top of page

#082 - Journal Club 33

NICU journal club the incubator podcast

Hello Friends 👋

Journal club is back after our NeoHeart coverage. This week's episode is quite longer than usual. As it turns out, the AAP released its new guidelines for the management of hyperbilirubinemia on August 5th, 2022, a few hours after Daphna and I had recorded this week's Journal Club episode. But, after reviewing this new publication, we realized it had to be included in this week's episode and could not be pushed off to the next Journal Club. Thus, we recorded the review of the article and plugged it at the beginning of the episode so you can listen to it as soon as the episode comes out without searching the audio file.

Thank you for your continued support. Enjoy!


Please find here the new bilirubin nomograms for your convenience:


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

Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation.Kemper AR, Newman TB, Slaughter JL, Maisels MJ, Watchko JF, Downs SM, Grout RW, Bundy DG, Stark AR, Bogen DL, Holmes AV, Feldman-Winter LB, Bhutani VK, Brown SR, Maradiaga Panayotti GM, Okechukwu K, Rappo PD, Russell TL.Pediatrics. 2022 Sep 1;150(3):e2022058859. doi: 10.1542/peds.2022-058859.

Outcomes of dialysis in neonates with anuric end-stage renal disease at birth: ethical considerations. Han DS, Bock ME, Glover JJ, Vemulakonda VM.J Perinatol. 2022 Jul;42(7):920-924. doi: 10.1038/s41372-022-01328-2. Epub 2022 Feb 4.

Efficacy of occlusive wraps used for delivery room care.Reuter C, Ehlers F, Vana P, Küster H.Arch Dis Child Fetal Neonatal Ed. 2022 Nov;107(6):645-647. doi: 10.1136/archdischild-2021-322611. Epub 2021 Oct 19.

Antimicrobial utilization in very-low-birth-weight infants: association with probiotic use. Ting JY, Yoon EW, Fajardo CA, Daboval T, Bertelle V, Shah PS; Canadian Neonatal Network (CNN) Investigators.J Perinatol. 2022 Jul;42(7):947-952. doi: 10.1038/s41372-022-01382-w. Epub 2022 Apr 11.

Breast milk vs 24% sucrose for procedural pain relief in preterm neonates: a non-inferiority randomized controlled trial. Velumula PK, Elbakoush F, Tabb C 2nd, Farooqi A, Lulic-Botica M, Jani S, Natarajan G, Bajaj M.J Perinatol. 2022 Jul;42(7):914-919. doi: 10.1038/s41372-022-01352-2. Epub 2022 Feb 23.

Ampicillin dosing in premature infants for early-onset sepsis: exposure-driven efficacy, safety, and stewardship. Le J, Greenberg RG, Yoo Y, Clark RH, Benjamin DK Jr, Zimmerman KO, Cohen-Wolkowiez M, Wade KC; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.J Perinatol. 2022 Jul;42(7):959-964. doi: 10.1038/s41372-022-01344-2. Epub 2022 Feb 24.

Pacifier use and breastfeeding in term and preterm newborns-a systematic review and meta-analysis. Tolppola O, Renko M, Sankilampi U, Kiviranta P, Hintikka L, Kuitunen I.Eur J Pediatr. 2022 Sep;181(9):3421-3428. doi: 10.1007/s00431-022-04559-9. Epub 2022 Jul 14.

A randomised trial comparing weaning from CPAP alone with weaning using heated humidified high flow nasal cannula in very preterm infants: the CHiPS study. Clements J, Christensen PM, Meyer M.Arch Dis Child Fetal Neonatal Ed. 2022 Jul 18;108(1):63-8. doi: 10.1136/archdischild-2021-323636. Online ahead of print.


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

Ben 1:02

Hello, everybody, we are re recording a part of our journal club episode to include the latest release of the American Academy of Pediatrics clinical practice guideline revision, looking at the management of hyperbilirubinemia in the newborn infant 35 weeks or more of gestation. We're putting this at the beginning of the episode because it's an information that most of us were looking for. And it's quite long, it's a long paper, it's the review takes about like 30 minutes to 40 minutes. And then journal club will follow after this discussion. So here's why I think it was important for us to do what we're doing today in between the time we record the journal club, and the release of the episode, the AAP released its new clinical practice guideline for the management of hyperbilirubinemia. And the reason we we discussed it with Daphna, right, we were saying, Remember, we're saying like do we push it off to the next to the next journal club. But there's a lot of things in this paper that are going to be subject to strong, opinionated discussions. And I feel like if we push it off, too, by two weeks, it will be too late you need I think it will be helpful for the audience to know what's inside the paper to then be abreast of what the discussion is going to revolve around. And so we will add this on to our older recording.

Daphna 2:25

And yeah, and if you're like us in our unit, we were just we just rewriting our Billy Reuben protocol in the nursery?

Ben 2:35

I think if I mean, I drafted that protocol, and I think if I'm not mistaken, it finally, like integrated into the EMR last week. Yes. Okay. Just in time for me to see the service or efficiency in any case. So the paper is very long, there's a lot of different categories. And I'm going to go through the paper from beginning to end. And the key to remember is that they have the these key action statements is que es and I'm gonna go and there's 25 of them. And I'm gonna go through each one of them so that you can know. So the paper is titled clinical practice guideline Revision Management of hyperbilirubinemia in the newborn infant 35 weeks or more of gestation. The first author is habit right here who have to scroll up is Alex Kemper. There's a lot of impressive people in that paper, as you probably imagine, Jeffrey Maysles. The last others, Jonathan slaughter, there was another person that I wanted to mention. But anyway, Vinod Vitani. Right so, and Thomas Newman, lots of very accomplished bilirubin researcher on that statement. Alright. So the first the first chapter is about prevention of hyperbilirubinemia. And the first thing they're talking about is preventing hyperbilirubinemia associated with chemo with ISIL immune hemolytic disease. And so the first key action statement is that if maternal antibody screening is positive, or unknown, because the mother did not have prenatal antibody screening, the infant should have a direct antiglobulin test at bat. And the infant's blood type should be determined as soon as possible using either the cord or peripheral blood. And that's already a little bit of a shift. Everybody is wondering, should we type all these babies that are being born in LNG, and this is saying that if you have the maternal antibody screen, you may and it's negative, you may skip it, but if the mother is antibodies when positive or unknown, you should get it. The other thing that's interesting is that they were talking about mothers who receive Rogaine during the pregnancy, and they were saying how mothers who receive RhoGAM during the pregnancy can have a positive antibody screen for anti RH D And RhoGAM can cause a positive DHT in the infant, but generally no hemolysis. So, sometimes you have a mother that received Rajam, the baby is Coombs positive and all hell is breaking loose. But yeah, maybe no hemolysis ad Exactly. If the maternal blood is so positive, and the maternal antibody screen is negative, it is an option to test the cord for the infant's blood type and ODT. So again, going back to what I just said earlier, they're saying you may not need to test the cord blood. And that is probably going to be a huge point of discussion. Finally, the determining the infant's blood type or the 80 is not necessary. If bilirubin surveillance and risk assessment follows this clinical practice guidelines and appropriate follow up after discharge is arranged. So the big the big point of discussion is, are we going to move away from testing these babies blood and also it's kind of nice to know when they're DHT. Positive. And and and train them accordingly. So that's going to be something where hospital protocols are going to be an issue. But that's that's the first part. The second,

Daphna 6:09

but it's interesting, right? Because certainly you have babies, let's say who are born to a parent whose Oh, right, and they and their Coombs positive even though the aunt, the paternal aunt, that parental antibody screen is negative. So it's interesting. Yeah.

Ben 6:31

Then they talk about providing feeding support, and they're talking about breastfeeding jaundice. As you remember from board review, it's it's the type of jaundice that usually peaks at about three to five days of life. And it's really just the lack of intake. And they are saying, actually, it should be called sub optimal intake hyperbilirubinemia, which I thought was was cool to talk about breast milk jaundice. And so then they talk about, should we supplement these kids a little bit and the paper does a little thing that I'm not so sure. I mean, what you're seeing, they're saying that the decision about temporary supplementation of either donor breast milk or formula should be made with the parents when possible, discussing risk benefits. So basically shared decision making with the family that you mentioned in key action statement to that oral supplementation with water or dexterous water should not be provided. But later in the paper, we will see that there's a little bit of a hint that if you cannot get Billy to come down, you might want to use some formula. So we'll see a little bit it goes a bit in contradiction to what we're just saying. But yeah, okay. The second part of the paper talks about assessment and monitoring of hyperbilirubinemia. A, Part A is identifying risk factors for hyperbilirubinemia. And the risk factors. We all know them and they reiterated here, lower gestational age, jaundice in the first 24 hours after birth. For board review. John this in the first 24 hours of life is never physiologic, right, remember that? Pre discharge Transcutaneous or serum bilirubin concentration close to phototherapy threshold, any form of hemolysis phototherapy before discharge, the family history of having like a parent or a sibling requiring further therapy or exchange transfusion. Any family history of inherited red blood cell disorder like G six PD, exclusive breastfeeding with suboptimal intake scalp hematoma Down Syndrome macrosomic infant of a diabetic mother. Interestingly enough, they do mention some of these rates of G six PD DCP deficiency and they're quoting in the African American population 13% of African American males and 4% of African American females with GCSB deficiency which is higher than I than I would have guessed. Yeah. It is important and talking about GCPD. They mentioned something that's quite interesting that I tend to forget myself, which is that it is important for clinicians to recognize that measuring G six PD during or soon after the Humala, the melodic event, or after an exchange transfusion can lead to falsely normal results. If the six PDS strongly suspected but the measurement is normal or close to normal. The G six PD activity should be measured at least three months later, again. So that was interesting. Now identifying patients for the need of treatment, and then we're going to k s three I can never remember what K is stands for key actions action statement. Yeah, you said it. I know. But it's just like it's just comes in one way. So they're talking the use of total serum bilirubin level as the should be distributed definitive test to guide for therapy and escalation of care decision including exchange transfusions. So let's talk about that for a minute when they talk about escalation of care decisions, meaning that you're giving phototherapy and the bilirubin continues to increase and you're going to have to go to other means to To try to get the bilirubin to come down. And that can include extensions fusion IVIG. And we'll talk about that in a minute. But what's very interesting is that as we'll talk about it dimensioned serum bilirubin that phototherapy should be driven only by serum bilirubin measurements, decision to initiate for a therapy or escalate care are guided by gestational age, our specific serum Billy, and the presence of risk factors. So what are the risk factors for neurotoxicity they're less being less than being preemie less than 38 weeks, having ISIL immune hemolytic disease, having sepsis, having significant clinical instability, or having an albumin of less than three, so the abdomen is making an appearance here. We always knew that albumin played a factor right we know that low serum albumin can increase the risk of neurotoxicity. Because of the greater availability of unbound bilirubin right bilirubin will pair with albumin whenever possible. Most clinical laboratories cannot directly measure unbound bilirubin concentration. And even if this information were available, there's insufficient according to the paper data to guide clinical care using specific unbound bilirubin concentration. So to address those gaps, the guidelines considered an albumin of less than three to be a neurotoxicity risk factor. Although there's insufficient data to recommend checking bilirubin on every newborn infant, measuring albumin is recommended as part of escalation of care. So if you're getting your initial set of labs, and then you have to get to do more things, again, beyond phototherapy, you should automatically get an albumin level. We'll come back to some of these abdomen bilirubin albumin ratio. They talk a little bit about visual estimation of the total serum bilirubin level. I'm gonna skip that the key action statement for says that all infants should be visually assessed for jaundice at least every 12 hours following delivery until discharge. And serum or Transcutaneous. bilirubin level should be measured as soon as possible for infants in order to be jaundiced before 24 hours after birth. So they talk about visual estimation of serum belly, there's not too many things that are controversial there. They're saying that it's a way to to screen babies for jaundice, but it should never be used as an estimate of serum belly, because you could be way way off, which is something we knew from before.

Daphna 12:21

Yeah, but I think they are a little more heavy handed in this recommendation, which I think is a good thing that we shouldn't be relying on, you know, the actual estimation, which which happens a lot on the outpatient side also.

Ben 12:37

I mean, there's this, there's still like, you can Google these these pictures of how far does agendas go? And they'll give you the estimate. But the paper like you said, it's pretty heavy handed in the sense that they will give you how far off you can be. And it's quite shocking, but I want to try to skip some of these things so that it's not too confusing, but I'm not going to skip skip any key action statement. Okay, Transcutaneous bilirubin levels. Although Transcutaneous measurements do not directly assess bilirubin level they are valid and reliable when used as a screening test to identify infants who require serum bilirubin measurements. And so they're basically saying that the only thing that Transcutaneous bilirubin level can help you get is a serum level, you will not dictate initiation of therapy based on Transcutaneous level, the implementation of universal Transcutaneous screening during the nursery stay and at subsequent public health nurse visits has been associated with a prevention in levels of bilirubin rising above 20 and decrease in number of blood draws. And they're giving you a little bit of the estimate how far off is Transcutaneous bilirubin level and that's very interesting. So they're saying that a transcutaneous measurement is generally within three milligrams per deciliter of the serum bilirubin level as long as the serum is less than 15. So if you're operating under this, the ceiling of 15 milligrams per deciliter, and you're comparing serum and Transcutaneous, you should be off by about three. And that leads to key to key action statements six, which I'll get to five, I know I skipped five, but this is more relevant. Now. Key action statement six says that serum bilirubin level should be measured if their continuous bilirubin exceeds or is within three milligram per deciliter of the phototherapy treatment threshold. Or if the TCB is superior to 15. So if you get a transcutaneous, and you're within three milligrams per deciliter of the threshold to start phototherapy, you should get a serum and if you're above 15, then the measurement becomes very unreliable and you should actually get a serum level regardless. The I'm going to finish and then we can discuss Transcutaneous. The recommendations for the use of Transcutaneous measures takes into account the degree of uncertainty related to skin melanin concentration, and without getting into too much detail there. Basically explain meaning that there's to two devices that are recommended for the measurements of Transcutaneous belly and I think one of them overestimates in darker skinned individuals and the other underestimates So, you have to take that into account and the recommendation does key action statement five states that the Transcutaneous or total serum belly should be measured between 24 and 48 hours after birth or before discharge, if that occurs earlier. He action statement seven says that, you can pretty much use the if more than one Transcutaneous or serum belly measure is available, you can use the rate of increase to identify infants at higher risk of subsequent hyperbilirubinemia a rapid rate of increase which is defined as point three milligram per deciliter per hour in the first 24 hours, or point two milligram per deciliter after 24 hours is is the is an adequate, they say exceptional and suggest the analysis and you should do a DA t if you haven't done it beforehand. Another thing that we're going to talk about again, key action statement number eight, if appropriate follow up cannot be arranged for an infant recommended to have an outpatient follow below and measure discharge may be delayed. And so we're going to talk about that about discharge. among infants with serum bilirubin concentrations below the phototherapy threshold, the potential need for future for the therapy or escalation of care increases. The closer the serum belly is to the phototherapy threshold, so discharging a baby that is close to a phototherapy threshold is not a good idea. However, once a spontaneous decline in TCP, or serum belly, not associated with phototherapy, obviously, over at least six hours has been documented, the risk of hyperbilirubinemia is low. And it is not necessary to obtain additional bilirubin measurements, if you like this is something that we deal with all the time around the time of discharge, where it's like, is the bilirubin rising, is it stable? Is it coming down? And here they're saying obviously, that as long as you have a spontaneous decline in continuous orocrm belly over six hours it should do. There's a section on direct and conjugated bilirubin concentration. I'm going to skip that because it's interesting, but it's not going to change dramatically how you practice. It's interesting how they're mentioning that direct and conjugated bilirubin are different. And they're mentioning that in key actions statement nine. That if a breastfed infant is still jaundice at three to four weeks. Or if a formula fed infant is still jaundice at two weeks, then you should look into direct conjugated bilirubin concentrations and see if there's any cause for CO stasis. Moving on. So far. Okay, any questions about what we talked about? That's not especially the Transcutaneous. I know you're I know that was that was I was thinking about you when I was reading.

Daphna 17:50

I don't have any questions. I'm I'm thrilled at the way I see it. This makes me feel good about our practice to include Transcutaneous Billy Rubin's as a screening tool, right. And it does, especially baby who's going to get a lot of Billy Rubin measurements. This is a good way to reduce peel sticks, which is no small thing.

Ben 18:18

Agreed. Okay, so now we're getting into treatment of phototherapy treatment of hyperbilirubinemia of hyperbilirubinemia. First part is providing photo therapy, boys 17 minutes already. So the effectiveness of photo therapy is dependent on the intensity of the light and the surface area exposed. They're mentioning that intensive phototherapy means that the radiance is at least 30 microwatts per centimeter squared and per nanometer at a wavelength of about 475 nanometers. Light outside that range of 460 to 490 provides unnecessary heat and potentially harmful wavelength. So some very interesting mentions here about phototherapy. phototherapy should not be used in order to prevent what's also known as bind these adverse neurodevelopmental findings. Because and the article is stating that the literature linking subtle abnormalities with bilirubin is conflicting. There is no evidence that phototherapy improves or prevents any of these outcomes. And there is some evidence that phototherapy may lead to a small increase in the risk of subsequent childhood epilepsy. I actually did not recall that information and looked it up. And there are two reports that the paper is suggesting where there's a slight rise in childhood epilepsy and babies received phototherapy the committee, you

Daphna 19:37

know, we looked at we looked at a lot of things the last time we reviewed Billy Rubin, but epilepsy was not one of them.

Ben 19:43

No. The committee believes that the benefit of phototherapy exceeds the small potential risk of epilepsy when the serum belly is at or above the phototherapy threshold. They have a whole discussion about sunlight and explaining how it's complicated to provide sunlight in a safe manner to Baby. So basically, it's not recommended. I'm skipping a bit of what was the discussion there. And it leads us to key action statement 10, which has intensive for a therapy is recommended at the total serum bilirubin threshold on the basis of gestational age hyperbilirubinemia neurotoxicity risk factors and the age of the infant in hours. And now we're getting into these new normal grams. So there's new normal grams people and it's quite a change. If you recall, the nomogram for phototherapy thresholds, used to be one graph, three lines, low risk, medium risk, high risk, right. So now you have two graphs number one, so you no longer have one you have to, and you have one for babies who have no neurotoxicity risk factors and one for them for the babies who have one or more neurotoxicity risk factors. But the babies will have no neurotoxicity risk factors. The the six curves that you'll have on this graph represent six different gestational ages. So you'll have one for 35 weeks, 3637 3839 and 40 or above. When you go in the neurotoxicity graph, you have four graphs, four lines which represent 3536 37. And then the bunch 38 weeks and the rest together. So the neuro the normal grounds for phototherapy look way different. They have still that very steep upslope until about 96 hours, and then it gets pretty flat quickly, like the angle is quite sharp. And there's data published in pediatrics, which we'll review next, the next time on journal club that supports the raising of the phototherapy threshold. So the thresholds are much higher than they were before. So let me just give you an example. If we're looking at phototherapy thresholds for babies with no risk factors, because these are sort of the babies that we all remember. And we're talking about 37 to 38 weeks, right because now I have to give you the gestational age, right. So a 24 hours, the phototherapy threshold for 38 weaker is about 12 something. So that's that's that's, that's pretty high, if you're looking at 48 hours, for 38 weaker, it's about 16. And again, we're talking phototherapy. And again, if you're talking about a 40, weaker at 24 hours, the phototherapy threshold is about 13 and a half and at 48 hours for a 40 weaker, it's about 17. I mean,

Speaker 1 22:22

I'm like the exchange levels.

Ben 22:25

It's massive. I mean, I remember as a resident to remember I used to memorize a memorize it like 48 hours a belief 10 I have to look into it, right? I never did anything. But I remember like, Oh, if it's 10 at 48 hours, I have to just make sure that it's not like either, a rate of rise is not too high, but like that, that was my cut off. I mean, this is way, way different. And when you're looking at the 35 weekers, like a 35 weaker at 48 hours, the phototherapy threshold is 14. It's very high. So it's not a I was afraid that when we were going to say that the thresholds have risen, people might say, oh, yeah, by like point five now they're significantly high. Yeah. Okay, moving on. clinicians and families may choose to treat at lower level based on individual circumstances and preferences. What does that mean, after we just said that it might increase a little bit of risk of epilepsy. But they're giving an example they think it might be an option for sub threshold level during a birth hospitalization to reduce the risk of readmission, if the rate of rise is very concerning that you're thinking that the slope is really going to get to a point where it's going to cross the phototherapy threshold. So that's that's a reason. Now those making the decisions to begin for therapy below the treatment threshold should consider all the risks. And if they do it, they're recommending that phototherapy be provided in the mother's room, or in the room in which the mother can remain with the infant. So then it leads us to key action statement 11 for newborn infants who have already been discharged and then developed serum belly above the phototherapy threshold treatment with a home lead based phototherapy device rather than readmission to the hospital is an option for infants who meet the following criteria.

Daphna 24:10

Just to be clear, that's, that's led based that lead based

Ben 24:15

that's correct, not, not the the element now.

Unknown Speaker 24:18

That's Thank you. Just so there's no confusion.

Ben 24:22

So the babies who have been discharged who can get belly blanket at home have to meet the following criteria. They have to be born at 38 weeks of gestation or more, and that's going to exclude a bunch of people right away. They have to be over 48 hours old, which is not going to be always the case. They have to be clinically well feeding well. Fine. They have to have no neurotoxicity risk factor. They have to have not received any phototherapy prior, their serum concentration can be no more than one milligram above the phototherapy treatment threshold. Meaning if you're above one mil if you're 1 million if you're two milligrams above the threshold, you should actually go to the hospital that the belly blanket be available without delay and that serum belly be checked daily. So, it's not so simple to do. It's going to it's making it more difficult in my opinion to send to provide baby belly blankets at home for these babies.

Daphna 25:19

Well, I mean, I think previously, most of these babies were not getting home phototherapy right from the outpatient. They're being readmitted. So I think it's going to allow more babies to stay home. It's going to be a lot of work for outpatient pediatric and

Ben 25:35

so a lot of colleagues. And this is where actually I was mentioning earlier that they were talking about supplementation they're saying and I quote, although breastfeeding and human health have many benefits, brief use of formula might lead to a more rapid decline in serum concentrate in serum belly concentration, and reduce the risk of readmissions for phototherapy. So, again, this is different from before because before we were talking of about like, yeah, bad breastfeeding, jaundice and so on, but they're still mentioning here that supplementing or brief use a formula might help lower the bill. Okay, monitoring infants who are receiving phototherapy. So key action statement 12. They're saying that for babies who are hospitalized serum belly should be measured within 12 hours after starting phototherapy. So no more starting phototherapy in the morning and checking it again in the morning. It has to be checked that evening. 12 hours later, the timing of the initial serum belly measure after starting phototherapy and the frequency should be guided by the age of the child the presence of neurotoxicity risk factors the concentration and the daily trajectory. For as we've said key action statement 13. If you're receiving home therapy, it has to be checked daily. Key action statement 14 For infants requiring phototherapy measure the hemoglobin concentration can be adequate, or CBC to assess the presence of anemia and to provide a baseline in case anemia develops. And so in this statement, they're not really specifying which category of babies they're saying for infants requiring for therapy. I mean, in all honesty, where I've worked previously, and currently we're checking those things on babies who are who have ISIL immunization, you know, but it seems to say that if you start a baby on phototherapy, you should check that automatically evaluate the underlying cause or causes of hyperbilirubinemia and infants will require further therapy by obtaining a DHT in the infant whose mother had a positive antibody screen or whose mother is blood group O regardless of our HD status, or whose mother is Rh negative. And g six PD should be measured in infants with jaundice of unknown cause whose serum belly increases despite intensive phototherapy, whose serum bellerby increase increases suddenly, or increase after an initial decline, or babies will require escalation of care. Yeah. Thoughts on that Daphna? Oh, we can't hear you.

Daphna 28:03

Sorry. I said it's confusing, because, you know, we know that the G six PD at this time is just not that reliable. But it's helpful to have more and it's helpful if it's abnormal, I guess. But yeah, I think I think the bigger hurdle is going to be communicating to this infants, medical home or pediatrician that G six PD needs to be measured down the line.

Ben 28:34

What about the checking? H and H? Or CDC in babies who are required for the therapy? What do you think about that?

Daphna 28:43

Yeah, um, I think that makes sense. Like you said, our team checks it sooner. And I think particularly that measurement for me anyways, and this is I'll admit not not necessarily based on data, but having a very high ridiculous a count. Makes me more worried. Makes me check bilirubin sooner, maybe start more lights. So but I think they're saying you should at least have it when you start phototherapy? I think that's not unreasonable? Because I'm not sure. I'm just gonna say I'm not sure it's has it ever changed your decision based on the H and H?

Ben 29:27

Yes, I've actually, if there's a significant degree of hemolysis I tend to keep a closer eye on these kids. Yeah. And I mean, like if you get if you get a kid with a ridiculous a count of 17 in the first 12 hours of life, like

Daphna 29:41

compared to the kid who has a five right, yeah, great. Yeah. Yeah. Yeah. Okay, but, but yeah, so I think I probably still would for this DHT positive.

Ben 29:54

The next topic is discontinuation of phototherapy. So let's talk about rebound. So infants who receive for therapy during their birth hospitalization are much more likely to experience rebound hyperbilirubinemia than those whose first treatment with phototherapy occurs on readmission. The risk factors for rebound hyperbilirubinemia include a younger postnatal age, ie less than 48 hours at the start of phototherapy, hemolytic disease of gestational age below 38 weeks and a higher serum belly at the time of phototherapy discontinuation in relation to the phototherapy threshold. And so they're quoting a bunch of studies and they're saying that there's babies are so these babies are more at risk. And the range of rebound can go from about five to 25%. The rebound bilirubin and so this leads us to key action statement 15, which is discontinuing phototherapy as an option when the serum belly has decreased by at least two milligrams per deciliter below the our specific threshold at the initiation of phototherapy. Does that make sense? So you can stop photo if it's gone down by two milligrams per deciliter below the threshold that you were at at the time you started for therapy?

Daphna 31:19

Which is Yeah, I mean, this is this is a big change, right? Because yeah, after initiation of phototherapy was like the Wild Wild West, right. Everybody did whatever they wanted. However they felt based on but by based on photo therapy, so this is a big change.

Ben 31:37

Okay, let's talk about follow up after photo therapy, except in specific circumstances, as described earlier, at least 12 hours and preferably 24 hours should elapse to allow sufficient time of the bilirubin concentration to demonstrate whether there is rebound hyperbilirubinemia. So is another change, right? Yeah. Does that mean that it's not going to be enough to get a rebound like six hours later and then send them on their way they're going to need to go back to the pediatrician the next day to get a check. That's that's an interesting question. Key action statements 16 Repeat bilirubin measurements after phototherapy is based on the risk of rebound hyperbilirubinemia. And then they're talking about four different categories. Right. There's infants who exceed the fourth phototherapy threshold during their initial birth hospitalization. And who have like phototherapy in the first 48 hours of life or who are comes positive or who have some hemolytic process. These kids should have a serum measured six to 12 hours after the phototherapy is discontinued and a repeat on the day after phototherapy discontinuation, then they're saying all other infants will exceed the phototherapy threshold during their birth hospitalization. Should have the belly check the day after phototherapy discontinuation. So you should if you aren't phototherapy, you should get a check the next day, infants will receive phototherapy during the birth hospitalization and who were later re admitted should have bilirubin measured the day after phototherapy discontinuation. And then the last category is infants who are readmitted because they exceeded the phototherapy threshold following discharge, but who did not receive phototherapy in the original admission, and infants treated with home for a therapy who exceed the phototherapy threshold should have bilirubin measured one to two days after phototherapy discontinuation or a clinical follow up once two days after follow therapy to determine whether to obtain bilirubin measurements and to give more risk factors for rebound bilirubin to consider for this particular determination? Okay, almost done. We're talking next about escalation of care. And that means thinking about exchange transfusion. Key action statement 17 says that care should be care should be escalated when the infant serum belly reaches or exceeds the escalation of care threshold defined as two milligrams per deciliter below the exchange transfusion threshold. So you remember how when do we pull the trigger on on, you know, on DEFCON five in the in the hospital, and that's not when you reach the exchange level, but they're saying once you're too below the exchange threshold, you should start doing everything. And they have now that's

Daphna 34:22

the exchange threshold, the exchange levels are higher, so they're higher,

Ben 34:26

and they're changed as well. And similarly, as the phototherapy threshold, you have two graphs, one for kids who have no risk factors, one for kids who have risk factors, and they're broken down by gestational ages. So if you're interested, we're gonna go at 48 hours if you want for babies who have no neurotoxic risk factor and who are 38 weeks or more right. So at 48 hours, the exchange level is 24. For 38 weaker, it is about 23 for 37 weaker, it is about 20 to 36 weaker, it's about out. And it's about what it's about 20 Something 20.8 for 35 weaker.

Daphna 35:07

So it's interesting though, because it's still higher, even to less, it's still mostly higher than our current level.

Ben 35:21

And then they have a lot of key action statements regarding escalation of cares of care, and they're not really controversial. I'm going to go quickly through them and then we'll, we'll be done. The action statements 16 says that for infants requiring escalation of care you should send blood should be sent stat for total direct serum bilirubin, a CBC serum albumin serum chemistries and type and crossmatch fine key action statement 19. Infants requiring escalation of care should receive IV hydration and emergent intensive phototherapy. If you're in a place where pediatricians are covering it would be a good idea to cancel the NICU to prepare for potentially moving the baby key action statement 20. Serum belly should be measured at least every two hours from the start of escalation of care period until the escalation of care period ends. That's something that has never been explicitly said and is interesting, right? That you should check these things q2 IVIG at a dose of point five to one gram per kilo, over two hours may be provided to infants with ISIL immune hemolytic disease, ie comes positive, whose serum barely reaches or exceeds escalation of care threshold, the dose can be repeated in 12 hours. The end so so they're, you're mentioning IVIG. But they are acknowledging that the effectiveness of IVIG to prevent the need for exchange transfusion is unclear. There's a lot of conflicting data out there. And they're saying observational studies have associated IVIG and necrotizing enterocolitis. So be careful and don't Don't be respectful of the indication. I guess.

Daphna 36:57

This was one of the things I was most interested to see if what they how they were gonna say

Ben 37:02

they stood by IVIG I feel like yeah, key action statement 22. They're saying that if you need an urgent extended transfusion, it should be performed for infants with signs of intermediate or advanced stage acute bilirubin encephalopathy. And these include hypertonia, arching retro colas, which is basically the backwards form of torticollis of this delta nose, which I may be mispronouncing but you know exactly what I'm talking about. high pitched cry, or pista Tanis Thank you, high pitched cry or recurrent apnea. Key action statement 23 Very interesting statement that we all face if while preparing for the exchange transfusion, but before starting it, a serum belly concentration is below the exchange transfusion threshold and the infant does not show signs of advanced of intermediate or advanced stages of acute bilirubin encephalopathy. The exchange transfusion may be deferred. So that was I mean, right? We've often been in this situation where the threshold is reached somewhere else the baby makes it to the NICU and by the time you do everything the the you're below threshold by the time the blood is administered. They talk about the bilirubin to albumin ratio can be used in conjunction with the serum belly to determine the need for exchange transfusion. And they're basically giving you levels I think it's too boring for the podcast, but they're telling you that based on the risk factors, if it's if it's between basically 6.8 and eight, it could help you in your indications for extension as usual. Okay, we have two more statements and then we're done. post discharge follow up. People figure seven is revolutionary in this paper, because it actually provides guidance for discharge, four from the nursery or from the hospital and follow up measurements. The approach incorporates both gestational age and other hyperbilirubinemia hyperbilirubinemia neurotoxicity risk factor in the decision making process. The key action statement 24 is beginning at 12 hours of age. If discharge is being considered the difference between the bilirubin concentration measured closest to the discharge. And the phototherapy threshold at the time of the bilirubin measurement should be calculated and used to guide follow up as detailed in Figure seven. So how does it work? Basically, you have three columns, and it will tell you what is the difference between the bilirubin you measured and the threshold for phototherapy. Right? And then so for example, the first box is saying what if it's between 0.1 and 1.9? Right? Then it will tell you Okay, so if you're if your serum and your threshold are within this range, the difference between the two is within this range. Then it will ask you how old is the baby? And if the baby let's say is less than 24 hours, the district recommendation we'll say Did they discharge instead of phototherapy measure serum belly in 48 hours, which is quite impressive that they pulled this off. Other?

Daphna 40:11

I think this is what we all do to some degree, but that degree differs between exactly I think between institutions. Yeah, we're all making these right. What is our level of comfort? And they've, they've standardized it, haven't they?

Ben 40:27

Yeah. And so that's, that's pretty Yeah. So and they will give you recommendations when to follow up and so on. And then finally, key action statement number 25 says that before discharge, all families should receive written and verbal education about neonatal jaundice. Parents should be provided written information to facilitate post discharge care, including the date, time and place of the follow up appointment. And when necessary, a prescription and appointment for a follow up Transcutaneous or serum belly level, birth hospitalization information, including the last belly level at the age at which it was measured. And the DHT results should be transmitted to the primary care provider who will see the infant at follow up. If there is uncertainty about who will provide the follow up care, this information should also be provided to families. So this concludes our review of this clinical practice guideline. This was not just an add on, this is like a full podcast.

Daphna 41:28

Yeah, it had it's gonna have to be sorry, but I think you should

Ben 41:35

know, we may have to do a separate podcast, but that's okay.

Daphna 41:38

I my my closing thoughts about this is there is this group of babies that are high risk for depending on what their insurance coverages we see this all the time, they had an appointment, but the insurance coverage didn't come through here in the United States, especially here in Florida, it didn't come through and they are declined an appointment. And when they're going to be going home with higher bilirubin levels. This is a this is a group of baby that babies that worry me.

Ben 42:10

I tend to give these families a physical script for your follow up belly.

Daphna 42:17

And I say but my what I'm saying is there are families sometimes that we, we don't know that there.

Ben 42:23

That's true. That's the worst case scenario. That is the worst case scenario. I tried to give them that prescription saying if you can get through to a pediatrician that will take your insurance and things will work out then. Great. And if not, then rely on this and come back to the ER. So yeah. Oh, this is difficult. Ah, all right. Okay, I've done well, I

Daphna 42:41

now I feel like I don't I can't make I won't be able to make a billy ribbon decision without this on my desk, and not a single decision. I think

Ben 42:52

it's complicated. Yeah, we're gonna have to recreate our algorithm. And I have already saved the the nomograms. I'm going to post them on Twitter as well so that people can save them. The PDF is free, obviously on the APA website, so I'm not violating anything there. But yeah, I mean, yeah, none of the apps all the apps are now out of date.

Daphna 43:16

Until somebody makes a new app, this is gonna be much harder app to build.

Ben 43:22

Okay, thank you. Okay. Thank you for listening to this longer than anticipated review. And now on with our What is it are regular programming. How do they say

Daphna 43:33

previously recorded Journal Club? RPC reports? are no our our routine scheduled?

Ben 43:41

Yeah, I mean, people will know what I mean. Listen to it. Yeah, just listen. Hello, everybody. Welcome back to another week of journal club. Daphna, how are you?

Daphna 43:58

I'm good. It's a it's been a long it's been a long week, because we've done a lot of recording even more than usual. But, but we did remember how to do journal clubs. So here we are.

Ben 44:12

Yeah, that is correct. And Journal Club is one of these things that unfolded like, I feel like we can push off certain interviews. But Journal Club, it's just a mountain right? If you push it off, then sketches just more to be done. It's too much. Thank you to everybody who participated in our 100,000 downloads giveaway to end who entered to win a pair of AirPods AirPods pro AirPods Pro I guess I don't know where the yes would go. Should we announce the winner data,

Daphna 44:47


Ben 44:48

Alright, so the winner is Katie harsh. Who can be found on twitter at don't be too harsh. It's very clever. So Katie, thank you for participating and The airport should be on their way to you very soon. Actually, no, they're not going to be on our way. We're gonna we're gonna message you to get your address.

Daphna 45:08

And then they'll be on their way.

Ben 45:09

And then there'll be on their way. Okay, is there anything else that we need to talk about? We have a new series of episodes coming up tomorrow for board review. We're going to talk about renal tubular acidosis

Daphna 45:24

that we're going to cover. Yeah, this is a really high yield topic. And it is both easy if you remember a few main points and also hard also hard and easy to get yourself mixed up on the boards if you have like a few key pieces. stri

Ben 45:45

also think it's a it's a it's it's one of these things where I think I'm pretty much got all the questions if there was a new question on it on the board, I got it correct. But then to apply that into the NICU, you feel like, it's like such a big gap. It's not one of these pieces of knowledge that translates easily to the bedside, they're

Daphna 46:01

not as concrete as they, as they, as they're taught.

Ben 46:06

That's, that's very true. Okay. Is there anything else? No, no, there's nothing else that we need to talk about. We should get just get right into it time. To I start today, I guess I start Yeah, you start. Alright, I'm going to start easy tonight. Easy because of a paper that doesn't have a lot of patients in it, but a very interesting and it's called outcomes of dialysis in neonates with a Nurik and stage renal disease at birth, ethical considerations. first author is Daniel Hahn. This is a group out of the US, mostly out of Stanford in California. So this is a an interesting article, because it mentions it deals with the topic of renal failure secondary to bilateral renal agenesis. And most of us know this as a lethal diagnosis primarily because of the association with pulmonary hypoplasia Aliko or anhydrite muse. Now, the concern that is being raised by the paper is that postnatally if you are electing in a shared decision making process to to sustain these infants, you're going to need renal replacement therapy almost immediately after birth, until they can actually get to a transplant. Whether these babies are able to survive to transplant whether they actually becomes they become candidates for transplant, and whether they survive the period post operative period is not really well known. And so what the goal of this study was to analyze the outcomes of patients with bilateral renal agenesis or functional, bilateral regional versus by bilateral renal agenesis, defined as an uric and stage renal disease immediately after birth, who received renal replacement therapy within the first week of life with a specific focus on the baby's eventual ability to successfully receive and maintain a functioning renal transplant. They included patients who are an uric after birth because similar to bilateral renal agenesis. They also need window replacement therapy immediately in the postnatal period. And so this was a retrospective chart review, the electronic health record for pediatric patients who, on whom in renal replacement therapy was initiated within one week of age at the tertiary Children's Hospital. So the group began providing a new infusion in 2014. renal replacement therapy was defined as the initiation of either period no doubt, peritoneal dialysis, or continuous renal replacement therapy slash haemodialysis. They collected tons of clinical data. They included baby babies who were anuric at birth requiring renal replacement therapy within the first week of life due to primary renal dysfunction from bilateral renal agenesis or functional bilateral renal agenesis. The diagnosis was defined as the absence of renal tissue bilaterally on prenatal imaging via either an ultrasound or an MRI. Functional bilateral renal agenesis was defined as neonates who had renal parenchyma on pre or post natal imaging, but there were anuric from birth due to primary renal dysfunction. Babies who made urine or who did not undergo Window Replacement Therapy were excluded. So the primary outcome was the receipt of a renal transplant survival to one year and overall survival, including follow up time. Secondary complications, secondary outcomes were complications of renal replacement therapy, specifically peritonitis acquired comorbidities, which, okay, so I'm going over the methods and you expect that I'm going to give you like 600 patients, you're presenting basically a case series of five patients will take it. Yeah, and I think I think it's a very valuable series of patients just because this process is so frustrating, especially in neonates to try To provide renal replacement therapy, it's such a crapshoot, that getting other people's experience especially from such a big center is helpful to patients out of five had bilateral renal agenesis while the other patients were diagnosed with autosomal recessive, polycystic kidney disease, renal tubular dysgenesis renal dysplasia, and we know this pleasure respectively. Both patients with renal agenesis received cereal and new infusion treatments prenatally while the other three did not receive any federal intervention. The median the median gestational age at birth was 35 weeks, all patients had pulmonary hypoplasia. And except for patient number three, which also had a seizure disorder and type one diabetes, the others had either isolated or just functional bilateral renal agenesis. renal replacement therapy was initiated at a median of age of three days. The initial the initial mode was peritoneal dialysis in three patients and continuous renal replacement therapy slash haemodialysis in two patients. Of those five, only two patients received a renal transplant both coincidentally at 43 months of age, which is not bad, right? I mean, yeah, so past the edge. So I mean, right. It's something to put in perspective, neonates who have to be sustained for three something years, right yeah, long time on on dialysis. The diagnosis of the two patients who received the transplant were renal tubular dysgenesis. That was patient three, and MC KD that was patient five, only four patients survived to one year and the overall survival was 60%. With a median follow up of 39 months, there were two patients who had significant complications from renal replacement therapy patient for developed NEC and from recurrent peritoneal dialysis failure and peritonitis. This patient with neck ultimately passed away after being placed on comfort care due to persistent peritoneal dialysis and hemodialysis failure. Patient one had developed superior vena cava syndrome from prolonged intermittent hemodialysis, which was performed to peritoneal dialysis failure. This patient then was ineligible for renal transplant due to the acute to some acquired cardiovascular comorbidity as well as extensive thromboembolic disease resulting in the absence of vascular access for graft anastomosis. Two patients in total did not survive. One is the aforementioned with, with neck and both the peritoneal dialysis and CR RT failure. And the other patient who did not survive passed away after transplant. So that was that was tragic. And so the conclusion of the paper are that in patients with an earache and stage renal disease requiring dialysis in the neonatal period, they undergo multiple treatment challenges with low renal transplants and low survival rates. And this is data that they're recommending should be shared with families and considering the intervention for cases of severe renal this disease diagnosed prenatally. And the future directions are indicated to develop shared decision making strategies and decision aids to better counsel families making these difficult decisions. So obviously, this is low numbers. But it is a senator that treats a large volume of patients with renal conditions. And the ethical considerations that despite this being the ethical consideration for me is that despite dialysis being viewed as this bridge, right, that's going to get you to transplant. If there's not too many complications, you may still not be able to get to a transplant, and you see that with some of their patients. So it's, it's quite, it's quite, it's quite a traumatic journey for these children to go through without potentially getting to a transplant. And the fact that in one of their one of their five patients actually got to a transplant and died after their transplant is just terrifying. So interesting data really to, to look at so.

Daphna 54:00

Yeah, and I agree with everything you've said. And, um, you know, when I was training, the sense around these cases was that, like, the mortality was so high that we should convince, convince, quote, unquote, right, we should counsel parents, not to, you know, not to intervene, right. And actually, what I got from this small case series and some other studies like it is that, you know, I mean, there are some kids that do that do make it that we have to put that into perspective, especially with newer technologies like amnio fusions in the infusion is not a new technology, but I'm saying this these targeted prenatal therapies. That being said, you I mean, you know, my interest is in prenatal counseling. And so it really I think depends on on the family and what they think is a you know what What quality of life means, you know, to them. But

Ben 55:02

yeah. And I have to say I've worked in centers where doing dialysis and neonates was not our forte. And and these catheters if you don't have people who know who know how to deal with them, whether it is the surgeon, the nurses, the whole team, right? It's it's difficult, like it's, it's just a recipe for disaster. So I'm wondering if these kinds of papers are going to push towards more regionalization of air, maybe, maybe maybe for the benefit of these babies to get them to transplant in a safer manner? Because this is, this is pretty terrifying. Yeah.

Daphna 55:39

And I think that's another thing, you know, being real advocates for families and patients and making sure we get them to the right place.

Ben 55:47

Absolutely. But you know, how like, sometimes we think of, sometimes there's a bit of, of bad press for regionalization of care, because it really removes resources from the periphery. But I feel like I remember, you know, from my, from our days in medical school, when you're talking about adult disease where you need the surgeon who does it the most, like more experienced equals better outcome. I think in those specific cases, especially when you're talking about peritoneal dialysis, like, yeah, maybe maybe the regionalization of care in that specific context is perfectly acceptable. All right, where are you? Next?

Daphna 56:21

Okay, well, we have this interesting article that actually we've been carrying over. So to do it. The title is efficacy of occlusive wraps for delivery room, air. Lead author Christina reader, senior author, Helmut Custer, this is coming from archives of diseases child and fetal neonatal edition. It's coming to us from Germany. So the question was really which occlusive wrap is best for temperature management, and I'm not gonna lie to you. We use the occlusive rack that we use, and I had given it any other thought. So I thought this was an interesting scent. So given

Ben 57:01

it some thought you have, I've called some of my colleagues abroad. I'm like, what do you use? Do

Daphna 57:05

you use Yeah,

Ben 57:07

don't like plastic bag, just like, like a regular plastic bag, like in low resource countries? Sure. Like it and so yeah, cuz I always wonder like, are we paying 100 bucks for this plastic bag and ziplock bag? Exactly?

Daphna 57:23

Well, here, well, I'll tell you what I found what they found, I should say. So they used they evaluated seven different types of plastic wraps on this is interesting as well, I thought because they didn't have to enroll any babies. They used pre heated aluminum blocks. So they pre heated them to 36.9 degrees. And they use two different types of blocks, one that are 983 grams, and one that are 548 grams, so that they could compare that's right does does the size of the block change any of these

Ben 57:59

crazy aluminum is a great heat conductor. Yes, very good point.

Daphna 58:04

And so they looked at they put temperature probes on the surface of the block and they put temperature probes into the center of the block. And the temperature blocks were measured every minute for 90 minutes and they perform the measurements seven times with each rep on each block. So lots of measurements. In addition, the blocks were soaked with 20 ml of water and then wrapped in one of these plastic wraps. So they were looking both at heat loss and and water loss through the weight of the blocks. They weighed the block immediately after preparation and then after 23 hours at 37 degrees Celsius. And measurements are repeated six times for each rep so again, lots of measurements and then to your point they use these different reps they used to freezer bag, cling film, drugstore food rap, three M healthcare 1003 Rap polyethylene occlusive rap and that vibrate for were, quote unquote individual bags and three types were these three single layer films. So those are the types of bags but the the makeup of the bags were different also of all the seven five consisted of polyethylene only one was polyethylene and poly vinylidene chloride

Ben 59:37

I prac poly vinyl lid and chloride and one is like this this like shiny thing right sometimes

Daphna 59:45

and one of polyurethane. So the primary outcome was to look at heat loss. And so without arap, the core temperature of the smallblock decreased by two degrees centigrade within eight plus or minus, I have 2.4 minutes. But this time increased to 11 plus or minus two and a half minutes using the most effective rap and decreased to 6.7. So with some of the raps, the blocks got colder faster, which is terrifying. One rap had no effect. And I'll tell you which block which rep came out ahead. For surface temperature, the most effective rap nearly doubled the time to lose two degrees centigrade. And the time periods for the larger block were were longer, but they were proportional they were they were comparable. And then I told you they looked at water loss of water loss within 23 hours without a rap was 20.3 plus or minus point two grams and was reduced 2.6 plus or minus 1.2 with the most effective rap and 10.7 plus or minus point seven grams for the least effective rap. So the most effective rap reduce water loss by almost twice as much as the least effective round the thickness of the wrap and varied but there was no correlation between thickness and either the temperature or water loss. And drumroll, the full polyethylene wrap performed best both in terms of heat and water regulation. So I guess that's the key. Make sure the rap you're using has is optimally full polyethylene.

Ben 1:01:40

That is very interesting. Yeah, I'm gonna go check the brand of our bags.

Daphna 1:01:44

That's great. You know, I meant to and I reviewed this the first time in.

Ben 1:01:50

Yeah, I know there are polyethylene bags, but I just don't know which brands

Daphna 1:01:54

if they're right, right. And if they're full.

Ben 1:01:57

Yeah, I want to make sure it's not the Belgium the one from Belgium that has like the most water loss. That's right. Yeah, there's

Daphna 1:02:04

because the combos some of them did worse than Yeah, no.

Ben 1:02:09

That's right. Okay. Okay. Um, next up. Okay, so the next paper I'm presenting is called anti microbial utilization in very low birth weight infants association with pro biotic use. First author is Joseph Ting, and it's coming from the Canadian neonatal network investigators from Canada. So, the background mentions that obviously, perturbation of the gut microbiomes ecological balance by antibiotics may exacerbate the possibility of acquiring more disease in the future. And this group had previously reported a high antimicrobial, anti microbial utilization rate and au are in and and and this association between antimicrobial utilization rates and neonatal morbidity and mortality, and adverse neonatal outcomes at 18 to 21 months corrected age among infants without cultural proven sepsis, or necrotizing, enterocolitis. So they're mentioning that there's currently not a ton of evidence, the effect of probiotics on antimicrobial use in the preterm population. So their study really aimed to describe to had aim to do three things. First, to describe the use of probiotics and tertiary NICUs in Canada. Number two, to evaluate the association between probiotic use and antimicrobial utilization rates among VRB W's. And finally, to understand whether any such association is affected by the mode of delivery at birth. So the study design is pretty straightforward. It was a retrospective cohort study that was conducted using the CNN, the Canadian neonatal networks database, which includes data on over 80% of tertiary NICU, tertiary NICU admissions of the RBW infants in Canada, they included very low birth weight infants with the birth weight less than 1500 grams admitted to these participating NICUs between January 1 2014 and December 31 2019. They excluded infants who had planned comfort care and resuscitation who had major congenital anomalies who were missing information on provide cues who died within three days of after birth, or who were never fed before death. Yeah, so these these babies were excluded. So what was the intervention? Probiotic use was defined as exposure to probiotics given for preventive purposes during the NICU stay and which probiotics were used. So there's two preparations that are available in Canada. Both products have what they're calling the Health Canada natural product number, which means that they're regulated and that there's like some form of quality control and The billing requirements, the name of these two probiotics are Flora baby and BioGaia. The primary outcome of the study was to look at this antimicrobial utilization rate as the primary outcome. And the CALC and, and using the antimicrobial utilization rate is such such a mouthful, I'm sorry, they calculated. So they use this as the primary outcome, the antimicrobial utilization rate, and calculated this as the number of patient days when the infants were exposed to more than one antibiotics divided by the total patient days of hospitalization. There's tons of clinical variable that they collected. And that's it all that is all available in the Methods section. So in the results section of the 16,000, eligible VLBW w 7279 infants received probiotics during the study period. So they had the seven or 7000 and change in one group, and then almost 9000, in the no probiotic group. There were some significant differences that they obviously tried to correct for in their statistical analysis. But I also, it's one of these things where the P values, I think, are kind of useless, because the numbers are so large, that for example, right, let me just give you some examples. So there's a significant difference in the gestational age of these infants. So you'll see that the P value is like less than 0.1, less than point o one, but it's like the kids in the probio. In the in the probiotic group had their gestational age was 27.8. And in the non probiotic was 28.4. Right? So statistically significant, but clinically, not crazy. Same thing for the birth weight, right? The mean birth weight was 1050 grams in the probiotic group 1079 in the non in the No, no probiotic group. So when you look at the baseline characteristic, you're like, Oh, my God, like dramatically different groups, right. But when you actually start teasing apart the numbers, they're kind of close to each other. And maybe this is where, yeah, more more data would have been helpful. Now, let's get into something, some of the some of the things that are interesting. When you're looking at the baseline characteristics, and you look at how many babies received probiotics, it's very interesting, because obviously, they start in 2014, and they go year by year to 2019. And so in the no probiotic group, in 2014, it's like 90 and 10 90%. No probiotics. And as you move forward, that that balance shifts completely, until you reach 2019, where almost 70% are receiving probiotics. So you see that this period that they've captured, is really showing a shift in the practice of these of these NICUs. So the rate of probiotics, as we just said, increased overall from 10% in 2014, to 68% in 2019. Compared to infants who received probiotics, those who did not receive probiotics had a higher mean birth weight, they received longer duration of TPN. And they had higher rates of being of airborne status SGA status and exposure to Formula during the hospitalization. The antibiotic utilization rate was significantly lower in in among infants who received probiotics versus those who did not 107 versus 129 per 1000 patient days. The other interesting finding the antibiotic utilization rates were significantly lower in the probiotic group versus the non probiotic group, irrespective of the mode of birth. The median number of blood cultures taken per patient and the median number of sepsis evaluation episodes per 1000, patient days were significantly lower among infants who received probiotics versus those who did not receive probiotics. The number of culture negative sepsis, as defined above, which was basically treatment with antibiotics with no really positive cultures, was also significantly reduced among infants receiving probiotics. So the conclusion of the paper is that in this population representative, pragmatic and unselected cohort, they identified that probiotic has increased over time in Canada and was associated with a significant reduction in antibiotic use utilization rates among the w's future studies are needed to determine whether or not this effect is independent of other infection reducing intervention, obviously, because that's the biggest culprit of this study, is that it spends, like so much. It spends like six years, obviously, there's lots of stuff that I mean, we're not units are not remaining stagnant and things are evolving. So yeah. Could there be something else?

Daphna 1:09:46

Well, especially around our into microbial stewardship, right,

Ben 1:09:50

absolutely. Absolutely. But a very interesting study. Because I think a lot of the issues with antibiotics, it's like, Hey, you're giving live bacteria to these kids. So are you going to end up Having, are you going to go through multiple scares where you're gonna be like, Oh, maybe this kid got infected. And it turns out they get less than two biotics less workups. So yeah, another another nail in the coffin for the no probiotic.

Daphna 1:10:14

Yeah, I mean, I'm hopeful it will continue to be positive. You know,

Ben 1:10:18

we're having a great experience in our unit using probiotics. And so yeah.

Daphna 1:10:25

Yeah. You know, I was thinking again, about this time period, you know, there was a time where, you know, we were you, we, the community was using probiotics, but in select patients, for example, the kids who are on a lot of antibiotics. And so I wonder what role that plays in these findings. But anyways, interesting. Thank you. All right. My next Oh,

Ben 1:10:51

no, go ahead. I said I said I have two mores. I have two tomorrow.

Daphna 1:10:55

My next study is entitled breast milk versus 24%. Sucrose for procedural pain relief in preterm neonates, a non inferiority randomized control trial. Lead author Pradeep Kumar of Velu moolah. Senior author money goodbye, Josh. And this isn't a journal apparently tautology, and it's coming from the Children's Hospital of Michigan. So the question is, would would breast milk being used as like analgesia for painful procedures be non inferior to the use of sucrose? And is it a valid question? So? Absolutely, because we've had a huge we've had a sucrose shortage, right. Like we could get sweeties for a while. I won't say that it's a free or cheap alternative, because obviously, the procurement of breast milk is either free or cheap for the families who are doing it. But I would say

Ben 1:11:52

you're talking from a financial standpoint,

Daphna 1:11:54

I'm talking from a investment standpoint,

Ben 1:11:58

right? Yeah. From a resource invest from a resource utilization. That's right. I mean, they

Daphna 1:12:04

would be nice if you have it, right. Yeah, absolutely. So the study design, this is a randomized, single blinded, non inferiority trial, they converted from October 2019 to April 2021. So they looked at neonates born between 30 and 30, and one weeks to 36 and six weeks gestation, in whom mother's own milk was available, and who were nipple feeding some feeds and their unit they begin trialing nipple feeds around 32 to 34 weeks, depending on a staff seeing. And today we're looking at Babies who, in addition, were within the first 30 days of life. And then so they approached parents of infants who were having a plan to Lance procedure heel stick, and they were approached and then randomized to either receive the 24%, sucrose or mom's own mil exclusion criteria and neonates who were critically ill and congenital anomalies diagnosed neonatal and stuff, floppity seizures, neonatal abstinence syndrome, and those on antiepileptic or analgesic medications were otherwise excluded from the study. They use the premature infant pain profile, revise the PIP bar, if you're not familiar with it, it's a pain assessment tool. It does include some physiologic parameters like heart rate, oxygen saturation, it uses some objective, subjective criteria, sorry, facial indicators like a brow bulge, eyes squeeze nasal labile furrow, then it takes into account gestational age and the baseline behavioral state. So it does require some training. And they were pretty clear about that their investigators have undergone that training. The PIP our score can range anywhere from zero to 21. And basically, they had these two investigators who were blinded to what the baby had received, or was receiving for the procedure of and they score the infant at baseline. So before the procedure during the procedure 3060 90 and 120 seconds after the procedure and the final score for each time point was the average of these two scores. Okay, so their primary outcome, like I said, was pretty much the pain scores, and then they wanted to look at some of the other physiological parameters. They screened to under 45 infants 128 met inclusion criteria. And not surprisingly, non availability of breast milk was the most common reason infants could not be included in randomized 94 infants 47 in each group, but only 8888 of those infants completed the study. Interestingly, they had 44 in each arm which was to their anticipated sample size, they had a mean gestational age of 33 weeks mean birth weight of 19 109 grams of mean postmenstrual. Age, at the time of this study was 34 and 34.5 weeks. This is also an interesting thing that they needed to factor in, what was the median number of heel pricks prior to the study? Because we know that babies do have sort of like a desensitization to painful stimuli

Ben 1:15:29

in the situation. Yeah.

Daphna 1:15:31

So it was 17 for both groups. So there was not a difference between groups, and 17. Sounds like a lot. But actually, given the literature, it's actually less than I think, most studies have have shown for how many heel sticks a baby, a baby gets in the NICU, they looked at a number of other maternal neonatal characteristics, and they didn't find any difference. So the primary outcome, so the baseline Pip, our score was zero for all infants. That's amazing. The PIP our scores during the procedure range from five to 12, in the two groups with a mean score of 8.3. And they have all of the parameters there for both groups combined, but I will tell you about babies separately, all infants reach their baseline score of zero by 90 seconds post procedure, which fits with our kind of documented stress response. Um, what did I want to tell you? So the major difference was that 60 seconds postprocedure, there was a statistically statistically significant difference between the two groups, with the babies in the breast milk group, and actually having lower scores than babies in the sucrose group, the mean heart rate was lower, but not statistically significant at every point in the breast milk group, the So basically, what they were looking for was for there not to be a difference and that breast milk was non inferior, which is what they found. And in fact, at 60 seconds post procedure, they found that the breast milk group had lower scores than the sucrose. Some of the other interesting findings, the number of needle sticks prior to the study was significantly associated with scores at 60 seconds, which isn't surprising, that fits with our kind of peak and stress response. And the other thing that they found was they did a group time interaction regression, they found those statistical significant at 60 seconds post procedure, suggesting that there was a faster decline, or a faster decrease in the scores in the breast milk group as compared to the sucrose group. And they had a number of hypotheses for this. Were those babies doing more were the babies who are getting breast milk getting more skin to skin doing more kangaroo care. But, but they didn't measure those things. So I think those are potential things that can help explain it. But we know that there are lots of moms who bring breast milk and don't do those things. And with a lot of moms who do those things and don't bring restaurants so so we don't know. But I what I liked about this study is if you don't have sucrose, and you do have restful, you should definitely be using it. And both is better than no analgesia at all.

Ben 1:18:49

Yeah, and like you said, the potential of, of sucrose is variable, maybe, maybe you need to get the blood and the the, the Omnicell is empty, and you have to go. So it's great to know that this is the alternative and it's and it's, you know, there's right the it's, I mean, right osmolarity is better. So it's good to know that this that from a pain standpoint, it does the job yet again, yet again.

Daphna 1:19:17

Liquid Gold.

Ben 1:19:19

That's right. That's right.

Daphna 1:19:22

Hey, I'm just realizing, I think I said minutes earlier instead of seconds.

Ben 1:19:28

I didn't realize when

Daphna 1:19:33

when I was setting up the

Ben 1:19:37

methods. You want to say that again? Yeah. Okay. Okay, my next I'm gonna stay in an inner antibiotic vein. Because I got very interested in all these antibiotics. That is, actually we should give props to one of our listeners for this one. Not that not that she suggested. Not that she suggested this paper particularly, but Vivian. Val car say, Louis's who's Vivian if you're listening, who was a resident, University of Miami, and who brought up this discussion point about the dosing of ampicillin and how people are looking at the actual dosing of ampicillin. She was responding to our episode on GBS in the neonatology review podcast and mentioning some of the work that Dr. Kelly Wade is doing. And so this is one of these papers. So let's let's get right into it. It's called ampicillin dosing in premature infants for early onset sepsis, exposure driven efficacy, safety and stewardship. first author is Dr. Jennifer, Jennifer Lee. I think I'm pronouncing this correctly because it's spelled L, E, or Lu in front of us. And they're from California. So, a few statistics before we begin from the background that are quite interesting, ampicillin is the most commonly prescribed medication in the NICU. Not really surprised by that more than 75% of VRB W's of RBW infants received antibiotics in the first three days after birth, and dosing is highly variable. Now, interestingly enough, they do mention that the American Academy of Pediatrics GPS guidance recommends a lower standard dose of 50 mils per kilo per dose to 12. For infants who are less than 34 weeks of gestation and who are less than seven days postnatally. However, they said that the most common regimen in clinical practice is 100 Mix per kilo per dose q 12. So much higher dose, and that's that good that actual regimen goes even higher than what is the recommended dose for min angelic doses, which is 100. Meg's which which did not which is close to the min injury dose, it's not higher, I apologize, which is close to the managering dose recommended by the AAP for babies as in three four weeks, which is 100 meg per kilo per dose Q eight. In a recent survey, they're quoting only 26% of level three or level four NICUs reported using the standard 50 mils per kilo dose regimen. And they're obviously mentioning some of the pharmacokinetic saying that in preterm infants ampicillin concentrations remain. Bacteria settle for bacteria settle for two three days after the last dose and stewardship practices encourage limiting this unnecessary duration of exposure. So what is the question of this paper? So, this paper looked at the pediatrics database, and they performed a simulation study to evaluate ampicillin exposures in a large retrospective cohort, right this pediatrics database of the RBW infants. The aim to define the optimal ampicillin dosing strategy for empiric early onset sepsis evaluation using exposure based metrics for efficacy, safety and stewardship. So using the pediatrics database, right, which includes over 300 NICUs, they created a retrospective cohort of the LBW infants that spanned 1997 to 2016. And they included in that cohort, babies who had a gestational age of 22 to 27 weeks of postnatal age at birth of less than seven days of birth weight of less than 1500 grams and the receipt of ampicillin on Day Zero to One of age. So then they they perform this pharmacokinetic model based simulated exposure, so they use the ampicillin population based pharmacokinetic model for a neonate that was previously published by Tremblay and colleagues. So they used a previously published I guess, algorithm if we want to call it or pathway since it most closely matched their target population. The model was derived from 143 episodes and concentration obtained from 73 neonates including 21 born at less than 34 weeks, and that's from the the one they're using less than seven days of life. And then they use the Monte Carlo simulations with this populations pharmacokinetic model to simulate just to simulate ampicillin concentration following three different dose regimens used in clinical care and are recommended by either the AAP or FDA guidance and so, they they did the simulation and they they considered a standard dose 50 mils per kilo q 12, which if you need to recall is what the AP recommends a medium dose which was the one that when they did the survey was common to use 100 mils per kilo per dose q 12. And then the high dose which was min energetic according to the AP guidance, 100 mils per kilo per dose Q eight. For all dosing regimens, simulated infants received their first dose on the day of birth and all simulated dose were administered IV over 20 minutes. ampicillin was continued every day. to 12 hours to provide 48 hours of therapeutic coverage and they picked it 48 hours therapeutic coverage because that's what we usually use to rule out blood cultures, and dose exposure evaluation and pharmacodynamic exposure metrics. So ampicillin exposure was evaluated relative to the MICC. The minimum inhibitory concentration, right? And do we need to review what am I see as this is not board review?

Daphna 1:25:24

No, but I but we have a lot of learners. So

Ben 1:25:27

yeah, sure. It is it is the smallest concentration of the antibiotic that you need to actually kill the bacteria.

Daphna 1:25:33

So very useful when you're evaluating the sensitivities.

Ben 1:25:37

Absolutely. And so they evaluated the the exposure relative to the MSE susceptible interpretive breakpoint tables obtained from the United States committee on antimicrobial susceptibility testing and European Committee on antimicrobial susceptibility testing for the most common us pathogen, so obviously, right, so they were saying how we're going to figure out the MHC right, the MHC, usually the lab gives you the MHC based on the blood sample you send. So they use these reference tables, and they use these for the most common us pathogens which included GBS, streptococcus, Listeria and E. Coli. Alright, and then we're gonna go into the results, so they use the population pharmacokinetic model to simulate ampicillin concentration during 48 hours early onset sepsis evaluation in a cohort of 34,689. Premature neonates born at a median gestational age of 26 weeks and a birth weight of 790 grams. interesting results neonates born at 22 to 24 weeks had smaller birth weight, obviously and slower apparent ampicillin clearance, an immediate predicted elimination half life that was one hour longer than neonates born at 25 to 27 weeks of gestation. And that right away shows you that a one dose fits all for all these kids who are quote unquote less than 34 may not be adequate. All those regimens achieved bacteria Siddal, ampicillin concentration that were far above the MIT susceptibility breakpoints of point 2518, to cover GBS, streptococcus, Listeria, and E. coli respectively. So, yeah, at the end of the 48 hour culture incubation window, the mean ampicillin concentration for the entire cohort were 59.31 19 and 221 microgram per ml in the standard medium and high dose regimens, respectively. The bacteria said all exposure targets was predictively, achieved in 100% of infants through 48 hours. So in case you're getting a bit lost, the point they're trying to make is that we're overdoing it with the current doses that we have. And so a few more interesting results is that even though they're saying even though the last dose is administered at about 36 to 40 hours of age, the median MPN concentration remained above the MHC for common pathogens through 72 hours, and they have some very impressive graph to show you how long it takes for the concentration to actually drop off after the last dose is given. So then, from a safety perspective, the steady state C max, which is the constant the mat, the steady state maximal concentration was far above the NYC and rarely below the neurotoxicity exposure metric. So during a 48 hour course neonate, receiving 50 mils per kilo for four doses, had concentrations above the neuro toxicity exposure metric for a minimum of about 6.2 hours, compared to 32 and 41 hours for the 100 milligram, medium dose and high dose regimens. So that's quite concerning actually, right. That you may actually cross this neurotoxicity threshold. Now from an antibiotic stewardship perspective, you're mentioning that at the end of the 48 hour course the four doses 100% of infants in the standard 50 Mix particular Q 12 regimen still had concentration above the MRC breakpoint for E. Coli. After discontinuation of therapy. The probability of target attainment for ampicillin concentration above the MICC decreased over time based on the MACD susceptibility breakpoint. However, more than 90% of neonates maintain concentration above the micb for a total of 54 hours for MICF E coli streptococcus and GBs. Okay, a few more things. The prolonged exposure after discontinuation led the investigators to evaluate shorter courses right so they so they get all this data and they're like maybe if we use a shorter course we will avoid having this concentration remains significant in the baby's body for extended periods of time, we may actually crossed the neurotoxicity threshold less often. And so what they looked at is episodic concentration using a short worth two dose course 50 mils per kilo at time zero and 12 hours after blood cultures limited antibiotic exposure beyond 48 hours, MPs and concentration were below the neurotoxicity exposure metric for an average of 46.6 of the 48 hours, so much lower than in the current dose, at 48 hours, the mean concentration was 6.3. Mike's per ml, more than 90% of neonates had concentration above the MICC through 40 to 54 and 66 hours respectively. And then they have this very great figure which is figure two of the of the paper, which shows the mean episodic concentration with this standard dosing regimen with an overlay of all three exposure metrics. And then they have the two dose regimen. And they're basically showing you that they created this black box where this is where you want the concentration really to remain in and showing you that with a two dose regimen, you just might be just just as well off. So the conclusion is that this study defined empiric ampicillin dosing for V RBW premature infants at risk of us. A short course of ampicillin regimen provides bacteria settle exposure minimizes the risk of potential toxicity and promotes stewardship by limiting empiric exposure to 48 hours. Now, they're mentioning that a prospective study is planned to confirm that the emphasis on exposure and to explore the potential early and late effects of this foreign therapy, meaning they're not expecting you to take this data to the bedside right away, they are understanding that this has to be tested from prospective standpoint, and they're doing it and I'm pretty sure Dr. Kelly Wade is one of the principal investigators of this of this study. Now, where this is quite interesting to me, is that right? There's very often where you're like, do I stop the antibiotic a little bit early, because the culture is negative because baby's doing well. And having this pharmacokinetic data that shows you that the antibody concentration does remain pretty significant in the baby system for an extended period of time is is very reassuring. And knowing that simulations with two doses show that you have the adequate coverage for the most common us bacteria is quite valuable. And that's why I wanted to review this paper. I hope I didn't get no hope I didn't lose the audience in the in the nitty gritty of the MICC, and so on. But you should I mean, we're going to put the paper on the website, you should check it out.

Daphna 1:32:25

Yeah, no, that's a lot of numbers, obviously. But the graphs and the the that accompany that paper, I think are really useful. They're pretty powerful. They say a lot. And obviously, if we can do the same amount of work with less toxicity than than we should, what I'm what just impresses me with these pharmacokinetic studies, is just a reminder of all of the things that we put into these babies that they're, you know, immature Oregon's have to manage, right and navigate. And

Ben 1:32:59

and also, this is something that we've discussed ourselves, which is that some of the old way of thinking about this preterm babies is is remaining, which is we saying, Oh, are they less than 32? Are they less than 34? But now we have this huge spectrum of babies ranging from like the 22, weekers.

Daphna 1:33:18

Totally, totally different groups, different groups.

Ben 1:33:21

Absolutely. And and then and then having, like we said, having a one single dose for them all, is may not be appropriate. Now to the people who are writing these guidelines. We don't have yet a ton of data on them. But as this data is coming out, we will see for sure, a breakdown of of indications and doses for different age groups. That gestational age groups.

Daphna 1:33:41

Yeah, and then obviously, the end game is individualized to the patient. Right?

Ben 1:33:46

Absolutely. Like doing these things. For each patient. Yeah, right. Non invasively.

Daphna 1:33:53

Are we almost there? I'm not sure we're almost there. We can hope maybe by the end of our careers. That's right. individualizing medication dosing using the ice stat at the bedside. Well, I

Ben 1:34:07

have to bring back Kellyanne O'Meara

Daphna 1:34:09

Oh my god. That's right. That's right. Okay, we're getting behind as usual. So my next paper pacifier use and breastfeeding in term of preterm newborns, a systematic review and meta analysis. Lead author only to Pola and senior author, Laurie, cute Chunin. This is from the European European Journal of Pediatrics and coming to us from Finland. So the purpose of this study was to assess whether pacifier use is associated with breastfeeding success in term and preterm newborns and whether it influences hospitalization time and and time to feeding in preterm newborns. So is this a valid question? And obviously there's a lot of there's a lot of discussion around pacifier use in the world. breastfeeding community and frequently are hospitalized. Patients the families who are hospitalized patients are concerned about pacifier use. So this is helpful study the study design, they did a search, they looked for either the terms pacifier Demi su there plus breastfeeding lactation. And they had two authors individually screened all the abstracts, and then evaluate them, obviously for bias in using grade methodology. So the inclusion criteria was all randomized control trials and cluster or quasi randomized trials were included. The trials had to focus on the effects of free or restricted pacifier use in newborns, they didn't have any exclusion criteria about prematurity or birth weight. And because they were interested in looking at preterm infants in the exclusion criteria was just observational studies. They didn't include any observational study. The primary outcomes they looked at were the main outcomes of rates of any breastfeeding and full breastfeeding during the first six months of life. But they looked at two months, three months, four months and six months, especially because different studies had different outcomes. The analyses were then stratified on gestational age, so they looked at the less than 37 weeks of pre term group, and then the full term which was 37 weeks or more. secondary outcomes were like I said, duration of hospital stay and time to achieve full world feedings in the preterm neonates. Okay, baseline characteristics, they screen 772 abstracts, they assess 44 Full Text, and they attend randomized controlled trial in three studies. So again, now just to get into the primary outcome, they had three studies that looked at the two month breastfeeding rate, it included 18 162 term newborns, and, and it showed similar rates between the groups. They had three studies that looked at both term and preterm babies at three months. And so they had three studies, including 1621 newborns, 283, of which were preterm, and they looked at any breastfeeding at three months. And then they found they had two studies that included 1338 term newborns and looked at all breastfeeding at three months. And again, at the three month mark for all of those groups, they did not report any differences. They had three studies that included 1862 newborns, they looked at the rate of full and and any breastfeeding at four months, and reported that the restricted use of pacifiers did not improve breastfeeding rates. They then had three studies that included 1160 newborns, 281 of which are preterm, and they looked at the rate of any breastfeeding at six months, and they did not find any significant differences. So I'll tell you, if you look at the plots for these, it does. Yeah, it's wide, it's super wide, it does almost appear to favor restricted use of pacifiers at some time points. But the cumulative risk ratios are always approximating one. They're always crossing

Ben 1:38:28

one. Yeah. And they're there. They're definitely crossing them. Right. Not like it's not like, yeah.

Daphna 1:38:36

So I think this was an important. One of the ways we look at data, right? So if you just look at the plots, but you don't understand that they're all super wide, because they're all crossing one. And so they didn't find any difference. At two months, three months, four months and six months. And again, they had studies of the preterm babies at three months and the preterm babies at six months that did not show any difference. And then they looked at these secondary outcomes. So four studies including 283, preterm neonates looked at hospital stay duration, and they found that pacifier use shorten the duration of hospitalization by seven days, which was pretty pretty impressive. And they ranked the quality of evidence as moderate they did have some concerns or risk of bias due to the randomization. So something to consider for studies that again included these 283 preterm neonates and analyze the time of transition from lavage. Feeding to floral feeding, and pacifier use reduced the time of transition by three days. Quality of evidence ranked as moderate, again, some concerns due to randomization. But there's definitely a signal that specifically for preterm babies, maybe getting to practice at the pacifier before feeding may may incur some benefit.

Ben 1:40:06

Yeah, I mean, this is this is a massive meta analysis, in my opinion, because it's something if you cover the nursery at any point in time, this comes up every day. And parents, I mean, listen, I think that parent, I've rarely seen parents feel strongly about the pacifier itself, right. They don't really care about the pacifier, they care about doing what's right for their baby, right. And so, I think having this data where you can tell them, hey, it's up to you. And even though read the background, and the background of the paper is very interesting, because they quote all the studies that show that hey, like a pacifier means that you're going to wean off breastfeeding sooner. And it's, it's good to know that when you actually put all these data, all these data points together, you can tell parents No, it's okay. If you want to use a pacifier. And if you don't want to use a pacifier, it's okay to I like the idea of giving them a choice. And I like the fact that this gives options, especially when it comes to soothing babies. And, and again, yeah, some of them, some of them had earlier discharge. So

Daphna 1:41:12

when I tell you what we did, I'm thankful to say we did exclusive breastfeeding, and that first night in the nursery, I, I we delivered where I trained. I mean, did I sneak into the nursery and get a pacifier? Yes, I did. I'll tell you what, we were using a pacifier on day one.

Ben 1:41:35

We used a pacifier for my daughter. I was my parents tried to not use a pacifier for me and I was apparently a very loud kid. So I think the first time the first time they handed me over to my grandparents, my grandfather went and bought a pacifier was like you guys are done. Sounds this kid.

Daphna 1:41:55

Anyways, I thought it was a cool study. It's very cool.

Ben 1:41:58

Yeah. Thank you, too. I'm gonna say this for myself. Because I was aware I was made aware of this study by Michael Murphy who posted it. So thanks, Michael, for doing that. Okay, I have one more study. Can I can I go ahead. It's an important one. It's called a randomized trial comparing winning from CPAP alone with winning using heated humidified High Flow nasal cannula in very preterm infants. The chips study first author, Joan Clements, from New Zealand. I think this is published in the Archives. Let me just make sure. Archives of disease in childhood, correct fetal and neonatal edition. So this is a very interesting study, right? They're realizing in the background, that early weaning from nasal CPAP is important. And the recording all these trials that have been published in the past with the majority reporting that winning from nasal CPAP, using nasal High Flow nasal cannula is just as effective as CPAP alone. So the question that they're asking is, how long will a baby remain on respiratory support? If they're weaned either through high flow or just through CPAP? Only? Right? So how does that impact the duration? Now? I'm going to start this because if we go through the study, you're going to say this is a stupid study, because you're gonna say, Well, if a kid can tolerate high flow, then maybe they're more stable. And if they right, I mean, the idea that you could tolerate, quote, unquote, lower levels of support may mean right, that you're more stable, and then you're more likely to be less on oxygen overall. However, what I think this paper is asking, more subtly, is, when you put these babies on high flow, they tend to linger on high flow, right? And so the question is, would you be better off just weaning them off straight from CPAP? Because if you can wean them off straight from CPAP, you you truncate that period, that you're going to have them on a floor where technically, they could have been on room air. Does that make sense? Yeah, yeah. And so that, I think, from when when you look at this study, from this angle, you understand what they're trying to do, and it makes sense. The study design is that it's a single centered randomized control trial, and done at the Middlemore Hospital in New Zealand from 2015 to 2019. preterm infants were included if they were born below 30 weeks of gestation, and they were basically provided CPAP through its a bubble CPAP through Hudson prongs for at least 48 hours. And then they were to be included in the study. They had to be deemed ready to win. Now, what does that mean to be deemed ready to win? They had to meet what they are calling stability criteria for the 24 hours prior to randomization. And the stability criteria were as follows meaning no requirement for oxygen supplementation, or respiratory rate less than 60 or less breaths per minute, and no significant desaturation bradycardia requiring outside intervention makes sense. Yeah. The excluded infants who had previously been offered buttery support for more than seven days or had significant congenital heart disease, surgical condition, chromosomal abnormalities, genetic syndromes or other major congenital malformations. So what are the intervention? So prior to randomization, even infants received routine clinical management primary bubble nasal CPAP, via Hudson by nasal prongs with humidification. infants were then randomized to either wean off nasal CPAP, either by changing to nasal high flow and progressively winning the flow compared with weaning off the nasal CPAP pressure. And so they have a very elegant algorithm. And it's very straightforward. So you have group one, which is the CPAP group. So you're on CPAP of six for 40 hours, CPAP of five for eight hours, and on day five, you're off. And then you have group two, which is you're on CPAP. So now you get wind first to HiFlo six liters for 24 hours, four liters, 24 hours, three liters, 24 hours, two liters 24 hours and on day five, you're off, right. If nasal CPAP support of six or have more than six centimeters of water or nasal High Flow support of more than eight liters per minute were required. Then the infants received rescue nasal CPAP and stability criteria were met and they recommend their protocol as originally assigned. Infants completed winning by successfully remaining off respiratory support for at 72 hours or reaching 36 weeks PMA. The primary outcome of the study was the duration of respiratory support in hours from randomization until weaning was completed. And then secondary outcomes were subgroup analysis of the duration of respiratory support in infants who are less than 27 weeks of gestation at birth, chronic lung disease defined as any respiratory support or oxygen at 36 weeks postmenstrual age, nasal trauma age of first sucking feed I guess that means oral enteral feed age when forsaking feed was achieved the type of feeding at discharge weight, Z scores and other neonatal more morbidities. Interestingly enough Daphna day included parental stress questionnaire to see if having the baby on high flow was a bit less stressful for the parents obviously, it's done through the OptiFLOW prongs, which is more comfortable for the baby less cumbersome to see if that actually reduced parental stress. So interesting stuff. So they randomized 120 infants 61 into the nasal CPAP group 59 into the nasal High Flow group. Some interesting differences in the groups. At birth, more babies in the high flow group required intubation, so 23% versus 8%. And they also required more chest compression. Also pre randomization the babies in the nasal HiFlo group required a bit more mechanical ventilation 34% versus 20%. Okay, let's get into the primary outcome of the study. So the restricted mean hours from randomization to 72 hours of all respiratory support or 36 weeks PMA was 401 hours in the nasal CPAP group, giving an upper which is going to give you 401 hours in the nasal CPAP group. The restricted mean in the nasal HiFlo group was 375, showing that nasal high flow was non inferior to nasal CPAP weaning. So my fear was that they were going to linger right on nasal high flow right. But no they were they were able to win them. Just about the same time. 32 infants completed the primary outcome at 96 hours 15 in the nasal HiFlo group 17 in the nasal CPAP group. Let's talk a little bit about winning the first trial of respiratory support following randomization was took place at a similar postmenstrual age which was about 31 weeks. The point estimates prior to successful trial off the support suggested infants in the nasal High Flow group had a higher rate of escalating flow slash pressure. However, there was not really statistically significant reduced treatment failures prior to achieving 72 hours in the nasal High Flow group compared with the nasal CPAP group, the leading cause of treatment failure was desaturation slash bradycardia. Okay, secondary outcomes and then we're done in weaning from nasal CPAP using these all have high flow was non inferior to wheezing from nasal CPAP alone in stable very preterm infants when using Street district weaning and failure criteria and the postmenstrual age at successful outcome was about 33 weeks in the less than that in the less than 27 weeks gestational age group. They were unable to conclude that these are high flow was non inferior, so those babies did better with the CPAP in that specific subgroup of really small infants. Infants in the nasal HiFlo arm had significantly less chronic lung disease than those in the nasal CPAP arm 18% versus 36% That was statistically significant. The other secondary outcomes were not statistically significant. And finally, the stress scores that we were talking that were given to parents were reduced in the nasal HiFlo group in regards to relationship section of the survey. So it's very interesting. Now, the conclusions of the study that for infants ready to win from these CPAP, the trip study found that nasal HiFlo was non inferior to discontinuing nasal CPAP at five centimeters of water. So let's go back a little bit right now to the question that we asked initially, which was, are these kids going to linger on nasal Haifa, I still believe that they do, despite what this study shows, because this study shows that if you have a rigid protocol to win, then you will be almost pushed to try them off. Right. But if you were not to have that kind of protocol, they might I'm sure they would linger longer. And so I think, to me, the This study also shows that nasal high flow can be very safe and reduce a lot of negative outcomes. If you have a rigid protocol where you know that after 24 hours, you gotta keep winning. I am even guilty of that. But you have a kid that just went on high flow five, and it's like, I'm gonna wait one more day, you just I'm just waiting one more day.

Daphna 1:51:14

Always something right? The exam or?

Ben 1:51:18

Or there's exactly, there's like, Hey, I'm going up on Fifth today, I'm not going to winter vaccinated is always and they stay on longer. And that increases risks of chronic lung disease. So I think the biggest thing by this paper is this winning algorithm that is very nice. And ensuring that with a winning algorithm, and then using these or high flows is just as good. Except in the right I mean that they didn't mention that in the less than 27 weeks subgroup, they were not able to conclude non inferiority. So that's that's the only caveat but these kids are very small anyway, so that's not really surprising. That's it for me.

Daphna 1:51:56

Okay, yeah. Wow. Some cool articles.

Ben 1:52:00

Yeah, some very interesting topics. We hope you enjoy it. And we will see you tomorrow for neonatology review. We wanted to congratulate again, Katie, harsh for winning the giveaway. And we will see you all tomorrow. Thank you for everybody who tuned into the new heart coverage. We're very humbled by that. And we were very humbled by the guests that we were having on there. Pretty impressive people

Daphna 1:52:21

super cool. If you haven't had a chance to check it out. It's really neat. It's really neat. Next year, we'll break we'll get even more, more.

Ben 1:52:30

Yeah, and I made I made a web web page on the website with all the different guests so that there's many guests that came on the show, so I didn't want to just overwhelm the podcast page. So they are all in one web page, but you can find out their bio and who they are on that on that page that covers that is dedicated to the new art coverage. Thank you all and see you tomorrow.

Thank you for listening to the incubator podcast. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address NICU You can also message the show on Instagram or Twitter at NICU podcast or through our website at WWW dot v dash incubator that org This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns. Please see your primary care professional. Thank you

Transcribed by


bottom of page