a healthier population. And they do describe an additional limitation is we don't know how skin -to -skin care was done. So... Because it's a registry. That's right. So there's not a lot of that extra data and it wasn't, it's not a randomized central trial. So it wasn't protocolized. So obviously some teams are doing skin -to -skin care but with head midline.
So something to consider and some teams potentially are not because routinely skin -to -skin care is not done. Kangaroo care is not done with Edmond line. So there's no data on turning of the head. But it's an interesting study nonetheless. I think it's to me it's a frustrating study because it addresses some of the things that I definitely want to talk about. But I just wish the data was a little bit cleaner because I think that's the issue. I mean we can talk about our unit but like we have these bundles that...
are applied to a baby based on gestational age, for example. You say, okay, the baby is less than 30 weeks, so we're going to have a neuro bundle or whatever you guys call this thing in your own institution. And then you try to then minimally move the baby and you want to really prevent IVH. But then the question becomes, okay, maybe in a 22 -week -old, that's a great idea. But like in the 29 and two, when could...
What is more beneficial for that baby? Is that more beneficial for this baby to be on the mother's chest or to remain untouched the first day or so to prevent IVH? That's an interesting question. Yeah. That I don't know what the data might show. And this paper with the limitations of its data seems to point to there is a benefit to early skin to skin. And while it's interesting that I review this paper as well with Gabriel on the French podcast, like some people might say.
The Incubator (01:04:43.886)
Not that he said that, but like some people might say, well, the babies are big. But maybe that's the population we want to study. Maybe that's true. The 300 gram 22 weaker, you don't want to move. But the one kilo kid that's 29 and one, isn't that better for this kid to be doing skin to skin on day one? I don't know that this might not be the right answer. And maybe that's the population we should study. It's just unfortunate that the two groups were so different. But man.
I mean, I do think that the available data is moving towards we can push our limits, right? We can probably do it earlier. We can probably do it younger. We can probably do it on smaller babies. And so at the very least, I mean, there's no excuse for not doing skin to skin and like a term baby on day one. There's literally no excuse. And then these, you know, getting into the, you know, moderately preterm. Yeah, it's the neuro bundle kids basically.
And I think if you listen to the podcast, then you listen to someone like Nora Coleman, who's trying to basically design the environment around the bed so that you could do some of these more tedious procedures, moving a baby from bed to chair, doing it safely, and then maybe it's all these things together that would allow us to do skin to skin on an IVH, on the baby at risk for IVH, and do it successfully. Yeah, and I think, I mean, the available data is actually leaning towards that.
might be neuroprotective, right? So we might be causing harm by not doing it. So I think we're refining it. I'm still not going to present this paper, but I have one paper that I prepared that keeps getting pushed back. I'm going to mention it because it's a paper in the archives of disease and childhood called Kangaroo Mother Care Improves Cardiovascular Physiology in Preterm Infants. It's an observational study. I don't have time to go into it. I want to review something else about therapeutic hypothermia and we're very low on time. We're basically out of time. We're basically out of time. So.
This paper is getting pushed yet again. But yeah, I mean, like you said, skin to skin makes things easy. It's more stable, especially from a vinyl sample. Okay. How am I going to do this in quick fashion? Five minutes. Holy shit. JAMA Network Open, Mentaldo and colleague, the Comet trial group, whole body hypothermia versus targeted normothermia for neonates with mild encephalopathy, a multi -center pilot randomized clinical trial.
The Incubator (01:07:03.95)
It's a pilot trial. The way we approach mild HIE is fascinating. They say, they mentioned some data that I was like, my God, the Canadian Neonatal Network, the California Perinatal Transport System and the New South Wales in Australia have reported that created an 80 % of neonates with mild HIE receive hypothermia. I would have not guessed 80%. That's a lot. And by the way, I have treated babies with mild HIE with hypothermia.
We're going to talk about initiation of hypothermia within six hours. I've done it past six hours. So I'm by no means standing on high grounds and judging people. And I think and I and I did this knowing the evidence, knowing that there was not much basis to that. And so I think it's a it's but it's fascinating to see how we are our whole field. Yeah, it's shift is shifting slowly.
And they're talking about this widespread therapeutic drift that has raised concern about the lack of equipoise for conducting an RCT because people are cooling. And so you're like, I don't want to study this. I just want to cool. And I said, I've called these kids. I mean, in mild HIE, they mentioned how it's a very interesting point that the brain injury is primarily seen in white matter rather than in the deep brain nuclei. And that.
white matter is associated with metabolic perturbation in the thalamus, even in the absence of visible injury to the brain nuclei and conventional MRI. So they basically also referencing some animal studies that are showing how in the Murine model of neonatal mild HIE, even short periods of hypothermia are highly neuroprotective, like three, four hours. They wanted to thus find out if whole body hypothermia initiated within six hours of birth and continued either for.
48 hours or maybe 72 hours had any effect on MRI and spectroscopy biomarkers in babies compared to normal thermia in babies with mild HIE. This is an open label multi -country pilot RCT that includes six centers in the UK and in Italy. They looked at data from 2019 to 2023 eligible babies that had to be above 36 weeks, above two kilos. The inclusion criteria, they had to have evidence of an intrapartum hypoxic ischemic event.
The Incubator (01:09:22.062)
Evidence of mild HIE. They have the whole breakdown of how they scored the Sarnath. I'm going to let you go through that. Normal amplitude on amplitude integrated EEG performed for at least 30 minutes between one and six hours of age. Excluded, obviously babies with moderate or severe HIE, babies who had seizures or had received anti -seizure medication before randomization or who had moderate or severe abnormalities on their EEG. They did conventional MRI at four to seven days.
The intervention was either normothermia or hypothermia and then you were split between 48 or 72 hours. The way they did hypothermia was fine, rectal temperature, blanket, the whole thing. Nothing really to write home about. Outcome, primary outcome was thalamic N -acetyl aspartate, the NAA, I know I'm banging the desk, NAA concentration in millimole per kilo. And then secondary outcome were the ratios of thalamic lactate to NAA.
and the NA to creatinine peak area metabolite, brain injury scores on MRI at one week, and mean duration of hospital stay. OK. Basically, it's interesting to read because as clinicians, we're making a mess. This whole study ended up being messy because babies were cooled outside of protocol. I'm going to give you some data instead of just blabbering.
57 % of eligible neonates were approached for participation. That was 129 parents. And 20 declined, 101 were recruited. 47 % were younger than six hours. And 52 % were six hours or older at randomization. Again, you're seeing that it's hard to stay within that time frame of zero to six. The median age at admission to the cooling center were one hour for the normothermic group, 3 .3 hours for the 48 hour group. And...
0 .7 hours for the 72 -hour group. At randomization, so that was at admission. The median ages at randomization were four hours in the normothermia group, 36 hours in the normothermia group, 28 hours in the 72 -hour hypothermia group. So, a few more things.
The Incubator (01:11:42.51)
More neonates were randomized to 48 hours and 72 hours required invasive ventilation. The mean duration of invasive ventilation was longer than in the no more thermic group. Although no neonates randomized within six hours were sedated that neurological assessment, opioid administration during the first two days occurred much more commonly in the babies that were cold. Shivering happened much more in the babies that were cold. The median hospital stay was longer.
in the babies that were cooled. And in the 72 -hour group, they mentioned how one neonate passed away 24 hours after birth due to early onset E. coli sepsis with subsequent septic shock, and there was no other serious adverse events reported. Interestingly enough, they mentioned how four neonates recruited developed electroclinical seizures beyond six hours after birth. One in the one...
each in the normothermia group and in the 48 -hour group and two in the 72 -hour group. And I think that some of them in the one in the normothermia group ended up being cooled, but they didn't intend to treat. Looking at primary outcome, I think this is what we're looking at right now. The magnetic resonance imaging performed in 98 % of the cohort, short normal results in 53 % of the normothermia group, in 27 % in the 48 -hour group and 34 % in the 72 -hour group.
in terms of these NAA concentrations. And I'm not going to go through everything, but the NAA concentration in the 48 -hour group were 8 .36. They were, in the 72 -hour group, they were 9 .02. And they were 10 .98 in the normothermia group. So just for clarification, in case we forget this, N -acetyl aspartate is a marker of neuronal integrity.
And basically the authors mentioned how a reduction of one millimole per kilo of thalamic NAA is associated with the reduction of five to 10 units on the belly at two years. But that usually you don't see much moderate or severe disability as long as the levels stay sort of above six. And so they make a comment that's saying it's interesting how the NAA concentrations are lower in the babies that got cooled.
The Incubator (01:14:01.39)
But yet in the end, the numbers are still good enough that they're not in that range that's concerning for moderate to severe disability. I'm going to go to the conclusion. Those were the primary outcomes. They mentioned how this is a pilot RCT. And they mentioned how whole body hypothermia did not reduce brain injury, as measured by quantitative MR biomarkers, but increased the need for invasive ventilation, hospital stay, the use of opioids.
and that an RCT of whole body hypothermia versus targeted no more them is feasible in mild HIE despite extensive therapeutic drift, but will require training and sterilization of neurological assessment. And until safety and efficacy is established, we suggest they say that the whole body hypothermia should be offered to neonates with malice only within the context of an RCT and hypothermia should not be initiated without performing adequate neurological assessment. I have to show you this because in the in the supplement, there's this.
recruitment site and number of neonates randomized within six hours versus those randomized after six hours. And basically you can see that like in blue are the ones that are randomized after six hours. And you can see that so many of them. There's like one center in Italy that did very well. They randomized everybody within six hours. But it's hard. Like many babies show up. It's more than I would have expected. Yeah, absolutely. But I guess that makes sense, especially in the mild group. Right. So.
Yeah. Yeah. I think to me, at the end of the day, what does this paper show? This paper shows nothing that you don't really we don't have evidence. It shows we don't have evidence. So it's not telling you to cool. And it's telling you that it's telling you that if you're going to call these babies, you should have it done in the context of an RCT. However, what it demonstrates very clearly is that we're all over the place. We're all over the place. We're all doing stuff and there's not much evidence. And it's scary, I guess. Yeah.
But again, we're right in the, we're going to see a few more papers coming out about cooling the mild group and then hopefully we'll make a decision about it. And granted, like I said in the beginning, I'm more of a cooler. I will lean towards cooling. Even mild cases. And knowing full well that there's not much ground for evidence. I have long discussion with families. With the families, yeah. We'll do some shared decision making. But I mean, this paper made me think about, is this,
The Incubator (01:16:24.686)
truly like, I finished the rub and was like, what am I doing? Well, I think that's why a paper like this is very important to at least give you pause and say if you're not sure. So I really enjoyed the reading of this paper. It's a very important beginning because as I said, it's a multi -centered pilot trial. So more is supposed to come. Yeah, it was interesting to take the step about.
head versus whole body when we really haven't even addressed like, should we call mild kids or not altogether, I guess. Yeah, I think, yeah. I think, but I think that's all going to come forward in the evidence. All right. I want to just, I don't have a paper. I'm just going to - No, this op -ed. This op -ed by Dr. Sarah Swenson and Dr. Shetal Shah in the Pioneer Press, but they're -
opinion paper has a great headline. The mental health of new dads needs attention too. I'm not going to read the whole thing, but I think their first line says it all. This Father's Day, we must confront a national reality. We are failing new fathers. And it is a reminder that the AAP calls for screening of all parents whose infants require care in the NICU for postpartum depression. I'm not even sure people really know that that is part of our recommended guidelines that...
All parents, NICU infants, of infants in the NICU should be screened for postpartum depression. I mean, we're hardly doing that for the birthing parent. So I certainly think dads, non -birthing parents, are not getting routinely screened. Obviously, they discuss the significant barriers for our NICU teams in doing this. But we overcome significant barriers for lots of things in the NICU. And so...
we shouldn't leave out mental health screening for families and that fathers are especially going unrecognized. When you think about it, they mentioned this in the op -ed that options are limited for fathers seeking mental health care, many of whom do not have insurance or primary care physicians. And while most states have extended Medicaid coverage to mothers for a year, there's no such provisions for fathers. That's right. So even if they wanted to. No.
The Incubator (01:18:45.358)
They could hardly get it. So it's definitely a place for an opportunity in our units to connect people to the services that they need. And this is, like you said, it's in the Twin City Pioneer Press, so it's fully available online. So it's not a PubMed article. You guys can read and write that right now. Daphne, this was fun. Thank you for another great episode of Journal Club. As always, we'll see you all next week. Sounds good. Bye. Bye.