Hello friends 👋
After a splendid week discussing thermoregulation, we are back with a new episode of Journal Club. This week, we touch on a variety of topics, including GERD, proteomic predictors of BPD, developmental significance of short apneas in former preemies, and much more. We also review a touching study looking at parental perspectives on neonatal autopsy and organ donation after the loss of a baby in the NICU.
As customary, you can find articles, notes and transcripts below.
Stay tuned for our upcoming episode next week where we sit down with the EBNEO team to rank the articles competing in the article of the year campaign.
Have a nice sunday!
The articles covered on today’s episode of the podcast can be found here 👇
The Irritable Infant in the Neonatal Intensive Care Unit: Risk Factors and Biomarkers of Gastroesophageal Reflux Disease. Njeh M, Helmick R, Alshaikh E, Marcano K, Alexander A, Osborn E, Jadcherla SR.J Pediatr. 2023 Sep 29;264:113760. doi: 10.1016/j.jpeds.2023.113760. Online ahead of print.PMID: 37777170
90 versus 60 min of early skin-to-skin contact on exclusive breastfeeding rate in healthy infants' ≥35 weeks: A randomised controlled trial. Raj Kumawat S, Vyas H, Mohan R, Sasidharan R, Yadav B, Gupta N.Acta Paediatr. 2023 Oct 31. doi: 10.1111/apa.17021. Online ahead of print.PMID: 37905336
Trends in infant mortality due to haemolytic disease and other perinatal jaundice in the USA, 1999-2020. Vidavalur R, Bhutani VK.Arch Dis Child Fetal Neonatal Ed. 2023 Sep 21:fetalneonatal-2023-326006. doi: 10.1136/archdischild-2023-326006. Online ahead of print.PMID: 37734928 No abstract available.
Diagnostic Yield of Exome Sequencing in Pediatric Cardiomyopathy. Keisling J, Bedoukian E, Burstein DS, Gaynor JW, Gray C, Krantz I, Izumi K, Leonard J, Lin KY, Medne L, Seymour C, Skraban C, Ritter A, Ahrens-Nicklas RC.J Pediatr. 2023 Nov 1:113808. doi: 10.1016/j.jpeds.2023.113808. Online ahead of print.PMID: 37923198
Developmental consequences of short apneas and periodic breathing in preterm infants. Yee AK, Siriwardhana LS, Nixson GM, Walter LM, Wong FY, Horne RSC.J Perinatol. 2023 Nov;43(11):1420-1428. doi: 10.1038/s41372-023-01748-8. Epub 2023 Aug 9.PMID: 37558750 Free PMC article.
Parents' Views on Autopsy, Organ Donation, and Research Donation After Neonatal Death. Crouch EE, Damas C, Bartrug WC, Shamiyeh A, Scelfo M, Dreyfus M, Gano D, Segal S, Franck LS.JAMA Netw Open. 2023 Nov 1;6(11):e2341533. doi: 10.1001/jamanetworkopen.2023.41533.PMID: 37930699
Use of Dexmedetomidine and Opioids in Hospitalized Preterm Infants. Curtis S, Kilpatrick R, Billimoria ZC, Zimmerman K, Tolia V, Clark R, Greenberg RG, Puia-Dumitrescu M.JAMA Netw Open. 2023 Nov 1;6(11):e2341033. doi: 10.1001/jamanetworkopen.2023.41033.PMID: 37921767 Free PMC article.
Proteomics-based Mapping of Bronchopulmonary Dysplasia-associated Changes in Non-invasively Accessible Oral Secretions.Ahmed S, Odumade OA, van Zalm P, Fatou B, Hansen R, Martin CR, Angelidou A, Steen H.J Pediatr. 2023 Oct 13:113774. doi: 10.1016/j.jpeds.2023.113774. Online ahead of print.PMID: 37839510
Find some of our notes here 👇
The transcript of today's episode can be found below 👇
[00:00:00] Ben: Hello, everybody. Welcome back to the incubator podcast. It is Sunday. We are back with a new episode of journal club. Daphna, how are you?
[00:00:08] Daphna: doing well. There were, there were lots of articles
[00:00:11] Ben: I've been loading the folder up. I have to admit I've been filtering less and adding more, but they're all very good articles, so.
[00:00:20] Daphna: You know, I mean, I think that's the point, right? Like we started doing this because we couldn't find another way to keep up with the literature and it's, there's still so much that we just can't, can't put out there.
[00:00:33] Ben: that's right. That's right. Um, yeah, so I have a bunch of articles to review Um, let's do some announcements first and foremost. We will have a few cool Content some cool episodes coming up on the podcast. Number one. We'll have like a thanksgiving special. There'll be a giveaway So stay tuned for that Um, we will also repeat what we did last year with the eb neo team where we will actually have a special [00:01:00] episode for the article of the year campaign where people will be presenting that and there may be a second giveaway for For that campaign.
[00:01:08] Ben: So please listen in in the coming weeks for that episode um, and then we are going to have some, um, new collection dropping on the store. So stay tuned for that. And, um,
[00:01:22] Daphna: Just in time for the holidays.
[00:01:23] Ben: right. That's exactly right. So yeah, if you have gifts to uh, to give to colleagues, co workers, friends, families, that might be a good source.
[00:01:34] Ben: Um, that's the announcements for today. Anything else I forgot?
[00:01:38] Daphna: No, we have been very busy.
[00:01:40] Ben: Yeah, we have, we have. Um, all right. Do you want to begin or should I begin? I have a lot of
[00:01:49] Daphna: you always begin. You have a lot of articles. I'm not sure how you envision getting through all of them.
[00:01:54] Ben: I have a, have a plan. So I guess the first article I'm going to talk about is an article that I found in [00:02:00] the, in the journal of perinatology about, um, actually I'm, I'm, I take that back. It's in the journal of pediatrics. Ooh, my bad. But it's basically, uh, an article called the irritable infant in the neonatal intensive care unit, risk factors and biomarkers of gastro esophageal reflux disease.
[00:02:22] Ben: Um,
[00:02:23] Daphna: I thought this was a very interesting title. It really grabbed my attention
[00:02:28] Ben: I definitely did definitely gave some thoughts to, um, to that title. And, uh, yeah, we're, we're thankful for that. The first author is Mina Negev, I think is how we pronounce it. And this is a paper out of the U S so. The introduction is actually quite interesting, and I think if you have some confusion about what is it again that we are considering disease versus not disease, I think it's a good review.
[00:02:54] Ben: They mention how gastroesophageal reflux is not gastroesophageal reflux disease, that GER [00:03:00] is physiologic, and that when symptoms occur, then we talk about GERD with a D at the end. Now, they do acknowledge, though, that the definition is, um, Uh, the definition of like troublesome symptoms is kind of unclear.
[00:03:15] Ben: We're, we're challenged to diagnose, to prescribe therapies for what we perceive to be reflux disease. Um, and we're not always sure whether What we're seeing at the bedside is actually correlated with the pathology itself. They're talking about how empiric prescriptions are a cause for concern. There's been a lot of articles about that as the true origin of the infant symptoms are left unaddressed and the medications can have adverse consequential effects.
[00:03:41] Ben: When we give medications for acid suppression, it increases risks of infection and so on. So it's definitely a concern there and could eventually also prolong hospital stay and increase economic burden. Now, one of the symptoms that is very frequently reported is arching and [00:04:00] irritability. And these are somatic signs, um, basically where you have, uh, back arching that involves extension of the neck and is often accompanied by fussiness or crying, making the infant appear irritable.
[00:04:13] Ben: Something we've. in the NICU and had to address. Now, a few of the, um, International Association, NASPGAN, and ESPGHAN, the North American and European, uh, societies along with other recent report have recommended the use of a pH impedance testing for further clarification and identification of potential mechanism of symptoms associated with gastroesophageal reflux disease.
[00:04:40] Ben: And that really is a key because that's really how you should be diagnosing, uh, GERD. And so, um, It's not if your institution has access to to a gastroenterology team to ph impedance testing then that's great but for many that is not a that is not a possibility and so the aim of the study what they're then trying to show because of that is that [00:05:00] to to basically the the goal is to examine the potential risk factors comorbidities and the reflux aids characteristic in relation to arching and irritability.
[00:05:11] Ben: and the clinical outcomes among infants. So trying to see a little bit if how does how do the symptoms that we observe at the bedside correlate with the diagnosis as it is made per the recommendation of these organizations. So the study design is basically the following. They took data from 24 hour pH impedance studies that were analyzed retrospectively from Patients and infants that were hospitalized in the NICU, uh, who were referred to the infant feeding program at Nationwide Children's Hospital for the evaluation of GERD.
[00:05:48] Ben: So I kind of like the sampling bias here because These are the babies that people were super concerned about. So like when I started reading this, I'm like, Oh boy, these are all going to have reflux. [00:06:00] The inclusion criteria, uh, were that babies were included. If they underwent 24 hour pH impedance testing between June, 2012 and, uh, June, 2020 with more than 18 hours of analyzable, analyzable pH impedance data and values for acid reflux index.
[00:06:19] Ben: ARI, number of reflux events, distal baseline impedance, and symptom associated probabilities that were recorded. They excluded infants if they had a postmenstrual age that was above 52 weeks, or if these kids were already on a protein pump inhibitor at evaluation, and if the one year outcomes could not be obtained.
[00:06:37] Ben: So what was the intervention? I mean, this is like the GERD referral center, so. Top notch level stuff. Uh, the infants underwent 24 hour pH impedance testing using a disposable pH impedance probe with six impedance channels and one distal pH sensor. So for [00:07:00] those of us who need a bit of reminders and who are studying for the board, as we are diagnosing gastroesophageal reflux disease, there are those two things, pH impedance.
[00:07:11] Ben: testing, you have pH probe where you could just look at the change in pH in the esophagus to see and document reflux, which is not ideal because a lot of the time the reflux in these neonates is not acidic, but you then have impedance testing, which looks at the difference in resistance along the esophagus.
[00:07:28] Ben: And then that could be diagnostic. So in this case, they were using both. So they had pH impedance probe. So very sophisticated. Thank you. That's right. Yeah. So, so that was very thorough. Um, they defined frequent arching and irritability as more than 72 events in the 24 hour pH impedance study. So I was like, that is intense.
[00:07:51] Ben: 72, 72 documented events of arching and irritability. And the bottom line is that they conducted studies that, uh, allow [00:08:00] them to use this cutoff of 72. But what's interesting, obviously, as you're starting to, to get gather is that. It seems like this, this sample is being selected to really include the most high risk kids, the one that are being referred, the one that have over 72 events of arching and irritability.
[00:08:18] Ben: And I think Despite all that, we'll be very surprised with the results they looked at a variety of different clinical outcomes and in terms of outcome definition, I think that's important because they define something called acid gER and bolus GER as we were saying. So acid GER means that when they were doing the pH impedance testing, the pH did, uh, was there was any drop in pH less than four, uh, to less than four for more than five seconds. And then you had bolus GER, which were defined as retrograde movement of a bolus shown by a 50 percent drop in impedance beginning in the Z6 channel and reaching at least one channel above.
[00:08:54] Ben: So obviously if you imagine. the, the probe, it has these different channels and obviously it has to be measured [00:09:00] across two different channels to show that it actually moved from one to the next. In terms of the acid reflux index that was analyzed as the percent of time in the 24 hour pH impedance study in which the esophagus was exposed to acid, acid GERD was defined as an acid reflux index of more than 7 percent as per published guideline and detailed characteristic of acid exposure events per day were examined.
[00:09:22] Ben: So. Um, I'm not going to bore you more with the, the methods as you can see, I hope that you gather that this was a very thoroughly done, uh, study. I was trying to like read the method and try to poke holes at like, let's see where, uh, this is going to unravel, but this was rigorous methodology. Um, 516 infants born at a median age of 30 weeks were evaluated at a median postmenstrual age of about 42 weeks using the pH impedance methods. And they had data from 10, 000 hours of recording. Now, figure one shows the possible combination of [00:10:00] arching slash irritability irritability events and bolus reflux events on pH impedance. So listen to this Daphna 11 percent of arching and irritability events were associated with bolus reflux. So. 11 percent I would have expected a much higher number. Now talking about acid reflux, arching irritability events showed a sensitivity of 8%. The specificity in not detecting acid reflux or arching irritability was 94%. The positive predictive value for arching and irritability was 17 percent for bolus reflux, 16 percent for acid reflux with negative predictive values of 87 percent for acid reflux and bolus reflux, which is nuts, basically. So to me, if a baby has a bit of a spit up, it's one thing, but if they have arching irritability, I'm like, Oh, they're symptomatic, but it is re it. It almost reminds me of when we started realizing that our assessment of clinical seizures is not helpful.
[00:10:57] Ben: It's one of these things where it's quite impressive. [00:11:00] I'm going to give you a few more results and then we can, we can discuss this a bit further.
[00:11:04] Ben: NO difference were observed in the frequency of distal or proximal refluxate per day. So again, nothing really there to grab onto. Adjusted comparison for GERD biomarkers and the prevalence of clinical characteristics. Were performed These were shown in figure two and I think figure two is quite interesting What they showed was that there's no acid GERD biomarkers that were attributed to frequent arching and irritability I think I have that that figure here So I think, I think that's, that's already quite, let me see there right here.
[00:11:39] Ben: I think that's quite interesting. Um, infants with positive symptom correlation to bolus GER with any symptom or signs were more likely to have frequent arching and irritability event. So now we're seeing a little bit of this relationship where arching it, irritability are not necessarily symptoms that could help you [00:12:00] specifically diagnose gastroesophageal reflux disease.
[00:12:03] Ben: However, when they did have. Um, they did have confirmed GERD, then you did see arching and irritability. Infant comorbidities associated with frequent arching and irritability were preterm birth, Orally feeding at evaluation, moderate or severe neuropathology, and chronic lung disease. So probably some of these medically complex infants.
[00:12:26] Ben: The conclusions of the paper are that from these 500 and change infants referred for GERD. confirm that acid gastroesophageal reflux is unlikely to be the primary cause of arching and irritability in infants, and that factors such as immaturity or neuropathology might be at play. Therefore, arching and irritability alone should not be a concern to parent or providers when diagnosing, when diagnosing GERD in infants.
[00:12:55] Ben: Although future pathophysiology studies Um are needed this information [00:13:00] should help minimize basically the use of pharmacologic therapies and perhaps shorten the duration of such therapies to prevent unintended. So a very interesting paper. I think you're muted.
[00:13:12] Daphna: Yeah, I think it, um, I mean it fits with the literature that we're not good at identifying the symptoms of reflux, but I, what I thought was particularly interesting is it, obviously the arching, grimace type symptoms are nonspecific, but babies with reflux do do those things when they're uncomfortable, so, I mean, I think, I think.
[00:13:37] Daphna: Uh, we can't say it's not for any baby. I think of the babies we know have reflux when they're showing us those symptoms, it, it, it, it may be a sign of, you know, less, less of the, less of those behaviors or improving control, worsening those behaviors or, or, uh, worsened control. But for the [00:14:00] bulk of babies, it's, I guess it's not enough for us to diagnose reflux.
[00:14:04] Ben: I would say probably hopefully it gives us a bit of pause. I think sometimes when we see a baby with a bit of reflux and arching slash irritability, we may be We may have a looser finger on the trigger to start ordering meds and so on But maybe this is going to give us time to pause and say well most of the time that's not what it is So let's let's see.
[00:14:25] Ben: Um
[00:14:25] Daphna: Yeah, and I mean that's, that's consistent with, This, this isn't the first study to say that, you know, so it's, it's nice to have consistency in the literature. Um, but it's, it's tough for, to explain to, I think, our bedside nurses and parents that it's, baby may be irritable for so many other reasons, right?
[00:14:45] Ben: Yeah, I mean to me i'm going to remember this that 11 percent of arching and irritability are associated with bolus reflux And that for acid reflux arching irritability events shows shows a sensitivity of eight percent Um,
[00:14:58] Daphna: Yeah, and there's still a lot [00:15:00] of use of acid reducing agents, and we know that there are a lot of negative effects. You know, we've reviewed a bunch of papers about that, including now long term neurodevelopment and the preterm baby who gets that type of medication. So it's just more fuel to say let's be much more restrictive with those things. Okay.
[00:15:26] Ben: All right, where are you taking us
[00:15:27] Daphna: Interesting. I wanted to talk about this, uh, paper. Um, it was circulated on Twitter, on X. Uh, it's called 90 vs. 60 Minutes of Early Skin to Skin Contact on Exclusive Breastfeeding Rate in Healthy Infants Greater than or Equal to 35 Weeks, a Randomized Controlled Trial. lead author Shalini Kumawat.
[00:15:51] Daphna: This is an act of pediatrica and it's coming to us from India. So the aim was actually to compare the effect of 90 [00:16:00] versus 60 minutes of early skin to skin contact among vaginally born healthy infants greater than or equal to 35 weeks of gestation on their exclusive breastfeeding rates and breastfeeding.
[00:16:12] Daphna: behaviors. So what they did, this was a parallel group, uh, open label randomized control trial. It enrolled healthy term and late preterm infants who were born vaginally. Interestingly, they did, they put between 8 a. m. and 8 p. m., but that makes sense. That's probably when the study team could, could, could check on them.
[00:16:30] Daphna: Um, and I think it's interesting to note that skin to skin care for the term infant was actually It seems like not standard of care, so, um, they were taking, you know, I think sometimes it's hard to say, oh, can we randomize babies to less skin to skin care, but, um, it seems like for all groups, this is more skin to skin care than, uh, they, they usually get.
[00:16:52] Daphna: So then they asked, um, moms, uh, to, they were either randomized to do 60 minutes or 90 minutes from the [00:17:00] time of birth. So birth straight to the mom's chest. And, um, Basically, it was continuous, except for they document 5 to 10 minutes when moms have to transfer from the labor bed to their postpartum bed, and during that time the baby is both examined and receives the vitamin K to disrupt the skin to skin care as little as possible.
[00:17:23] Daphna: They included all healthy singletons born via vaginal delivery. Um, the exclusion criteria were infants who required resuscitation, um, in the form of positive pressure ventilation, uh, major congenital malformations, um, babies who needed to go to the NICU for respiratory distress, infants born, um, to mothers where they may have conditions that would prohibit skin to skin.
[00:17:47] Daphna: So these are moms with um, active tuberculosis, concerning dermatologic lesions, moms with complications in the immediate postpartum period, and they included mothers with psychiatric illness, I guess [00:18:00] not felt to be able to care for the infant. And so the primary outcome was a proportion of infants on exclusive breastfeeding at 60 plus or minus 12 hours and at first I was like 60 hours, that's, that's not that long.
[00:18:15] Daphna: But the truth is, you know, we rotate in the newborn nursery and there are lots of moms who intent, who are documented as intending to breastfeed and they are not breastfeeding. breastfeeding by 60 hours. So, uh, I did not think this was an unreasonable primary outcome. But the secondary outcomes were looking at breastfeeding behavior, um, using the breastfeeding assessment tool at the 60 hour mark, um, and then documenting exclusive breastfeeding rates at 6, 10 and 14 weeks postpartum. Okay. So baseline characteristics, they randomized 198 dyads. The enrolled mother's mean age was 24. 72 years. The mean gestational age and the mean birth weights were 39. 8. Uh, 1 1 weeks and [00:19:00] 3083 grams respectively. Uh, almost 60 percent of the mothers were first time mothers, and mostly from urban areas.
[00:19:09] Daphna: And the maternal and neonatal care characteristics were comparable for both groups. So, the infants in the 90 minute skin to skin care group were more likely exclusively breastfed at the 60 plus or minus 12 hour mark, and those in the 60 minute skin to skin care group. This was 76 percent versus 52. 5 percent just at the 60 hour mark, um, and that kind of 52 percent kind of persisted across the way for the babies who got the 60 minute skin to skin care, um, and.
[00:19:44] Daphna: I'll tell you a little bit about the breastfeeding behavior at the 60 minute mark. So they use, like I said, the breastfeeding assessment tool. It really talks about, like, how efficient does breastfeeding appear to, to be? Like, how, how well are, is breastfeeding [00:20:00] going? Um, and so they looked at the modified infant, uh, BAT or breastfeeding assessment tool score was significantly 90 minute skin to skin care group as compared to the control group.
[00:20:11] Daphna: A score of 9, uh, versus 8. This was statistically significant. And then looking across time, the proportion of infants on exclusive breastfeeding at 6, 10, and 14 weeks of age was also significantly higher in the 90 minute skin to skin care group compared to the 60 minute skin to skin care group. So 73. 19 at 6 weeks versus 52.
[00:20:35] Daphna: 5. 73.13 at 10 weeks versus 52.08 and 69% at 14 weeks versus 50%. Um, they also looked at the median time for initiation of breastfeeding. So they were doing skin to skincare, but how quickly did they do breastfeeding? Um, but this was the same between, um, both the intervention and the control groups, about 20.
[00:20:58] Daphna: minutes. [00:21:00] Um, one thing that I thought was, um, important to know is what are the exclusive breastfeeding rates in India? I mean, uh, around up to the six month mark. So they're much better than the U. S. breastfeeding rates. We're about 25 percent for exclusive breastfeeding, but in India they're about 55 percent, um, which notably is the kind of percent for the 60 minute skin to skin care group across, uh, to 14 weeks.
[00:21:26] Daphna: Um, but I thought this was It's useful information to, to really feed that kind of narrative that that first, you know, initial contact is really important for establishing breastfeeding, breast milk production. Um, we know once babies get past that kind of two to three hour mark, they're just
[00:21:54] Daphna: I thought this was a really interesting study. Um, I, it makes sense to me that more [00:22:00] skin to skin care improves breastfeeding rates. We know that, but I, I thought this was, not a stretch for units that are already doing immediate skin to skin care to just prolong that and maybe have improved outcomes.
[00:22:12] Ben: How feasible do you think that is?
[00:22:15] Daphna: Well, I think it depends on the unit.
[00:22:17] Daphna: Our units are still, uh, admittedly are, you know. Labor and delivery, we're still working on getting really good immediate skin to skin care. Um, I think some units are already doing that, some delivery centers are already doing that. And so, could they go a little bit longer?
[00:22:35] Daphna: Um, I think a lot of units are, for example, doing immediate skin to skin care and then saying, Okay, the baby can be assessed at the one hour mark. But maybe it shouldn't be the one hour mark, maybe it should be the hour and a half mark. Um, so, I, I think this is really, valuable, especially as we're all trying to improve our breastfeeding rates.
[00:22:55] Daphna: I think it's also important for our NICU infants, can we get them to mom's chest? [00:23:00] Some of these late preterms, you know, these small babies who are going to come to the NICU. We know they're going to come to the NICU, but they didn't need resuscitation. They're not in distress. Can they spend some time doing skin to skin before coming to the NICU?
[00:23:13] Daphna: And will that improve our breastfeeding rates?
[00:23:15] Ben: Yeah, absolutely. And I think that's interesting because it's something that, uh, we've talked a lot about with, um, some of the people that we interviewed for this special series on thermal regulation. I think we, we talked a lot about that and how we assign ourselves so many things to do at the time of delivery that https: otter.
[00:23:36] Ben: ai
[00:23:40] Ben: The more regulation skin to skin. Uh, yeah, so, uh,
[00:23:45] Ben: yeah,
[00:23:45] Daphna: And to your point, I think we, we perceive that we are much better at controlling the baby's temperature than the, the mother is, but we know that there are lots of, there are lots of places around the world that are exclusively [00:24:00] using the mother, uh, to do thermoregulations, so.
[00:24:03] Ben: Yeah. That's something that um that sometimes is is forgotten where Yeah, I mean there's there's a necessity to um to do it this way so that Uh, you can actually maintain a certain amount of temperature but I think it's always fascinating to see how this this this organic relationship between mother and baby and how Everything is influenced, but I think that's very cool.
[00:24:27] Ben: Very cool paper. All right
[00:24:30] Ben: I'm going to talk about um Quick i'm going to talk about two quick papers and then we can i'm going to i'm going to go do a quick review Of some articles that I saw uh, not too much in depth, but the first one Is called diagnostic yield of exome sequencing in pediatric cardiomyopathy.
[00:24:48] Ben: That's in the journal of pediatrics The first author is julia kissling I think it's something that we uh discussed in our unit not too long ago about sending Genetic testing for babies with cardiomyopathy and I [00:25:00] stumbled upon this paper and I was like, oh, that's an interesting paper I just wanted to read it quickly I think It's, um, it's quite a dense paper.
[00:25:08] Ben: So feel free to read. I'm just going to do a quick review. Some of the things that are always fascinating about pediatric cardiomyopathy is that it is very rare, like 1. 13 per 100, 000 children annually. And that the most common type again, for people studying for the boards, the most common type of cardiomyopathy, uh, Dilated is the most common.
[00:25:27] Ben: 51 percent of all cases followed by hypertrophic in
[00:25:30] Daphna: Yeah. It feels like it's not,
[00:25:32] Ben: right. I don't know why I don't know why I feel like it's not that but it is that, um, this was a single institution retrospective chart review of 91 patients with pediatric cardiomyopathy and then all the patients were between birth and 21 years of age, but it doesn't really matter.
[00:25:49] Ben: Ignore the fact that they're 80 There's some almost grown ups in there, but we're talking about like, how helpful is it to do exome sequencing? Um, uh diagnosed with at least one subtype of cardiomyopathy and they [00:26:00] were evaluated by the CHOP, the Children's Hospital of Philadelphia, cardiomyopathy and or genetics team.
[00:26:05] Ben: Each patient had a clinical, um, exome sequencing performed by GeneDx, which is a company that is really trying to move the needle forward. When it comes to that, we actually interviewed, uh, their Chief medical officer. So if you want to find out more about this company, there's a tech Tuesday episode somewhere, um, and you can find it, uh, the CHOP division of genomics diagnostic or another clinical laboratory.
[00:26:25] Ben: We have no ties to GeneDx. They, yeah, they're not paying us anything, but. It is a subject of discussion. So that's why I'm mentioning it And so what they were mentioning is that while pediatric cardiomyopathy is often genetic in nature No genetic test is recommended as a standard of care So all their patients were diagnosed with cardiomyopathy and evaluated by medical geneticists between 2010 and september 2022 And they had some demographic and clinical data.
[00:26:52] Ben: So results of these 91 patients Um, 39. 6 percent received a diagnosis by exome [00:27:00] sequencing, so still a frustrating endeavor, right? I mean, still 60 percent of these patients who are going to go, yeah, 22, which is 61. 1 percent of these diagnoses would have been missed on cardiac multi gene panel testing. So, This is comparing, right?
[00:27:16] Ben: These multi gene panel testing for cardiomyopathy versus exome sequencing. So, I think it's interesting to see how we're, we're changing, shifting gears a little bit as to what we want to test. Uh, the diagnostic yield for cardiomyopathy presenting under one year of age was 38. 3%, while the yield for patients over one year is slightly higher, 41.
[00:27:36] Ben: 9%. The conclusions of the paper are that ES has a high diagnostic yield in pediatric cardiomyopathy compared with the gene panel and that over 60 percent of patients with diagnosis by exome sequencing would have not, would not have received their molecular genetic diagnosis if only multi gene panel testing was sent.
[00:27:55] Ben: Um, so I think that's interesting, um, because we do send these tests. [00:28:00] Sometimes they're expensive. Sometimes parents are asking like, is that going to give us an answer? But most likely, I guess not most likely, uh, 60 percent still go on diagnosed with exome sequencing. So, um, still a frustrating endeavor, probably also, uh, opportunities to continue working these patients up for other sources of cardiomyopathy, um, whether they're infectious and so on.
[00:28:20] Ben: So, That's exactly right. Um,
[00:28:24] Daphna: But I mean, I think it's interesting, I mean, our standard of care is less than that, so, right? With the, the multi gene panels, so it's an improvement. And to your point, that GeneDx episode was 153, and we had a great interview about whole exome sequencing at the CHNC, so if somebody wants to take a look at that coverage also.
[00:28:48] Ben: Another interesting short, um, article that came out in the archives of disease and childhood, it's called trends in infant mortality due to hemolytic disease and other perinatal jaundice in the U S [00:29:00] between 1999 and 2020, the first author is Ramesh Vidavalor and second author is Vinod Bhutani.
[00:29:07] Ben: None other than Dr. Bhutani. So, the objective of this study was to try to fill some of the gaps by utilizing a national data set to assess the, um, infant mortality rate, prevalence rates, causes, and trends associated with perinatal jaundice. I think there's been a lot of changes in how we approach perinatal jaundice.
[00:29:27] Ben: And I think, I think it's a very valuable thing that Dr. Vidavalor and Dr. Bhutani did by just trying to give us a sense as to how have things changed. And so they use the the U. S. CDC wonder birth slash infant death linked database from 1999 to 2020 to look at infant mortality rate, uh, up to one year.
[00:29:50] Ben: Deaths attributed to hyperbole rhubinemia had special codes. Um, and as the, uh, and so they look for these codes as the underlying cause of death and these were the patients they included. [00:30:00] So 86 almost 87 million births in the US between 1999 and during this 21 year period, uh, there were 291 deaths attributed to hemolytic disease and other perinatal jaundice, which I thought was not that much.
[00:30:15] Ben: I mean, it's still a large number of us. I'm not dismissing that. But when you see those numbers, I It's good to hear that not that many babies are dying from this resulting in an overall overall IMR of 3. 3 per 1 million life births among these deaths 61 Occurred in males infants. So I think that was interesting that the bulk of them actually happened in one Sex and not the other compared with interestingly enough.
[00:30:42] Ben: There's some interesting ethnic data here Where compared with white infants black infants had a higher risk of uh of death with It was 3. 2 per 1 million life births in white infants 4. 5 per 1 million life births in black infant [00:31:00] while Asian infants had a lower risk of 2. 5 per 1 million life births of mortality, which is Staggering because I mean, I always remembering for board review that Asian patients are at a high risk of yeah, so it's it's quite staggering to see that black infants are topping that list.
[00:31:20] Ben: So, hemolytic disease of the newborn and hyperbilirubinemia due to excessive hemolysis accounts for 52%. Of the deaths, while connector is contributed to 8 percent with an overall mortality rate of 0. 26 per 1, 000, 000 life birth. The the aspect obviously that's very concerning is that the higher mortality in black infants can be partially, they say, explained by the greater prevalence of glucose six phosphate dehydrogenase deficiency, elevated risk of a B.
[00:31:48] Ben: O. I. So immunization and disproportionately higher rates of late preterm infants. So it looks like it's not just. the hemolytic disease, but a combination of other factors that are contributing [00:32:00] to this disparity. The hyperbilirubinemia associated mortality rate remains stable overall during the study period, consistent with previous reports, and so they conclude that their findings indicate Stable, reassuring, jaundice related IMRs emphasizing the need for comprehensive approaches to address management gaps in risk stratification and to reduce, obviously, racial disparities in IMR through continued surveillance.
[00:32:27] Ben: So I thought that was kind of a nice little
[00:32:29] Daphna: Mm hmm. Mm hmm. Mm hmm
[00:32:31] Daphna: that's right. Okay. My turn?
[00:32:34] Ben: Yeah.
[00:32:35] Daphna: Okay. Um, I had a paper. Let's see how much time we have. Okay. I had a paper. It's called Developmental Consequences of Short Apneas and Periodic Breathing in Preterm Infants. Um, the lead author, uh, Alicia Yee. This is in the Journal of Perinatology. The question really was do respiratory events predict developmental outcomes at six months of age?
[00:32:58] Daphna: So they [00:33:00] included infants born between 28 to 32 weeks of gestational age, uh, recruited between March, 2018 and July, uh, 2021. And basically what they did is they, um, studied infant's longitudinally using. A sleep study, basically, which is exceedingly difficult to do inpatient in U. S. NICUs. Um, but these were done in Melbourne, so they had access to all of those things.
[00:33:28] Daphna: So they were studied longitudinally on four occasions. At 32 to 36 weeks postmenstrual age. At 36 to 40 weeks, um, either in house or, um, Back in their follow up that they had been discharged at three and in six months post term corrected age and then they were seen either in the sleep center or In their own home because this was during the COVID pandemic.
[00:33:54] Daphna: So at each of the four sleep studies Physiologic recordings made during two to three hours of daytime [00:34:00] sleep in the supine position and then all of the babies Well, most of the babies at six months corrected age underwent developmental assessments and using the Bayley 3. Uh, the exclusion criteria, they did not recruit infants who continue to require ventilatory support or oxygen therapy, which I thought was interesting, um, because the, uh, the The first evaluation was at 32 to 36 weeks, so, um, just know that, um, because they didn't want to use any confounding effect of lung pathology or chronic lung disease.
[00:34:37] Daphna: They were not recruited if they were growth restricted, they had major congenital anomalies, major intracranial abnormalities, or significant, um, intraventricular hemorrhage. The, uh, Excluded grades three and four, or if they had a hemodynamically significant PDA because the known independent effects on neurodevelopment, they did not define, uh, what they considered hemodynamically [00:35:00] significant PDA.
[00:35:02] Daphna: So what are the baseline characteristics? It was a small study. Um, 40 infants were recruited. Many were lost to follow up in particular, given the COVID precautions after discharge. 26 completed sleep studies and developmental studies. Okay. They had a median gestational age at birth of 30 weeks, a median birth weight of 1. 4 kilos, infant APGAR scores median of 7 at 1 minute. and a median of nine at five minutes. Other things about the infants, they were all administered caffeine after birth and 35 percent were still on caffeine treatment at the time of study one, which was again between 32 and 36 weeks postmenstrual age.
[00:35:43] Daphna: Um, infants on caffeine at the time of the first study had a median caffeine dose of 8. 6 milligrams per kilogram. And, uh, all infants completed at least three of the four sleep studies for evaluation. Okay, so what did they find, [00:36:00] um, on the sleep studies? All infants experienced isolated apneas up to three months corrected age.
[00:36:06] Daphna: And this fell to 92 percent at six months corrected age. But the isolated apnea definition, um, they used a respiratory cessation, either central or obstructive, lasting greater than or equal to three seconds. Okay. Um, in contrast, sequential apneas, which they defined as two sequential central apneas separated by normal breathing lasting less than or equal to 20 seconds.
[00:36:32] Daphna: So two periods of apnea that were greater than or equal to three seconds, but separated by a brief, uh, interruption of normal breathing. Were reduced to 63% and uh, 63%, um, at three months and below 40% at six months. So you see an improvement over time. They also documented [00:37:00] periodic breathing. So periodic breathing that was defined as three or more sequential central apnea is lasting greater than or equal to three seconds interrupted by normal breathing lasting less than or equal to 20 seconds.
[00:37:12] Daphna: So these were reduced to 63%, I'm sorry, reduced to 47 percent at three months and below 40 percent at six months. But all babies, many babies continue to have these brief. apneas even at six months. Um, periodic breathing occupied, um, a median of 8. 5 percent of the total sleep time at 32 to 36 weeks postmenstrual age and 6.
[00:37:40] Daphna: 8 percent at 36 to 40, uh, weeks postmenstrual age. While the isolated apneas and sequential apneas, occupied less than 5 percent of total sleep time at all ages. They also looked what, what happened, what other physiologic things were happening with these, um, brief respiratory events. Uh, falls in heart [00:38:00] rate during respiratory events increased with increasing age, which was interesting.
[00:38:04] Daphna: In contrast, the falls in SpO2, decreased with increasing age with falls and SpO2 at three to six months corrected age being significantly less when compared to falls at 32 to 36 weeks postmenstrual age. So less dips in the oxygen saturation, but they did have more dips in the heart rate during these respiratory events.
[00:38:27] Daphna: At all ages, the median group average time spent with SATs less than 90 percent was less than 1 percent of total sleep time. However, there was much, um, individual variability. So some babies spent much more time, um, less than 90%. The median group average time spent with a tissue oxygenation index less than 55 percent was less than or equal to 1 percent of total sleep time.
[00:38:53] Daphna: Um, with the majority of this time being during the periodic breathing type events, again, a wide [00:39:00] variability between infants. So then they looked at the six months, um, postmenstrual age, uh, Bailey, three infants had a median cognitive, uh, composite score of a hundred, a language compositive score of a hundred, motor composite score of 99, social emotional composite score of a hundred and adaptive behavior score of 103.
[00:39:23] Daphna: All infants scored greater than 85 in the cognition and adaptive behavior domains. One infant scored less than 85 in the language domain, four infants scored less than 85 in the motor domain, and three infants scored less than 85 in the social emotional domain. But then they looked at what was predictive of the Bailey scores.
[00:39:42] Daphna: Interestingly, in this little group, uh, gestational age, sex, and birth weight were not predictive of Bayley 3 scores. Percent total sleep time with all the respiratory events combined and the percent total sleep time spent in periodic breathing at the term corrected age 36 to [00:40:00] 40 weeks were significant predictors of language and motor outcomes at the six month corrected age. Um, percent total sleep time events and percent total sleep time, uh, in the periodic breathing at 32 to 36 weeks postmenstrual age at three months and six months were not associated with any of the, uh, Bayley 3 domains. And percent total sleep time in isolated apnea or the sequential apneas were not associated with any of the Bayley 3 domains.
[00:40:34] Daphna: There's no association between the percent change in saturation or the tissue oxygenation index during respiratory events. They also looked at a, a bunch of measures of infant temperament, which, which are interesting other, um, findings, um, but their, their overall, um, conclusion is that more time spent [00:41:00] in respiratory events, particularly these kind of periodic breathing, um, predicted outcomes at this six month.
[00:41:11] Daphna: So I thought that was interesting because. You know, in general, I feel like in the unit, when babies have these little dips, we tell parents, Oh, they're just little dips. You know, we're really worried about the, you know, frequent, prolonged dips. Not these quick, uh, brief, uh, dips that babies have, um, but potentially they add up over time.
[00:41:34] Daphna: Thoughts?
[00:41:36] Ben: Well, it's, it's an interesting study, right? I mean, I'm wondering what do we take practically speaking back to the bedside? Um, because I think every time a baby leaves our units on oxygen, you're like, man, did we not try hard enough to get this baby off oxygen? But then you read a study like this and you wonder, maybe, maybe we shouldn't send more babies on oxygen.
[00:41:54] Ben: I mean, what is. What is the rush trying to get these kids off oxygen as early as possible? If [00:42:00] there are going to be, uh, long term consequences to having even slight little events, uh, during sleep. Um, I think it's, it's a, it's a, it's a double edged sword. I mean, I don't really know what the right answer is, but. Yeah, it's I
[00:42:19] Daphna: you know, there are some babies who you take off oxygen, but they're really just making it, right? They're really just
[00:42:24] Ben: we always tell the parents your baby has been on some form of Respiratory support since birth. It's now five months old We're going to take your kid off and we're going to wait we're going to wait five days And if everything is good after five days, you're going to go home. How how predictive is that? and are we Yeah, I I don't know. I don't know what the answer to that is when you compound that with how difficult it is To have oxygen at home and so on and so forth. It's even Makes things more complicated.
[00:42:52] Daphna: Um, and to that point, I wanted to mention two other quick, um, articles. Um, one is an, an [00:43:00] actual study. Etiology and Mechanism of Intermittent Hypoxemia Episodes in Spontaneous Breathing Extremely Preterm Infants in the Journal of Pediatrics. Um, lead author, um, uh, Alay, Alay, Alalay Dormishian, um, with Dr. Bancalari group here in Miami. And they really wanted to look at the causes behind these intermittent hypoxemia episodes. And their conclusion was actually that, that maybe we've been wrong about the mechanism associated with these intermittent hypoxemia episodes. You know, we, we think it's mostly related to things like apnea prematurity.
[00:43:41] Daphna: Um, Where there's something wrong with kind of, there's something immature about the breathing center. But actually they were talking about that in this group of premature infants, the predominant mechanism associated with the daytime, uh, IH or intermittent hypoxemic episodes was this active exhalation and breath holding [00:44:00] physiology.
[00:44:01] Daphna: There's also in the Journal of Pediatrics this editorial. entitled, Rethinking the Pathophysiology of Cardiorespiratory Events in Infants Born Preterm. And I guess the reason I'm highlighting these is, you know, when we study it for the boards, like, what is apnea prematurity? Why do the babies have all these events?
[00:44:20] Daphna: There's still a lot of stuff we don't know. And I feel like for trainees, you feel like, oh, pulmonary is kind of, We know everything we need to know about pulmonary in the NICU, but that is like not the case. Um, and so I think there's just so, um, much opportunity for more exploration here. Um, so I just wanted to bring people's attention to that.
[00:44:40] Ben: Okay. Um, I have a few more papers. One of them that is fascinating since we're talking about respiratory physiology, we're talking about BPD. Um, This is a paper that was published in the Journal of Pediatrics that is called proteomics based mapping of bronchopulmonary dysplasia associated changes in non invasively accessible oral [00:45:00] secretion.
[00:45:01] Ben: First author is Saima Ahmed and we have a few of our friends on this paper, uh, most notably Dr. Cami Martin. So, um, a very interesting paper, right? They're, they're talking about The way we're collecting labs the way we're getting samples and how difficult it is and how There's a lot of unintended consequences when you're taking too much blood you get anemia and so on Now they're saying that the overarching goal of their study is to demonstrate the feasibility and the benefits of applying an advanced versatile sample proteomics pipeline comprising semi automated sample processing methodology and state of the art liquid chromatography mass spectrometry to oral secretions and tracheal aspirate samples with the latter representing the body fluid most relevant to pulmonary health and disease.
[00:45:51] Daphna: That was a tongue twister.
[00:45:52] Ben: was reading the sentence and I was like, where's the period? Where is the period? Um, and so they're making a case [00:46:00] for trying to get new forms of sample, but we're going to get into some of the things that they did and it's. One of the most earth shattering paper I've seen This year so in this context they hypothesize that oral secretions that are non invasively collected body fluid Can be alternative to tracheal aspirates for non invasive respiratory monitoring in preterm infants for babies with rds Since we're using more non invasive that means we don't get tracheal aspirates as easily as we would if they were intubated and Easily accessible body fluid alternative can be used as sources of biological information that are urgently needed to track lung development and better understand or predict disease risk.
[00:46:41] Ben: So the objective was to determine if oral secretions could be used as a non invasively collected body fluid in lieu of tracheal aspirate to track the respiratory status and predict BPD development in infants that were born before 32 weeks. I'm going to go through the study design briefly. If we had basic [00:47:00] scientists on the podcast, they would probably do a better job and we will start Featuring these members of our community soon on the podcast, but for now you're stuck with me So just bear with me for a second So the newborns were recruited at beth israel deaconess medical center in boston, massachusetts And they followed two cohorts both starting from week of life three And they wanted to do two things number one They had a cohort to compare proteomic signatures between tracheal aspirates and oral secretions You And then Cohort 2 was the oral secretion proteome between infants who developed BPD versus a control group who did not.
[00:47:36] Ben: The included infants were born at less than 32 weeks of gestation who were at high risk to develop BPD as defined and categorized by the 2000 NICHD definition, which considers the need for N type of respiratory support provided at 36 weeks postmenstrual age. The intervention is that the samples were collected from the third week of life, were used for analysis, oral secretions were collected before the infant's feeding [00:48:00] time from the buccal mucosa with a cotton swab.
[00:48:02] Ben: The tracheal aspirates were collected using suction catheter. Connected to a mucus trap. They have a whole explanation of what happened to these samples after they were collected. Be my guest, go read that. Now what they did is that they compared in the results They compared the tracheal aspirates and the oral secretions from the same patients to make a case for oral secretion as an alternative In total they identified 2918 Uh proteins in the tracheal aspirates and 3035 proteins in the oral sample respectively, right?
[00:48:36] Ben: When only including proteins observed in at least half the sample they still identified about a thousand tracheal aspirates and about 1300 oral secretion protein. These curated protein list list were used for all subsequent analysis. So then. They compared these two results by creating sort of a Venn diagram and what the Venn [00:49:00] diagram shows is that there's 607 protein unique to oral secretions 327 proteins unique to tracheal aspirate, but there's an overlap of 687 proteins present in both body and present in both body fluids highlighting a significant degree of similarities between oral secretions and tracheal aspirates proteomes now the, they, they tell you which proteins these were.
[00:49:27] Ben: But what I think is interesting is that as we are not really surprised that there's some concordance on certain proteins between oral secretions and trichal aspirate, it's interesting to see how, how that. Panned out when they applied it to patients at risk of BPD. So oral secretions, proteomic changes in BPD cases and control.
[00:49:48] Ben: So they tried to remove proteins that were associated with the gestational age to try to remove gestational edge as a confo co-founder. So they talk as a co-founder. They, they spoke about this, how there were some proteins that [00:50:00] are directly associated with gestational age and that might be used as a confessor.
[00:50:03] Ben: They remove these. A principal component analysis using all proteins from that second cohort showed a clear separation of BPD cases versus control. Using a t test and applying a strigin p value cutoff of 0. 01, they identified 37 proteins that showed significant difference in abundance between BPD cases and control.
[00:50:25] Ben: Now, I'm going to take a second, Dafna, and I'm going to show you this graph because this graph is Fascinating. And I'm going to post this on Twitter because it's quite impressive. So, um, I don't know if you can see my screen, but do you see this figure three B? And basically you can see the proteins that are shown to being upgraded in cases of BPD and the ones in control, and you can clearly see.
[00:50:52] Daphna: a beautiful, beautiful
[00:50:54] Ben: This is insane. So, hierarchical clustering of these 37 [00:51:00] significant protein differentiating BPD cases and control provides a sample resolved view of the protein abundance revealing clear differences in protein expression, increased or decreased, and you can see them in like purple and red. Now, in order to determine if the 37 oral secretions protein that show differential abundance between the cases, that develop BPD versus control have been previously associated with BPD. They did a literature search and they looked for BPD, biomarkers, they had like a bunch of keywords. And what they found was that 10 out of the 37 significant proteins had previously been linked to BPD or other premature related lung disease pathophysiology.
[00:51:38] Ben: However, these proteins had been observed in invasively collected blood or tracheal aspirate samples, but never. in oral secretions. So what's fascinating about this paper is that, as they say in the conclusion, they demonstrate the feasibility of using non invasively collected oral secretions for early detection of BPD associated protein alterations, some of which have been [00:52:00] previously described in BPD literature from invasively collected samples and highlight biologically plausible oral secretions proteomic markers predictive of future BPD risk.
[00:52:09] Ben: And The, the, the, the, the conclusion continues, but I mean, we've been talking about proteomics and the idea that there's a possibility to swab a baby's cheek and getting an idea of whether they are or not at a high risk of developing BPD is to me, earth shattering. Um, so super impressed by this paper and, uh,
[00:52:30] Daphna: yeah,
[00:52:30] Daphna: it's exciting, exciting work.
[00:52:34] Ben: Okay.
[00:52:35] Daphna: Um, okay, we don't have much time. I, I don't have another article per se, but I am loving the clinics in perinatology, uh, issues. And, um, the one that just came out was neonatal transfusion medicine. Uh, I referred to this already, I think, two to three times in my [00:53:00] last week on service.
[00:53:01] Daphna: So I just wanted people to know that it's out there. The foreword is written by, uh, Lucky Jean and, um, the editors for the issue, reviewers for the issue are, um, But there's just a host of articles that really just brings the kind of most up to date infusion, information on transfusion medicine, um, all in one place.
[00:53:26] Daphna: So they have Thresholds for Red Blood Cell Transfusion in Preterm Infants Evidence to Practice, Prophylactic Platelet Transfusions, Why Less is More, Hemostatic and Immunologic Effects of Platelet Transfusions. Uh, Blood Donor Sex and Outcomes in Transfused Infants, Neonatal Blood Banking Practices, Transfusion in Neonatal ECMO, a Best Practice Review, Anemia, Iron Supplementation in the Brain, Patient Blood Management in Neonates, Allogenic Cord Blood Transfusion in Preterm Infants, and NEARS to Guide and Understand the Effects of Red Blood Cell Transfusion.
[00:53:59] Daphna: So, [00:54:00] I mean, I think transfusion medicine is like a super hot topic right now, and they brought all the information in one place. So I would definitely recommend people take note and, and
[00:54:11] Ben: Can I tell you about two more papers that I have?
[00:54:14] Daphna: Hey, I know you're going to, that's why I was quick.
[00:54:17] Ben: Um, there's this one paper in JAMA network open called use of Dexmet met. D tomidine and opioids in hospitalized preterm infants. First author is samantha curtis. Last author is mihai puya do do mitrescu which is uh, mihai We met at chnc and actually was on the was on the podcast then he sort of give us like a little open mic So it's fun to see the name of the people that came on the show.
[00:54:41] Ben: Um In print and I think it's always interesting because when we're talking about press edX Um, we're using it more and more in our unit as well and And then we sometimes I sometimes wonder how are the other people using it? Is it like is everybody really using it or or what's happening? And so they [00:55:00] they basically are writing a report by the way a few things that I wanted to mention Just in the background because I think it's timely.
[00:55:06] Ben: So number one Presidex. Um, the use of Presidex over the past decade has increased 50 fold. If you all remember, alpha 2 adrenergic agonist, it inhibits norepi release. It decreases the release of substance P, activating receptors at the locus coeruleus, which leads to sedative, anxiolytic, and analgesic effect.
[00:55:25] Ben: Not surprisingly, Presidex is not approved by the FDA for neither neonatal nor pediatrics, and yet they're still using it. Wink, wink. Multiple studies have suggested that Prasidex has decreased the total dose of opioid or adjunctive medication required to sedate infants in these environments in the pediatric and the neonatal ICU.
[00:55:48] Ben: So, the objective of the study was to describe the use of Prasidex in the NICU in the past decade. They were using the, the pediatric slash Mednax data warehouse, um, [00:56:00] and examine the association between Prasidex and opioid use in infants that were born less than 37 weeks. Of gestational age. So they looked at this over the course of, uh, the study was conducted between 2022 and 2023.
[00:56:13] Ben: They looked at any infant born between 22 weeks to 36 and six, uh, who were born between 2010 and 2020. And they used the media, the pediatrics, medical group, NICUs. Um, they excluded infants who died before postnatal age, day two, or with known congenital anomalies. And the medication of interest were precedex, morphine, fentanyl, any combination of these medications.
[00:56:34] Ben: Um. Not going to go into too much details. Obviously we're running out of time, but um, they had 383 sites Uh looking at almost 400 000 infants And they had data on 374 000 babies now they had Interesting enough, a total of 384 infants, which basically represents less than 1%, received Prestidex during their NICU stay and were included in this [00:57:00] analysis.
[00:57:00] Ben: Most infants who received Prestidex were male, white with a median gestational age of 27 weeks and a median birth weight of 890 grams. Infants who were not exposed to Prestidex usually were more mature, higher birth weight. And in the presidex exposed group, opioid exposure was 64 percent versus 7. 5 percent in the non exposed group, which I think was quite interesting to be honest.
[00:57:31] Ben: Um, And what they showed was 312 of the 384 infants with prosthetics exposure were receiving invasive mechanical ventilation while receiving the medication. So we often think of prosthetics as a guard to more opioid use, but. It doesn't seem it seems like sometimes it's maybe just a marker of disease severity and that they're so sick that they need multiple um drips to control pain and uh, And [00:58:00] agitation so that's I think that that was interesting infants exposed to prosthetics had longer median length of stay Again going back to this point of 71 versus 18 days compared to the unexposed group and most infants exposed to prosthetics also received Opioids and experience high rates of clinical outcomes.
[00:58:18] Ben: So they have this table in the paper table too Where you basically can see kids who were either on presidex presidex and opioid or opioid alone or neither And what you can see is that for specific outcomes like ivh Opioids only was 8. 7 percent 16 in the kids who were on presidex and opioids and 10 in the kids who were on presidex alone So you can go back.
[00:58:39] Ben: It's hard to decipher what again, like I said what represents, uh disease severity or not But I think to me what was interesting about the paper is what are people doing? And the the use of presidex is increasing rapidly, but it's not something that is being used Uh, that's not the use its use. It's not rampant.
[00:58:58] Ben: So dexamet [00:59:00] Dex Meine increase, uh, from 0.003% in 2010 to 0.185% in 2020. So the use is still very, very low. You look at this Y-axis and the top, the maximal number is 0.3%, so it's not very much. While overall opioid exposure decreased from 8.5% in 2010 to 7.2% in 2020, so. Reassuring to see that our use of a period is going down, that our use of precedex is going up, but it's not.
[00:59:34] Ben: Something that is too concerning. In my opinion, the percentage of infants exposed to fennel decreased from 5. 8 percent while morphine exposure remained relatively stable during the study period. They also looked at clonidine use and they saw that clonidine use increased from 0. 02 to 0. 22 in percent in 2020.
[00:59:53] Ben: Is that related to our use of Presidex? That's not really being addressed. [01:00:00] Interestingly enough, we always have that discussion with our pharmacists who want to know how long are we going to keep the baby on Presidex? The median duration of exposure is six days, uh, with a variation with an IQR from two to 14 days and did not change significantly.
[01:00:13] Ben: over time. So the conclusions of the paper is that the, this multi centered cohort study of preterm infants show that presidex use increased significantly between 2010, 2020, while overall opioid exposure decreased. And although it's not approved by the FDA presidex, um, use in neonate appears to have significantly increased over time.
[01:00:33] Ben: I thought that was interesting.
[01:00:36] Daphna: Yeah. I mean, I think the exciting thing about pain medication use is, you know, some things work for some babies and not for other babies. So I mean, I think there's, I mean, I, we don't think we, we know that there's. Some genetic predispositions or something and that's like in its infancy and you know individualizing Pharmaceuticals, so [01:01:00] that's exciting.
[01:01:01] Daphna: Maybe that will help us pick the right bed for the individual baby.
[01:01:05] Ben: Last paper for today is another paper in jama network open called parents views on autopsy organ donation and research donation after neonatal death Yeah, that was a first author is elizabeth crouch and The whole paper is really great. I'm just going to go through a little bit of the background, not too much through the methods, but they're saying that despite concerns about causing further distress for bereaved parents, offering organ donation slash autopsy options can contribute to meaning making a central component of grief.
[01:01:35] Ben: processing. Now, among potential benefits for families, up to 48 percent of neonatal autopsies show findings that were previously unknown according to clinical and radiographic tests. So for many of us, sometimes we feel like the autopsy is not going to add much more, but that's not what the data shows.
[01:01:51] Ben: So don't be careful when you, when you say those things, although neonatal patients are rarely able to provide donated organs due to their size, [01:02:00] engaging the family. ask their preference surrounding organ donation can be perceived as validating the child's life whether or not the organ are suitable for donation.
[01:02:10] Ben: Now, despite the significant potential benefits to families of autopsy, organ donation, and research donation, clinicians rarely receive formal training. To skillfully conduct these discussions. I am terrible at these discussions I feel like this is the most awkward thing in the world to have to go back Uh to discuss these things with families So I was very interested in reading this because I never feel like i'm doing this at the right time or in the right way They talk about hurried insensitive conversations about autopsy contribute to a family's emotional distress With insufficient training clinicians are appropriately concerned about re traumatizing families 100 percent always on my mind and some completely avoid the topic Yeah, that's kind of For a lot of us, you kind of have to check that box, so you cannot completely avoid the topic.
[01:02:52] Ben: You kind of have to march in there and ask. So, um, so they basically [01:03:00] conducted a steering committee to design the study. It included a neonatologist, pediatric resident, three parents, it included an acute nurse, support group facilitator, social worker, neonatal neurologist, and, uh, a counselor who specializes in pediatric and perinatal palliative care, and a nurse researcher.
[01:03:14] Ben: In family centered care, they basically created these focus groups and they asked a bunch of questions and all that stuff is in the, um, Is in the supplements and you can have access to it So i'm going to go into the results because we're short on time But three virtual focus groups were conducted with two 90 minute sessions for each group And the final sample consisted of two groups of five parents and one group with four parents representing 14 different families um All participants identified as mothers, 75 percent were aged between 30 and 39 years and 66 percent of them were white. So from the eight main codes, they had 70 and 17 subcodes. They had three themes that emerged from their focus group. And these were number one, the parents lived experiences [01:04:00] around autopsy, organ donation, and research donation in the context of neonatal loss. Uh, theme number two was how these options can contribute to building a legacy to honor their child's life.
[01:04:12] Ben: Number three, the health system recommendations for providing a supportive environment around these decisions. So let's go into a little bit, each one of these themes, and then we can call it a day. So in terms of lived experiences, they're, they're saying that in the face of neonatal loss, their participants strongly supported discussing autopsy, organ donation, and research donation with all affected families when feasible.
[01:04:35] Ben: They reported that these conversations can be challenging, but also provided benefits in terms of the parent's ability to process the loss and feel supported by the medical. Participant 1. 4 reported and I quote we were offered autopsy and we did do it It was really helpful, especially because coco's passing was such a surprise to us The autopsy did actually help us get some good closure on [01:05:00] what happened It was clear to me that the doctors also wanted the autopsy for me It felt like the doctors were really invested in wanting to know what happened because it was this total out of nowhere thing And that gave me a sense of comfort.
[01:05:13] Ben: Another participant said, I remember when they came to speak with us about the arrangement, they stopped and asked if it was an okay time to talk about that. And I felt like that was helpful. So when framed with compassion and support, these options can empower families, provide. Transparency about the baby's medical course, parents of neonate who died have a few opportunities to parent that child and to make loving decisions for them.
[01:05:37] Ben: So the conversation about autopsy organ donation and research donation can offer a meaningful experience, a meaningful parenting experience under appropriate conditions. Another thing that was interesting is that parents reported reported that negative findings could offer reassurance. That there was nothing else that could have been done.
[01:05:52] Ben: So either you find something and that helps them or nothing. And that's also very helpful. Participant 2. 4 said, I know [01:06:00] it's to each, uh, their own, but for me, the more answers, the better. On the other hand, not fully discussing parental options can lead to regret when parents realize what was possible at a future date.
[01:06:12] Ben: A participant said, but I am an organ donor. Uh, the father is alive today because he received an organ donation. I have strong feelings about it and would have wanted to do that and simply wasn't asked. So these experiences point to the critical importance of the clinician's knowledge on the educational value of autopsy and whether organ and or research donation is possible before informing the family.
[01:06:34] Ben: These pieces will allow a thoughtful discussion on the family's wishes after death. So another theme was building a legacy So they talk about how even during these challenging time parents report receiving comfort At the idea that their child contributing to society through their loss Uh, one of the participants said I strongly believe that if the circumstances permit every single doctor should inquire whether a patient the baby Is a [01:07:00] candidate for organ donation because it just adds an other another level of meaning And layer to our children's lives that are cut short and then they say and I quote mostly from the paper here because they said most Poignantly parents reported that one of the greatest tragedies of losing a child So early in life was the missed opportunity to parent the child and to enjoy their presence Another parent reported that it was difficult to speak about her baby in the presence of other families They often did not know how to respond to her And this isolation brought additional sadness.
[01:07:30] Ben: Engaging an organ or research donation offered families a different way to talk about their experience and provided opportunities to remember and talk about their loved child. The last theme is Patient, uh, parent recommendations. They say parents who experienced neonatal loss had many recommendations for standardized approach in these challenging situations.
[01:07:51] Ben: So that was very interesting. One of the key ideas centered around the relationship that support parents at this time and lessen isolation. So because of the high [01:08:00] risk NICU population. They say that a lot of time this conversation happens on like off hours, nights, weekends. And so they said all personnel who work in the NICU or perinatal care should receive bereavement and communication training to be able to skillfully assist the parent to make these decisions.
[01:08:14] Ben: This cannot basically like be left for the daytime person. So everybody has to be skilled at doing this. Most participants recommended discussing autopsy, organ donation, and research donation in the context of other decisions about end of life care, such as baptism or whether to have a larger family visit, if that's something that your unit is considering at around those times.
[01:08:36] Ben: This approach lessens decision fatigue and allows families to think holistically about their parenting choice. In addition, they recommended written materials describing autopsy, organ donation, and research donation. During times of acute stress, it can be It can be difficult to remember details about these procedures written material can also be left with the families to make decisions at their own pace I feel like a lot of us don't even know what these entail like [01:09:00] we're not very familiar with that So I think this would be beneficial for us and then in figure two They basically give a proposed framework as to how to care for these families experiencing new data loss and they have like a five step process So it's very helpful.
[01:09:12] Ben: We'll post that on twitter. You can take a look at it The conclusion are that participating in autopsy, organ donation, and research donation is not the right choice for every family but informing every family of these possibilities should be a standard part of equitable care for neonatal death. If the request is made with sensitivity, some families will participate.
[01:09:30] Ben: in options that give back to society or the medical system, because it is a way to honor their child's life, build their legacy. Um, and the study highlights the necessity to partner with families, to discern their goals and wishes. So many things to take away from this paper. Um, for us, autopsies are not free.
[01:09:47] Ben: It's a big issue. They talk about this, like some parents say, well, it was free and I didn't know about it. And it's like, well, if you have free autopsies and you should definitely offer that for many also. Organ donation is not always [01:10:00] super straightforward if you're lucky enough to be in a big academic center where It's easy to get the right people involved quickly and so on that's not always an option um, but I think that's also going back to when they said to try to have these, um, To try to have these discussions as early as possible.
[01:10:15] Ben: Maybe you can actually plan for that. So um a very very interesting paper, um, yeah wanting me to learn more Have you been at an autopsy because I I tried to go as a fellow.
[01:10:28] Daphna: hmm. Yeah, same thing. I don't know what happened. We were supposed to go in, I think, residency. And I think mine got canceled. So, no, I've never
[01:10:36] Ben: I've been, I've been, I've
[01:10:37] Daphna: tried to go for a specific case,
[01:10:40] Ben: yeah. I went to see like the results to review the results with the pathologist. So like, but like showing us the organs, showing us the heart and stuff, but like the actual process that the kid undergoes is not something I've seen. So yeah, I mean, I think, yeah, I think this is a, an area of difficulty for me, for probably many other people.
[01:10:59] Ben: And, [01:11:00] and, uh, yeah, we, I think it highlights, uh,
[01:11:02] Daphna: I think, I mean, parents are always looking for answers and I think that was such an important point, like, even the negative autopsies where there was no answers, at least they felt like they tried to find an answer and that, and that's You know, something for them and this about the organ donation, I mean, I actually think I believe that lots of parents would opt if we had it, but you know, it's complicated because you need the certified training to like approach parents about organ donation.
[01:11:32] Daphna: So that really leaves the clinical teams out of the discussion and there's good reason for that. However. I think especially in pediatrics and certainly in neonatology. I mean, I think there are parents who would find this exceedingly valuable
[01:11:48] Daphna: in their grief and we don't, and we
[01:11:51] Ben: mean, so many parents have asked me about organ donation. I have never seen. Situation in which I was able to offer that to families in a meaningful way, like actually [01:12:00] organ donation for another human being. It's always like potentially we could send the brain to this lab that does,
[01:12:07] Daphna: So I've seen it a few times. They were able to take the Like corneas. Um, and give somebody their sight. Uh, you know, I mean, I, I think for families, and that can be done after death, I, I think for families that would potentially be enough,
[01:12:23] Ben: yeah. I think like, like you said,
[01:12:25] Daphna: to find meaning, you know. So, it's interesting. Somebody in the community, figure it out.
[01:12:32] Daphna: A
[01:12:32] Ben: Yeah. Yeah.
[01:12:36] Daphna: nice option for families. Okay, buddy, well, we are well over time.
[01:12:42] Ben: That's right. But that was a good bunch of papers
[01:12:46] Daphna: sure. For sure.
[01:12:47] Ben: right, buddy. I will see you next week for another interview
[01:12:53] Daphna: Sounds good. Have a good one.