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#048 - Journal Club 23

NICU journal club the incubator podcast

Hello Friends 👋

I wanted to start off by thanking all of you for supporting the incubator and specifically, our most recent initiative to help Ukrainian NICUs affected by the war.

This week, we have several impactful papers. We review the use of a novel rsv prophylaxis agent in both preterm and term infants. We review the possible benefits of enteral insulin supplementation to attainment of full enteral feeds. We review also a fascinating paper looking at the impact of genetic testing on our decision making in the ICU. And is it really okay to use cotton balls to collect urine samples in nicu babies?

Enjoy ! 🤓


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

Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, Simões EAF, Esser MT, Khan AA, Dubovsky F, Villafana T, DeVincenzo JP; Nirsevimab Study Group.N Engl J Med. 2020 Jul 30;383(5):415-425. doi: 10.1056/NEJMoa1913556.

Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, Muller WJ, Zar HJ, Brooks D, Grenham A, Wählby Hamrén U, Mankad VS, Ren P, Takas T, Abram ME, Leach A, Griffin MP, Villafana T; MELODY Study Group.N Engl J Med. 2022 Mar 3;386(9):837-846. doi: 10.1056/NEJMoa2110275.

Safety of Nirsevimab for RSV in Infants with Heart or Lung Disease or Prematurity. Domachowske J, Madhi SA, Simões EAF, Atanasova V, Cabañas F, Furuno K, Garcia-Garcia ML, Grantina I, Nguyen KA, Brooks D, Chang Y, Leach A, Takas T, Yuan Y, Griffin MP, Mankad VS, Villafana T; MEDLEY Study Group.N Engl J Med. 2022 Mar 3;386(9):892-894. doi: 10.1056/NEJMc2112186.

Influence of Genetic Information on Neonatologists' Decisions: A Psychological Experiment. Callahan KP, Flibotte J, Skraban C, Wild KT, Joffe S, Munson D, Feudtner C.Pediatrics. 2022 Mar 1;149(3):e2021052130. doi: 10.1542/peds.2021-052130.

Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants: A Randomized Clinical Trial. Mank E, Sáenz de Pipaón M, Lapillonne A, Carnielli VP, Senterre T, Shamir R, van Toledo L, van Goudoever JB; FIT-04 Study Group.JAMA Pediatr. 2022 May 1;176(5):452-460. doi: 10.1001/jamapediatrics.2022.0020.

Use of Cotton Balls in Diapers for Collection of Urine Samples Impacts the Analysis of Routine Chemistry Tests: An Evaluation of Cotton Balls, Diapers, and Chemistry Analyzers.Thomas SN, Stieglitz HM, Hackenmueller S, Suh-Lailam B, Pyle-Eilola AL.J Pediatr. 2022 Jun;245:179-183.e8. doi: 10.1016/j.jpeds.2022.02.051. Epub 2022 Mar 3.

Sixth-Hour Trancutaneous Bilirubin and Need for Phototherapy in DAT Positive Newborns. Papacostas MF, Robertson DM, McLean MD, Wolfe KD, Liu H, Shope TR.Pediatrics. 2022 Mar 1;149(3):e2021054071. doi: 10.1542/peds.2021-054071.

Discharge planning of the preterm infant. Anderson N, Narvey M.Paediatr Child Health. 2022 May 17;27(2):129-130. doi: 10.1093/pch/pxac001. eCollection 2022 May.

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


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

Ben 1:03

Hello, everybody. Welcome back to the podcasts, Daphna. How's it going today?

Daphna 1:08

It's going okay, you know, we're getting down to the wire for the people taking the test. But but you know, we still have some time. So. So Journal Club, it is

Ben 1:21

plenty of time. Yeah, this is, this is a bit of a bizarre week. Right. So we released an episode with Dr. Paul Offit a few days ago. And that was done as a special episode for or the first annual Eastern Medical Research Conference that took place March 10 to march 12. Thank you to everybody at Eastern society for pediatric research and the American Federation for medical research to reaching for reaching out to us and sponsoring the giveaway for allowing us to put ourselves put us in contact with Dr. Paul Offit. That was a lot of fun.

Daphna 1:58

So we love we love doing special episodes.

Ben 2:01

Yeah, yeah, that was that was actually a lot of fun. It was. Yes, it's always more work. But it's fun work. And for the people who are not following our other podcasts where we announced it as well. But we're very grateful and thankful to everybody who donated to our campaign to help make us in Ukraine. We have now officially exceeded our original goal of $20,000. Obviously, if you're following the news, you do not need any reminder that there's definitely a need. Especially considering what happened recently with the bombing of the maternity hospital. So yeah, there's thank you to everybody who donated your generosity is really appreciated. I was just in touch with some of the folks at the Coalition for preemies. And they're also expressing their gratitude towards everybody who has donated and who's helping them in their efforts to provide relief to the Ukrainian NICUs.

Daphna 2:55

Yeah, they're I mean, they're taking supplies over the border every day, it seems like and like they said in our interview, it's going to be an ongoing need. So certainly, if people haven't donated yet and want to or

Ben 3:09

fund that, we'll leave it we'll leave it open for anybody, but I'm pretty I wanted to mark the the moment of our of our community getting together and raising that kind of money within the span of a week. That's amazing. I'm very proud of, of calling ourselves recoil point. Yeah. Okay, and we have a lot of very important papers to go over today. So I guess I'm starting. Yeah. All right Daphna. I'm gonna give you the choice. You want to do RSV or insolent?

Daphna 3:45

Let's do RSV. Oh, yeah.

Ben 3:48

Okay, you're opening a can of worms. So, people this I mean, the papers I'm presenting today are pretty big. I think at least two of them are massive. So what is this whole RSV business? If you look in the New England Journal of Medicine, so there's a paper this week that is called near Sivan Mab for prevention of RSV, in healthy, late preterm and term infants. Now, this is a follow up study of an article that came out about last year in July 2020. That I do not think we reviewed on the podcast, which and that and that paper was called single dose, your Sivam AB for the prevention of RSV in preterm infants. So I'm going to read you this paper, and then I'll give you to the other people that came out as an addition because the protocol is pretty much the same. And I'm assuming people care more about preemies. I don't know why, but they want to hear about the preemie stuff. And then we'll go over some some of the extra things. So

Daphna 4:51

Well, I think, I mean, this is a very this is a very interesting paper. Oh, this is just for preemies. You know this is game

Ben 4:58

changing. So, let's start from the from the background. So they mentioned that RSV prophylaxis obviously is available currently in the form of synergis palivizumab, which is basically RSV IgG. And it's administered for the people who do not know in five monthly injections. And the cost of these injection is prohibitive to the extent that many regulating bodies and insurance companies have effected very restrictive recommendations. And basically, according to the paper, it limits prophylaxis to less than 2% of the annual us birth cohort. So, really, really, very tiny minority of babies are having access to synergis as you probably all know. Now there are seven Mab is a recombinant human immunoglobulin G, one kappa monoclonal antibody, it binds the highly conserved site zero epitope present on the prefusion conformation of the RSV fusion protein. Now why are they testing this new thing? Why are we doing this? Well, your civil Mab is a molecule that has a much, much longer high Flyff and might be even just as effective as synergis. And so the rationale is, if you could get away with a single dose of RSV prophylaxis, then you're going to be allowed to protect a much larger number of infants. Okay, so who were their participants, so they were healthy infants who had been born preterm between the gestational ages of 29 weeks through 34 and 634 weeks and six days, and who were one year of age or younger, entering their first full RSV season. The participants were randomly assigned in a two to one ratio to receive either an im injection of 50 milligrams of near Sivan Mab, or normal saline placebo during a two month period immediately before the RSV season. Obviously, this was not a trial to look at Babies against synergis. Right, and we'll get to that in a minute. But I want to clarify that right now, since we're talking about this. And so this is babies who would not have been candidates for synergis, right, who were now offered this other form of RSV protection against a placebo,

Daphna 7:22

because lots of kids get RSV, not just oh, and many die of ours, right.

Ben 7:28

So but we'll talk about synergist with synergist versus synergist versus OD, the name is escaping near Sivam. App. Okay, we're gonna get there. So the participants of the trial were monitored medically. And for 150 days after near city map or placebo was administered. That was either done by telephone every two weeks and in person during trial sites visits on day 831 91 151, as well as on day 361. After administration of the dose. The monitoring was done by site investigators, or if the children were treated elsewhere, then they had to review the medical records. And if they received medical attention at a location other than the trial site, then the parents had to take the child to the participant site where they could be evaluated for the respiratory illness. The trial was conducted at 164 sites in 23. Countries No need to say this was extensive. Yeah, that's the trial. However, I think this is important to mention just for disclosure was designed by the MedImmune and AstraZeneca and funded by MedImmune, AstraZeneca. And Sanofi Pasteur which I think is important, is important to disclose for sure. The primary endpoint was medically attended RSV associated lower respiratory tract infection through 150 days after near seven Mab or the placebo was administer the secondary efficacy endpoint was hospitalization due to the condition during the same time period, okay, so far so good. They also were they're also trying to determine the pharmacokinetics of near Sivan Mab and the incidence of anti drug antibodies as described previously. That means that they wanted to know the levels of the drug and they wanted to know if because it is an immunoglobulin have patients made antibodies to the drug itself? A positive titer for anti anti near Sivan Mab antibody was defined as a titer of one to 50 or more. This was the statistical analysis the efficacy analysis was performed in an intention to treat fashion and that's pretty much it for the methods. So to summarize, they're trying to find out preterm babies one dose of near Sivam AB does that cover you for the arm To be season. So now let's go into results. The participants enrolled between 2016 and 2017 they were able to have 1447 Babies who received injection 966 in the nursery map group 481 in the placebo group 97.5% of the participants who were actually randomized completed the 150 day efficacy period 94.2% of those assigned to the nurse near seven Mab and 93.8% of those assigned to placebo, completed the 360 day follow up,

Daphna 10:38

which is which is actually amazing. Yeah, I mean,

Ben 10:41

I, I am not going to stop mentioning these Hi follow up rates because if like me, you've done follow up work. It is atrocious, right. I mean, when I was able to get close to 60% follow up for up to three years. It was to me the biggest accomplishment and you read this the studies where it's like 97 95% It's tremendous.

Daphna 11:05

Well, I mean, we will talk about this but I would venture to say that's a higher percent than people who return for their subsequent doses of RSP you know, prophylaxis. So

Ben 11:17

having done this type of work I don't know it's not described in the in the paper did they give them like low incentive free car rides to medical appointments, free gift cards, we've done that in the past and these are just as good I mean, if you want to incentivize people to come back for follow up that works, but I don't know if they did. Okay, so let's talk about efficacy. Listen to this medically attended RSV associated lower respiratory tract infection occurred in 2.6% of the participants in the near Sivan Mab group and the 9.5% in the placebo group. hospitalization for this condition occurred in point 8% of those in the near seven map group versus 4.1%. In the placebo group. The incidence of medically attended RSV associated lower respiratory tract infection was 70% lower with near Sivan Mab than with placebo. The incidence of hospitalization for this condition was 78.4% lower when they're 70 Mab than with placebo. over the entire 150 Day efficacy period after administration of the dose infants who receive near seven Mab had a lower risk of medically attended RSV associated lower respiratory tract infection than infants who received placebo as well as a lower risk of hospitalization for this condition of the participant who were hospitalized because of our because of RSV infection, all those who were admitted to the intensive care unit that was five participants or receive the system ventilation that was for participants, they were all in the placebo group. among participants who had medically attended RSV associated lower respiratory tract infection, fewer nurses and Mab recipients for which was 16% than placebo recipients 32% received supplemental oxygen. So, like a third almost medically attended lower respiratory tract infection from any cause through the 150 day. 150 days after the dose occurred in 25.8% of the participant in the placebo group, and 19.7% in the near seven map group, representing a 23.5% lower incidence. Similarly, a lower rate of hospitalization due to any respiratory illness was observed when you're serving Mab than with placebo representing a 42.5% lower incidence in the near Sivan Mab group. The occurrence of non RSV lower respiratory tract infection was similar between the two groups. So really very specific to that pathology, which suggests that infections due to other respiratory pathogen was not affected by near Sivan Mab. In terms of the safety data, five deaths occurred through the 361 day period, two deaths in the near Sivam app group and three in the placebo group. One death in the placebo group occurred after the trial period. And no deaths were known to be due to RSV are considered by the investigator to be related to near seven map or the placebo. Let's talk quickly about pharmacokinetics. The mean half life of nivolumab is 59.3 plus minus 10 days on day 151 Serum concentrations of 98% of these of these children in the near seven lab recipients were above the targeted 90% effectiveness concentration threshold of 6.8 microgram per milliliters. So they still had good levels at that time. And in terms of anti drug antibodies, they were detected in about 5.6% of the participants will receive near seven Mab and in 3.8% of those who received placebo, so there is like a baseline effect there as well. So, in the discussion, near Sivam lab, they concluded an answer about provided protection with the single aim dose probably owing to its increased potency and extended half life of 63 to 73 days, compared to the shorter half life of synergis, which is 19 to 27 days. And they're highlighting the fact that on day 151, a single dose of near near seven Mab, most infants still had serum concentration that were above the target threshold. Okay, so this paper basically tells you that we may have a medication that even if I haven't been able, I haven't had the time, we've been very busy. I wanted to look at how much this injection would cost technically, right. But even if it's as expensive as one for synergis, right, one dose should lower the cost five times, because you do not have to go through these five monthly injections. So even if you say they're both antibodies, and so, so then

Daphna 15:51

well, and there's, there's a cost, right to the, to the system and to the society of a family having to come back every month, right? For another appointment. So it's not just money, but it is just money, right? Parents have to have gas, they have to have transportation, they have to have a babysitter for the bigger kids. You know, you know, there's there's a lot of costs that we were not we can't even calculate.

Ben 16:21

Exactly. You're absolutely right. I wonder how much time it will get missed speaking for 15 minutes and you continue quickly. So then you have the paper that came out this week. Was it this week, or Yeah, March March 3, which is basically the same trial looking at the use of near seven AB in late preterm and term infants. I'm going to spare you the protocol is pretty much the same, that the babies had to be now at least 35 weeks, right so they were no longer preterm. So they had almost 1500 infants that underwent random randomization. They had about 2000 in the near seven Mab about 500. In the placebo group. Medically attended RSV associated lower respiratory tract infection occurred in 1.2% of the near seven Mab group compared to 5% in the placebo group. The efficacy was 74.5% for near Sivam AB hospitalization related to RSV lower respiratory tract infection occurred in point 6% of the nursing map group compared to 1.6% in the placebo group. And then looking at anti drug antibodies after baseline were detected in 6%, of the nurse of a map group and in 1% of the placebo group. serious adverse events were reported in 6.8% of the near seven map group and 7.3% in the placebo group. So the bottom line is that in in late preterm interim infants as well, the single injection of near Sivan Mab administered before the RSV season, protected healthy, late preterm interim infants from medically attended RSV associated or respiratory tract infection. They tried to make a case by the way, I'm just going to say like the one thing I could, I could the first author on this latest paper is lower Hemet and this is all part of the melody study group. The one thing I would say is that they keep saying oh, this should cover for like the duration of an RSV season. 150 days is not a full

Daphna 18:16

RSPCA, especially down here in Florida, right.

Ben 18:18

It's right. Yeah,

Daphna 18:19

I mean, if you started five months in Florida, it's like eight months.

Ben 18:24

And you could say that like maybe 150 days is like the peak where you have like the winter months, but it is a bit more than that. So that's the only knock I would have on the paper. Now, the last thing I wanted to mention is that if you go into correspondence inside the New England Journal of Medicine, you should be able to see something a letter called safety of near seven Mab for RSV infants with heart or lung disease or prematurity. And so that's a very quick it's not even a correspondence, but it's almost like a very brief report on the study that they're currently running that's not completed. And they're reporting the safety and pharmacokinetics of near Sivan Mab through the the first RSV season, they're running a study that where they're testing it over to RSV season, but they have data over the first one. So they're reporting it. And what they're doing is that they're looking at preterm infants, and they're randomizing infants based on whether they have BPD or congenital heart disease versus neither. So they enrolled preterm infants who were eligible for synergis and who were born before 35 weeks, and who did not have congenital heart disease or chronic lung disease. And then they had infants who had uncorrected partially corrected medically treated CHD, or chronic lung disease warranting therapeutic intervention within six months. And the infants were random were randomly assigned to receive either near seven Mab in a single fixed intramuscular dose. If they were less than five, basically they change the dose based on whether they were more or less than five kilos or five once monthly intramuscular doses Have synergis So what's important for you to understand here is that you have a subdivision. So within each group, you have synergis, and then your visa map, and you have a near Sivan map group. So in the in the babies who had BPD and congenital heart disease, they split the two and one group got five doses of synergist, Windows seven or seven Mab. And for the just preterm cohort, they had they did the same one syndromes group, one year seven group, so they're not providing in a table format. But they are writing that seven of the infants in the trial had medically attended RSV infections of the lower respiratory tract for in the near Silverman group, that was point 6%, and three in the synergist. Group. Okay. I think the the safety and efficacy data was very similar. But what's interesting is that it doesn't seem that in this case, your civil Mab is is superior to synergis. It may be working just effectively. But again, it's a much simpler way of administering it. So are we moving towards the bottom line? Is it in 20 minutes? Are we moving towards a phase in our career, where synergis is going to become a thing of the past, and every baby at risk is going to get these nurses and Mab infected injections, so that they would prevent RSV infections? It's it's very possible. I mean, I think this is, yeah,

Daphna 21:27

well, I think, like lots of things in the pharmaceutical industry, it's good, it's good to have a little bit of competition, right, be it to lower the prices. And I mean, we have, we would have to show efficacy, but but even synergist, it's only efficacious if you get it right. And, you know, where I trained, we were a small community, and we it was all the offices eating, you know, pediatric clinics, you know, fed into the academic center. And so they were, they were good at doing the insurance referrals and in getting synergist for their patients. But our experience right now, where we are is is not the case, General, pediatricians are not doing the prior offs, they don't want to handle the injections at all, because it's a lot of work. And that's, that's five appointments, you know, that they that they have to make, you know, nurse visits for. And so that means relying on sub specialists to do something that's really

Ben 22:36

it's a vaccine appointment, right, which were, which are supposed to be very quick and get the lowest reimbursement. But if you have to be on the phone with an insurance company for two hours to argue whether it be needs surgery,

Daphna 22:48

it's where they're like, concrete criteria. Yeah.

Ben 22:51

And it's no wonder that they turn this to a pulmonologist and say, I'm not doing this.

Daphna 22:57

And so I mean, a lot of babies are not getting it. And that's, and that's, even if you have a place to go get it. It's a lot of effort for these families who may have, you know, babies with multiple comorbidities to go get. Yeah, it's all the appointments. So anyways, I'm glad to see that there's some, you know, something on the horizon to talk about.

Ben 23:21

Yeah, yeah, I think. And again, maybe because maybe the cost will be lower. I don't know. Well, I yeah, I think we'll have to see. But yeah, the paper for the preterm infants was published July 2020 2021. And the one for late preterm and term infants was published this this 2020, actually, so two years ago, so that's why that's why we missed it the podcast in existence. Yeah. So. Okay, definitely Europe.

Daphna 23:50

So I want to do this paper from pediatrics, influence of genetic information on neonatologist decisions, a psychological experiment, lead author, Catherine Callahan. And I thought this was a really interesting kind of study design. So their objective was to determine how different types of genetic information with kind of uncertain implications for prognosis would influence the decisions of clinicians to recommend like war intensive care versus moving towards palliative care. And you know, the author's talk a lot about why this is important. And they're right, we're using genetic testing so much more now. And it's just going to become more prevalent. And so I have this was a really interesting study. So in fall of 2020, they sent a 22 question questionnaire to 3600 Neos using the listservs of the American Academy of Pediatrics section on neonatal and Perinatal medicine, and the Children's Hospital neonatal Consortium. And so the questionnaire had questions. And then in addition, they used these for unique clinical cases. And there were two versions of each clinical case, and I'll tell you about them. But the the first case described a variant of uncertain significance. So you know, we get those all the time. The second case, a genetic diagnosis, that affects neuro development, but not survival acutely. And the third case, a genetic versus non genetic etiology of an equally severe pathology. And for the fourth case was a pending genetic testing result. And so participants were randomized to see all four clinical cases, but only one version of the case. So one version of the case had information about genetic testing, and one version of the case did not. And then they were asked to respond to each case using a Likert scale. So I'll tell you about the cases because I think it will help kind of elucidate what they did here. So the first case was a patient with chronic lung disease at a stage where they had to have a discussion about tracheostomy and gastrostomy tubes. And in the quote, unquote, genetic version, the patient had a variant of uncertain significance and a certain unknown significance. What did I say?

Ben 26:16

Uncertain, same thing, same thing

Daphna 26:20

in a surfactant protein, and in the non genetic version, it they said that there was negative negative genetic testing. In the second case, they described a preterm infant with sepsis and asked about, like a central line to continue the antibiotic antibiotic therapy. And in the genetic version, the patient was also incidentally diagnosed with Williams Syndrome. And in the non genetic version, the genetic testing was negative. And just for understand, just as a reminder, for people who are taking the boards, Williams Syndrome is a gene deletion associated with mild intellectual disability and unique personality characteristics, and some endocrine and cardiac problems. But the survival is not significantly reduced. It's not a life limiting condition, unless the cardiac abnormalities are very significant. The third case was a patient with pulmonary hypoplasia. And participants were asked about ECMO was the baby a candidate for ECMO? So in the genetic version, that hypoplasia was from a mutation with a broad spectrum of outcomes, which could include very severe lung pathology or not that severe, not severe lung pathology. So it, it didn't, you couldn't know for sure, what if the maybe symptoms were related to this mutation. And in the non genetic version, the etiology was oligohydramnios. The third case was looking Sorry, that was the third case. And then the fourth case, the patient was a term male with progressive muscle weakness and ventilator dependence. And the genetic version included attending whole exome sequencing, whereas the non genetic version really had no mention of genetic testing. So basically, participants were asked about their readiness for goals of care conversation. And they were also asked to what degree all of the information would inform their recommendations for goals of care, like need for long term IV nutrition, brain MRI results, social work, you know, Certified Nursing help, and other things that the baby might need. There was also a bunch of additional questions about their own demographic details and work work environment. So there were total 551 respondents about 20% of those who were asked to participate. So in the case, in the first case, the finding of a variant of unknown significance was associated with participants being less likely to recommend a tracheostomy and gastrostomy tube with a P value of less than point 001, and more likely to recommend transitioning to palliative care. And this confirmed the author's hypothesis that a presence of a variant of unknown significance would be associated with people being less likely to recommend invasive care. And even though they have no idea if the variant is related to the problem or not. They also asked about what helped what was a factor in their decision making. So they were they were concerned that pain and suffering were ranked is more important decision making factors for those who saw the case with the variant. In the second case, the incidental incidental findings of Williams syndrome was associated with participants being less likely to recommend central line placement P value less than point 001 And more likely to recommend transitioning to palliative Hear. And so this was also consistent with their their hypothesis that a genetic finding with even kind of mild to moderate neurodevelopmental implications would be associated with favoring palliative care over invasive interventions. Same thing, they listed pain and suffering and long term survival as more important, the most important factors in their recommendations, even though Williams Syndrome is not associated with the decreased long term survival. And the third case about providing ECMO, they were more likely to recommend transitioning to palliative care, the patient had a genetic etiology of disease, even though the patient's severity is were similar P value less than point 004. And their their hypothesis was that a genetic etiology would would mean that providers were more likely to remain in palliative care and less likely to recommend ECMO. They didn't have a difference in the rationale for their decision. And then the final case, so whether or not they had the whole exome sequencing back, they actually, the reported readiness for having a goals of care meeting did not differ if they had the sequencing back or if the sequencing was pending, or if there was no report on the sequencing. But the providers ranked finding a genetic etiology is the most important factor from forming the recommendations to the family. MRI results were the second most important informing recommendations followed by whether or not the patient would orally feed. So I thought this was a really interesting study, I think they did a good job at looking at a real severity, like a breadth of severity of cases and a variety of problems that we faced when we ordered genetic testing. i They were not surprised by the findings. I was surprised by the findings. But I'm reaching that assist. Yeah.

Ben 32:01

Yeah, I think I think we have I think this is great. I mean, I like psychology, I like psychological experiments. So when my two worlds are colliding, it's a lot of fun. And I think it underscores a lot of issues with the progression of our field that we've gotten so complex, that we've compartmentalized everything into big blobs of genetics versus no genetics. And like you said, we're not really being very granular and like what kind of genetic syndrome maybe it's not. Right, what about penetrance? What about mosaicism? What about all these things, right? Where these decisions should matter. And in truth, we hedge, basically, we say, well, genetics then more likely to get so and so. And that's what we've talked with guests on in the past, which is that because the prior data influences how we manage babies in the future, say, well, because I know that babies with genetic disease are more likely to need a trach, because that's what was reported. And that means that the one I'm presented with must also be needing a trach. And it's like, that's not always the case. So I want to see more, I want to see more of these

Daphna 33:08

studies. Yeah, I think they're really important. I think it underscores also the way we do informed consent about genetic information. Because if you're studying for the Board's it's a good reminder that you have the opportunity in some disease states to pick a very specific test. Because you, you may be in the situation where you get a lot more information than you intended to get. And, you know, how do you help a family navigate that, especially if they weren't? If especially if they didn't understand what the burden of testing results may may be? You know, I think it especially in some of these very acute severe cases, parents say yes, and send whatever tests you want, let's get all the information we can get. And I think a lot of times, that's how we feel too. But we get a lot of those variants of unknown significance. You don't know what to do with the information. So I thought it was a cool study.

Ben 34:02

Catherine press Callahan, who's on Twitter at kp Callahan. MD. Keep keep keep churning out these studies. I want more. This is too entertaining. All right, is my turn now. Yeah. Okay, let's go.

Daphna 34:18

So we're talking about insulin now.

Ben 34:21

Yeah. Okay. So this is a paper that was published in JAMA peds first author is Elise manque. The paper is titled efficacy and safety of enteral, recombinant human insulin and preterm infants, a randomized clinical trial for disclosure purposes. This is a sponsored trial by a company called New trivia, I think is the is the name and the obviously the company making the product. So again, I don't think I don't think it plays much of a role in this case, but I want to be fully transparent. So let's go over some of the information that's present. But in the background, I think it's interesting. So they are mentioning how the natural insulin concentration in human milk usually peaks in the early postpartum period, but then they declines to a basal level within the first three days postpartum. And insulin is not something that we supplement in formula or anything like that. Right. So that was an interesting observation. Recombinant human insulin formulation for enteral administration in preterm infants has been developed in order to combat feeding intolerance, and thereby improve short and long term clinical outcomes. So they did like a small like phase two trial that they're referring to where they had about 16 babies, and that was very successful. So now they want to take the next step. They are performing an international multicenter, double blind, placebo controlled randomized clinical trial to evaluate the efficacy and safety of two different dosages of origin insulin as a supplement to human milk and preterm formula in preterm infants with a gestational age of 26 to 32 weeks. So is it something the question is, are we are you going to start supplementing feeding with insulin? So this so let's talk about the study design. The multicenter, double blind, placebo controlled randomized clinical trial involved 46 neonatal intensive care units throughout Europe, Israel and the United States, and it ran from October 2016 to April 2018. So for the participants, they included babies who were born preterm between 26 weeks and zero days and 32 weeks and zero days of gestation, and with a birth weight of 500 grams or more, and they were eligible if they were clinically stable, able to tolerate enteral feeds and expected to wean off parenteral nutrition during their stay in the primary hospital. The exclusion criteria were thing interesting, major congenital malformation, not surprising suspected infection and FIU to above 60% or more at randomization, intrauterine growth restriction, which they defined as a as a weight less than the third percentile on the Fenton or less than the 10th percentile with the combination of an abnormal Doppler velocimetry. Confirmed and necrotizing enterocolitis Bell stage two or three. If the babies were already on four feeds at the time of randomization, if they were older than five days of age at the time of randomization, if they had hyperinsulinemia, requiring 12 Mix per kilo per minute of glucose. And if they had any other way any other form of systemic insulin administration, if there was a historically history of maternal diabetes, recurrent requiring insulin during the pregnancy, or if the babies were NPO, or had to go through extensive resuscitation after birth or CPR and so on. Obviously, right, this is a safety and efficacy study so so they're not looking to cure or fix anything, they just want to see can we give it and is it safe. The participants, they were randomly assigned to receive either a low dose form of the RH insulin which was 400 Micro international units per ml of milk, or a high dose which was 2000 Micro international units per ml milk per ml of milk. And then there was a third group which was the placebo arm and they were allocated in a one to one to one fashion. They did some stratification based on gestational age, I'm going to skip that, and the trial began within five days postpartum, so about 120 hours. If the infant was exclusively fed mother, the mother's own milk treatment was not initiated until 72 hours postpartum. This because of what we discussed in the introduction about the peak of the insulin, the standard duration of the intervention was 28 days, but the treatment was discontinued earlier in cases where a unit or hospital transfer was required. In terms of how they were advancing feeds and all these things, that was at the discretion of the of the providers and the neonatologist. What were the study outcomes, the primary outcome was the time to achieve full enteral feed and that was defined as an interval intake of 150 mL per kilo per day for a total of three consecutive days because obviously if you reach 151 day, and you go into the next that's that's not your secondary outcomes were the number and percentage of infants reaching for enteral feeds within six, eight and 10 days of the intervention time to achieve an interval intake of 120 mL per kilo per day for three or more consecutive days. The number of days receiving parenteral nutrition growth velocity body weight on study day 28 body weight Z scores on study day 28 and change in body weight Z scores. They had some safety outcome including serious adverse events and suspected unexpected serious adverse reaction. Blood Glucose tests were performed twice daily in the first four study days and thereafter on alternate days between 7am and 10am before enteral feeding, and an extra blood sample was collected at day of life to deal at study day. 28 What are the results? Alright, are you ready? I'm ready. Are you ready? Are you guys ready? 40 minutes later, this is like the slowest Journal Club we've ever done, but that's okay. 303 Babies met the eligibility criteria and underwent randomization. 110 infants were located to the low dose RH insulin 95 to the high dose RH insulin and 98. To the placebo. baseline characteristics were similar between the two groups, the trial had to end early. Based on interim futility analysis of the 303 included infants 86%, which the primary outcome, which was for internal feed, the major reason for failing to reach the outcome were early street termination owing to hospital transfer and early termination of the trial by the sponsor. Time to achieve full enteral feed at least 150 mL per kilo per day for three consecutive days was significantly reduced in 94 infants receiving low dose insulin and 82 infants receiving high dose insulin compared with 85 infants receiving placebo. Compared with the placebo. The difference in median time to full enteral feeds was four days for the low dose group and four days for the high dose groups. They were by the way, in this statistical analysis, they mentioned how their expectation was to maybe reduce the time from like, eight days to like 6.6 days, so they definitely overachieved Yeah, the proportion of infants who achieved for enteral feeds in the first six, eight and 10 days of the intervention was significantly higher in both active treatment groups compared to the placebo. In addition, time to achieve an enteral intake of 120 mL per kilo per day or more for three consecutive days was significantly reduced in both active treatment group compared to the placebo group. And the number of days to receiving parenteral nutrition was significantly reduced in both the high dose group compared with the placebo. So not really in the in the notice. Weight Gain rates did not differ between the different groups. Let's talk about that. So the the subgroup analysis by gestational age was interesting, the median time to achieve full full enteral feeds in infants with a gestational age of 26 to 28 weeks of 26 and zero to 28 and six was 15 days in the low dose group 12 days in the high dose group, and 16.5 in the placebo group. The difference between high dose and placebo group was statistically significant in the subgroup of 29 and zero to 32 and zero weeks, the median time to achieve full enteral fees was significantly reduced in the high dose group compared with the placebo group. From seven from 11 to seven days, the safety outcomes. They were a total of 16 out of 108 infants in the low dose group 11 out of 88 in the high dose group, and 19 out of 97 in the placebo group that had one or more severe adverse events, these events involved hypoglycemic events. When it came to neck it occurred in seven in 6% of the low dose group 5% in the high dose group and 10% in the placebo group. None of the infants developed serum insulin insulin antibodies. So the conclusion is that enteral administration of these two different types of origin insulin dosages were safe and compared with placebo, significantly reduced the time to achieve for enteral feeds in babies with a gestational age of 26 to 32 weeks. They support the use of Rh insulin as a supplement to human milk and preterm formula. Definitely.

Daphna 43:58

Yeah, I mean, it's an interesting study, especially because, you know, insulin does a lot of stuff, right. So it's also interesting that there was no difference in like the blood glucose values, and there was no difference in growth, which is interesting. You know, like for it to exert enough enough efficacy to make this major change, but not any of those changes. But, you know, we're always looking for a waist to get babies to full feeds faster.

Ben 44:35

I mean, we said it was gonna be an impactful Journal Club. I mean, we have a new way to profit as far as we we have a new in supplementing babies with insulin. I mean, what are we going to do next?

Daphna 44:49

Okay, so this was an interesting paper in Journal of Pediatrics. Because like so many things in our day to day work, it is evaluating something that we do Do all of the time without really thinking about it. So this paper is called use of cotton balls and diapers for collection of urine samples impacts the analysis of routine chemistry tests, and evaluation of cotton balls, diapers and chemistry analyzers something, yeah,

Ben 45:17

everywhere I worked before my first job as an attending, they collected urine through the bag, right? Yeah. And every time you ask for urine dinners, like Oh, my God, the bag falls off, et cetera, et cetera. And then I take my first attending job, and I see the cotton balls. And I'm like, This is so freakin smart. And anyway, I'm sure you're going to talk about like, what does that what do we talk about when we mean cotton balls? Because I'm sure there's some people who don't know. I know. Yes, sure. Okay,

Daphna 45:45

lead authors, Tiffani, and Thomas. And so this is coming out of the University of Minnesota, the Ohio State University Wexner Medical Center, in collaboration with Northwestern and Nationwide Children's Hospital. I think I got almost everybody. The objective was to see if the cotton balls affected the analysis of urine. And you're right, maybe not everybody knows what we're talking about. So I'll I'll tell I'll describe their protocol for you. So I mean, I guess if you've never seen it, basically, what they do is in an effort, not you know, the bags always spilling the bags always spilling so they put cotton balls in near the urethral opening in the inner baby diaper so that it catches urine. And that's basically what they did here. So they basically took well, it's what they tried to imitate, I guess. So they took basically leftover urine samples. And again, we're looking at electrolytes not anything infectious. So they pooled all of these kind of leftover urine samples to generate 20 samples with a minimum of 100 ml each. And then they saved a few the samples as control samples, 10 mils, each of urine that was not exposed to cotton balls or diapers, and it was stored. And then they created these six different treatment groups. So they wanted to look at different types of cotton balls, different brands, different brands of diapers, and different analyzers in the lab,

Ben 47:21

and different brands of babies. No,

Daphna 47:25

that would be it. So I'll tell you the I'm no expert in cotton ball brands, but I'll tell you the different treatment groups. So they had curity cotton balls with Pampers curity cotton balls with Huggies dirty cotton balls with loves dirty cotton balls with no diaper, and century in cotton balls with Huggies gentry and cotton balls with Pampers, so they didn't have all the combinations, or they didn't have all the same combination, suddenly

Ben 47:54

back to Calculus where I have to calculate like for the formation.

Daphna 48:01

And then, and then this is what they did with this. So for each of the six treatment groups, they took about 20 mils of urine, they applied it to five to 10 cotton balls, which is way more cotton balls than I've ever seen anybody put in a diaper, so just of notes, and then they put it either in a zip top plastic bag, so that represented no diaper. Or they put the they put sorry, it took the cotton balls, put a little piece of plastic over them to represent like skin in the diaper and then they wrapped the whole thing in a diaper. And then the these diapers full of urine soaked cotton balls were incubated for an hour at 37 degrees Celsius as if they were being held in a in a against a baby in a diaper. And then all the samples both the controls and those exposed to cotton balls were divided into Alec cots and sent to five different hospital laboratories for analysis each using a different analyzer. Okay, I think we got that hopefully everybody interesting about that. Okay, um, across the nine analytes and there were no apparent trends that were specifically associated with the brand of cotton ball or

Ben 49:21

diaper and when you say analyze You mean like your analysis.

Daphna 49:26

So now to your analysis. So they looked at they looked at like urine, electrolytes soy protein, albumin, creatine, calcium, potassium, magnesium, sodium, urea, and phosphorus. Hmm. Okay, so no, like that was actually my question. I was interested in the urine pH, but that wasn't one of the analytes.

Ben 49:50

Yeah, no, nitrites are leukocyte esterase stuff that we tend to look at for infections and things like that.

Daphna 49:56

Right. And I mean, I guess I because most of us, you know, if you're really worried about infection, you probably get a calf sample, right? So anyways, that's why they were specifically I think looking at, that's fair electrolytes. So there's, like I said, no apparent trends specifically associated with brand of cotton ball or diaper, which was, I guess nice to know. But there was significantly decreased measurements of albumin and total protein from the urine that was pre soaked in both brands of cotton balls, and in all brands of diapers, compared with the control urine that was not soaked in cotton balls not wrapped in diapers, regardless of which analyzer they used. Total protein demonstrated an inverse proportional relationship between the level of analyte and the extent to the negative bias based on the analyzer. And they decided that the diapers did not significantly contribute to the absorption of protein. As a result from the analysis of the purity plus no diaper, or the one in the zip top bag, also showed significant bias. Similar to the samples kept in diapers. The other tests that showed significant differences were calcium, potassium and magnesium. But they very much dependent on the analyzer in which they were run. And that's, I mean, that's valuable, right? Because depends on what your analyzer is. But to me, not the main part of the point of the story. So if you're interested in that, you had to take a look. Calcium, though, appears specifically affected. And I thought that was important because one of the ways we we test for a disorder of hypercalcemia is using urine calcium. So the other measurements, sodium, urea and phosphorus measurements for all urine treatment groups demonstrated consistent results, with measurements from the control urine and on all five analyzers. So definitely, if you were looking at if you were looking at albumin or protein, it would underestimate. If you're using cotton balls, it would underestimate those values. And that's a major reason why I think you would look for something like proteinuria. And chemist, I told you calcium was specifically affected. Nearly all platforms overestimated the concentration of calcium in the urine, and the magnesium and urine, when soaked in the cotton balls compared with control, unit control urine, but again, it depended on the analyzer. So when I think about the things that we test for using urine, and those are some biggies, I was glad to see that maybe the so the sodium was not affected. But the moral of the story is, it's not benign. It's not, it's not nothing. So I guess we have to deal with the bags, which I'm sure are also more expensive, and they're harder to use. And you definitely don't collect urine within like, the first few attempts is what I've learned. The cotton balls are definitely faster. But that's I thought it. I thought it was good to know.

Ben 53:17

Yeah, yeah, I like that paper.

Daphna 53:20

Now, you know, you're excited about that paper. Okay, your turn.

Ben 53:24

Yeah, so I'm gonna go with the most.

Daphna 53:27

Yeah, we don't have a lot of times.

Ben 53:29

We don't. Have you seen this paper six, our Transcutaneous bilirubin and need for photo therapy in DT positive newborn, we had a law argument definitely about that specifically,

Daphna 53:40

universally obsessed with the Billy Rubin.

Ben 53:44

So this is coming out of the Department of Pediatrics at the Naval Medical Center, which is kind of cool, because if you look at the author names, it's not doctor. It's Major Michael Piper Costas. Second author is Captain Dwight Robertson. And so that's, that's pretty neat. Anyway, this is this is the kind of joys we can have when we do the podcast, you know, chill wins. So what is this story about? So they studied basically a large sample of babies who had abo incompatibility and the at positive results, to better characterize the outcomes and to evaluate the predictive ability of an early hour six, like taking that six hours of life Transcutaneous bilirubin, as a timely, inexpensive, and non invasive screen for identifying which infants will need phototherapy in the first six hours. So Daphna has been pushing me to revise the bilirubin protocol at our institution to include Transcutaneous. Billy follow up for the babies who have the 80 positive results. And I've been making the argument that it's it may be unpredictable. So we've been having an argument on this so it takes months for us, but I want to highlights in all humility. How amazing it is that I'm the one who takes on this paper.

Daphna 55:06

Oh, that was not that was not I mean, I did that on purpose.

Ben 55:13

So yeah, in all humility, I'm reading really good. In any case, I'm getting tired. The this is a retrospective study done at the Naval Medical Center from 2013 to 2017. And what did they do? Basically, I'm going to stop reading from the paper, they do they do the usual thing that we do they get a sample from the court if they know that the baby is DHT positive, and they get like hemoglobin or retake and Billy. The one thing that they said was maybe we could also get at six hours of life as we're getting all these other tests, we could get a transcutaneous belly and that could help us determine what is the validity of doing a transcutaneous belly at six hours of life in babies for DHT positive in order to find out what is the likelihood based on the initial six hour belly that they will need for therapy. It's funny because they do mention how babies who are DHT positive like the protocol is that they have to be screened before discharge for for for hyperbilirubinemia right in the product. So in the introduction, they say this is really dangerous to just screen them once and I'm like

Daphna 56:24

we definitely weren't arguing about that.

Ben 56:26

Yeah, that we were not argument but they use the Drager Transcutaneous measurement tool. And you can look up online which one you have at your hospital if you have one. And the the way you do it is that you press it on the baby's skin and then it you get three measurements the way they did it is that the the saved the highest measurement. The initiation for the the initiation of phototherapy was left at the discretion of the pediatrician. But obviously they mentioned that they're following the AAP guidelines as we are we all are probably doing so that was not really earth shattering. The primary outcome of the study was the need for phototherapy at less than 24 hours. So they had 772 babies with abo incompatibility. phototherapy was required in 36.4% of infants 20% of the infants required it in before the first beat within the first 24 hours of life. They had to reduce the sample. So from 700, it went down to 346. Because of those were the babies where they actually had serum and Transcutaneous. So they had a correlation potential for the two. So that's that's where the numbers were so birth weight. So this is the crux of the results birth weight, infant blood type B, total serum bilirubin ridiculous side count and Transcutaneous, Billy were significantly associated with the receipt of phototherapy within the first 24 hours of life on univariate analysis. Looking at the multivariate analysis, it revealed that serum belly and the Ritek account were the only independent predictors when the Transcutaneous was excluded from the model. And conversely, when the blood test results were excluded. Instead, the Transcutaneous alone was the best predictor, there was no demographic variables that were independently predictive of phototherapy in the first 24 hours. And the are the ROC curves for the two model are shown in the figure in the paper. And the area under the curve for the two models were point nine six and point nine zero respectively. And so they established this, this, they establish these cut offs, right, so if you look at the table three, you have these different TCB cut off with the probability of phototherapy. So at the six hour, if you have a TCB of 2.4, the probability of rawtherapee is 8%. If you have a TCB of three, it's 15%, TCB 4.5, it's 48% 5.3 5.7. It's like 70 to 80%. And if it's above six, then you're at 9%. In the pep in the paper, they mentioned the cut off of three of less than three yielded a negative predictive value of 98%. And the negative likelihood ratio of point 09. For the newborns who are in this category, and only 2.4% below this cutoff needed for therapy within the first 24 hours, a cutoff of 5.3 milligrams per deciliter or more, you're the positive predictive value of 85% Positive likelihood like a positive likelihood ratio of 20.93 and 33 Babies 84% needed for therapy within the first 24 hours of life. So now again, pair the serum and Transcutaneous belly values were compared and the six hour TCB was completely off. No I'm kidding. That's not what they found. The pair TSB and the TCB worse. Were compared the Transcutaneous was slightly lower. And then the CRM and but highly correlated with an error of point eight and a p value of less than point one. So what I'm taking So the conclusion is that among high risk abo incompatible, the at positive newborns, the six hour TCB is highly predictive of the need for phototherapy in less than 24 hours. Definitely, what were your thoughts?

Daphna 1:00:19

My thoughts were at, you know, I don't even want to use it to predict phototherapy at 24 hours, I want to eat, you know what, what we do right now are very frequent Transcutaneous or not Transcutaneous serums really measurements, which really bother babies, and it really bothers parents in the newborn nursery. So I'm quite pleased with with the paper, I'm hoping you will recognize position,

Ben 1:00:49

my position for the people who my position is that I was thinking that for the at positive babies, the protocol should be left at the discretion of the physician. I feel like some some physicians want to follow the bellies more closely, depending on the degree of hemolysis, and so on and so forth. So there is no way you won't have an official protocol for DHT positive. But I do have to say that I really like this paper, as is, I mean, I'm thinking What about doing this where at six hours, you get both a serum and a transcutaneous? See where they both are, and then follow your Transcutaneous Q six q 812, whatever you want to do. That might save a lot of blood draws. Oh, yeah. But what I'm thinking is that there's there's this there's this unsaid question of can the TCB replace the serum, but maybe you just need like one serum at the beginning to sort of calibrate almost like the baby to find out where they are,

Daphna 1:01:46

you're saying your hypothesis is that there are some babies where this is not true?

Ben 1:01:54

Well, I'm just saying that this is

Daphna 1:01:57

it would have been nice if we had more demographic factors on the baby. That's, that's true. That's

Ben 1:02:04

all I'm saying is this. Before aiming for reducing the serum, the Polks and the serum bellies to zero? Maybe we can gather more evidence by just using it more frequently, all the while having maybe one or two time points where you correlate the serum with the Transcutaneous with a serum. And eventually, once our data accrues, and we have more confidence with the how reliable and how, how well do they pair you can potentially just get rid of rid of it altogether. But anyway, I think this is interesting. This is this, my

Daphna 1:02:40

argument is that we will use the trend, right? And if you were very close to light level, then you send us your and Billy. And I imagine that some of our friends on Twitter are already doing this in their units, because I know many units. So I hope they'll give us their input on their experience. Yeah, let's hope we can have a little discussion.

Ben 1:03:01

Yeah. All right. It's an hour and seven minutes. We have a meeting in six minutes.

Daphna 1:03:08

I'm not sure. Should we wrap it up? save these for next time.

Ben 1:03:15

I can I can do listen, you can save the one you have for next time. I just wanted to mention, I just wanted to mention one more thing. For all the trainees out there, the Canadian neonatal society, the kidney, the Canadian Pediatric Society, published a position statement on the discharge planning of the preterm infants, I love that basically outlines what are the objectives to safely discharged baby home, they will most likely differ on one or two things from what you do. But I really like when other countries who are practicing similarly to us, or publishing these things, because it allows you to get a baseline, especially when it talks about like, like bradycardia, monitoring, how many days all that stuff, it's nice to get a sense of what other people are doing around you. So that in cases where it is not straightforward, and maybe the medical team and the family have differing opinion, it's nice to have another opinion that you can base this on and say, Well, I know that in Canada, they do it differently. And maybe that's another way that we could do it. I mean, not that these recommendations are completely novel, like they're very much middle of the road and not expected but it's nice to have a document that outlines them like bullet point after bullet point. That was that was really good. And then so I recommend people check out this paper. And then there was this other paper by our friend, Ariel Salas that we didn't even get to that paper. We did not get to that

Daphna 1:04:44

I think we'll have to review it next time.

Ben 1:04:47

You know what I'm going to just mentioned the main outcome so that people can can check it out and we can have a reason to put it in our in our in our And our website. But basically it was a quality improvement project to try to reduce the time of hospitalization based on some feeding interventions. It is superb, like, Yeah, you should check the supplements, they have all sorts of things about queue based feeding provider directed feeding, there's so many great things and they were able to really make an impact at the University of Alabama. The paper is called improving time to independent oral feeding, to expedite hospital discharge in preterm infants. Yeah, I mean, this is like if you're interested in Qi, this is how you run a QI my friends, it's, it's really, really good. And yeah, I will post that. And maybe we'll review it next time. You're right. Maybe we'll start off with that next time.

Daphna 1:05:40

Yeah, I think we'll have to go into detail on that paper, but,

Ben 1:05:43

but I will post it on the website, because I want to advertise it that way. If people want to

Daphna 1:05:47

start, you know, start making changes they can do so.


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