Hello Friends 👋
We have an exciting episode of Journal Club scheduled for you this week. Daphna and I are eager to review the two-year outcomes of the PlaNeT2 MATISSE trial. If you recall, this trial published in NEJM (2019) showed that infants randomly assigned to receive platelet transfusions at a platelet-count threshold of 50,000 per cubic millimeter had a significantly higher rate of death or major bleeding within 28 days after randomization than those who received platelet transfusions at a platelet-count threshold of 25,000 per cubic millimeter. So we were eager to see the outcomes at 2 years CA. We also review studies looking at hindmilk in infants with suboptimal growth, a survey of NEC pain management in Europe and so much more. We hope you enjoy listening to this episode. Have a good sunday!
Do not forget to secure your spot for the DELPHI CONFERENCE taking place on March 27-28-29 in South Florida. Delphi offers opportunities to submit abstracts for poster presentation and will offer CME credits. Register at www.delphiconference.org use the code INCUBATOR for a special discount for our listeners at checkout.
The articles covered on today’s episode of the podcast can be found here 👇
Moore CM, D'Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Santamaria BL, Deary A, Hodge R, Hopkins V, Mora A, Llewelyn C, Venkatesh V, Khan R, Willoughby K, Onland W, Fijnvandraat K, New HV, Clarke P, Lopriore E, Watts T, Stanworth S, Curley A; PlaNeT2 MATISSE.Arch Dis Child Fetal Neonatal Ed. 2023 Sep;108(5):452-457. doi: 10.1136/archdischild-2022-324915. Epub 2023 Feb 21.PMID: 36810309 Free PMC article.
Alshaikh BN, Festival J, Reyes Loredo A, Yusuf K, Towage Z, Fenton TR, Wood C.Nutrients. 2023 Feb 13;15(4):929. doi: 10.3390/nu15040929.PMID: 36839288 Free PMC article. Clinical Trial.
Branagan A, Yu I, Gurusamy K, Miletin J.Arch Dis Child Fetal Neonatal Ed. 2023 Jul;108(4):333-341. doi: 10.1136/archdischild-2022-324184. Epub 2022 Dec 9.PMID: 36600484 Free PMC article.
Vereen RJ, Nestander M, Haischer-Rollo G, Aden JK, Drumm CM.J Perinatol. 2023 Apr;43(4):496-502. doi: 10.1038/s41372-022-01598-w. Epub 2023 Jan 12.PMID: 36635506
Hochwald O, Borenstein-Levin L, Dinur G, Jubran H, Littner Y, Breuer M, Kugelman A.J Perinatol. 2023 Mar;43(3):305-310. doi: 10.1038/s41372-023-01614-7. Epub 2023 Feb 9.PMID: 36759706 Clinical Trial.
Ten Barge JA, van den Bosch GE, Meesters NJ, Allegaert K, Arribas C, Cavallaro G, Garrido F, Raffaeli G, Vermeulen MJ, Simons SHP; ESPR Special Interest Group for Neonatal Pain and the NEC Pain Study Group.Pediatr Res. 2023 Aug;94(2):555-563. doi: 10.1038/s41390-023-02508-2. Epub 2023 Feb 24.PMID: 36828969 Free PMC article.
Solís-García G, Jasani B.Arch Dis Child Fetal Neonatal Ed. 2023 Sep;108(5):523-529. doi: 10.1136/archdischild-2022-324995. Epub 2023 Mar 1.PMID: 36858828 ---
Find some of our notes here 👇
The transcript of today's episode can be found below 👇
Hello, everybody. Welcome back to the incubator podcast. It's Sunday. How are you Daphna?
I'm doing great. How are you? You've had a busy few weeks.
Oh, yeah. It's been tough. Sickness, sickness and health, you know? That's right. But technically, we're recording technically, this is airing in the weekend of core topics, which we are very grateful for having the opportunity to be there. So yeah, it was. It's, it's really cool to be able to share the incubator podcast story with with the great folks at at cold topic. So thank you. Thank you to everybody who was involved in the planning of this conference and who invited us?
Yeah, I think, at this time on Sunday, we'll say we had a great time. Getting everybody cool topics.
Yeah, and no, everything. Everything else is pretty cool. We're planning a bunch of interesting things. So we are shuffling. Let's give you I mean, I know we've been talking about the Delphi conference where we're very pumped, we're like, we're over pumped about the conference, it's going to be quite fun. It's, there's a few seats left, feel free to register. But we're working on other stuff for the podcast. And one of the things that we wanted to make sure we announce is that we've actually shifted our schedule to address if you haven't seen the newest ACGME requirements for pediatric residency, and they have a significant impact on the NICU slash ICU exposures our residents are going to get what how will that affect how qualified and competent they can be as they enter fellowship and, and so we're gonna have some pretty amazing guests coming on the show to talk about this with us. And this episode will air next week. We will also have new episodes of board review coming out next week. And we are going to have more stuff on that board review podcast that's going to feature fellows from around the country. So if you are interested, we're in in participating in that podcast with a bunch of your co fellows, we'll have more info for you coming up soon. And I think for the next journal club, I think we're going to have a special segment where we feature someone from the EB Neo team to talk about one of the papers that they review every month. So that maybe by the time we get to the campaign at the end of the year, we've actually reviewed them with we've reviewed the the papers with them, they do the review anyway. But we'll have so all fun stuff. And
I mean, I think excited doesn't even like begin to explain our emotions about this, like this was the goal, right for the incubator is to really serve as like a conduit for the community and just engage with all of the amazing organizations that are ready, impact, neonatal care and support, you know, neonatal professionals, but to really get people, you know, in the studio to do some of
that, as people may think it's all about us, you know, we just want our voices to go far and wide. Just horrible.
To the contrary.
But no, it is it is about making the platform available to all and that's really cool. Yeah. Okay, shall we begin Journal Club? I have messed before papers that have very excited to present. I guess I'll get started if that's okay. Sure. The first paper I wanted to talk about is an important paper that came out in the archives of disease in childhood, fetal and neonatal edition. It's called two year outcomes following you see, I didn't use my phone.
Usually me that's getting reprimanded for that. We're all imperfect.
Now. So this paper is called two year outcomes following a randomized platelet transfusion trial in preterm infants and It's first author is Carmel Maria more and it's from the planet to Matisse group. And for those of you who are remembering, this was the trial that was published, amen. I'm blanking maybe 2019. And so, the planet to Matisse trial was a large international RCT that looked at platelet transfusion thresholds on both short term and long term outcomes. I think the initial paper was published in the New England Journal of Medicine. And it reported the short term outcomes. And it really looked at whether you had a liberal versus a more restrictive thresholds 50,000 versus 25,000, sorry, platelet transfusion thresholds, how would that affect the outcomes for these babies. And what the initial paper found was that those randomly assigned to undergo platelet transfusion at a platelet count of 5050 times 10 to the power nine had a significantly higher rate of death or major bleeding within 28 days after randomization than those who were randomized to a platelet threshold of 25. So the other interesting piece that because I mean, I think this paper came out before the even the inception of the podcast, so we never really had a chance to review it. But everybody read this paper. But what was also interesting was that the this benefit, this this, this was also demonstrated this difference was also demonstrated, irrespective of baseline risk of bleeding or death. So this paper really is about determining whether the higher versus lower transfusion threshold for platelets changed the composite outcome of death or survival with significant neurodevelopmental impairment at the correct age of two years. So it's the paper really giving us some of these long term outcomes. I'm just going to go through the methods. Again, we'll include obviously, some of the Northern metal stuff, but I feel like you may have forgot we had forgotten what exactly were the inclusion criteria, and so on. So the study really included babies who were born at a gestational age of less than 34 weeks had a platelet count of less than 50,000. And the cranial ultrasound performed within six hours before randomization. And that didn't really have a major ivh. Obviously, they excluded babies with life threatening congenital malformation, major bleeding in the previous 72 hours, fetal intracranial hemorrhage, immune thrombocytopenia, the refusal to administer vitamin K, and babies who had a very low probability of survival. Now, interestingly enough, preterm infants with a major bleeding could be eligible once that 72 hour period passed. And so they could then be included. The intervention was basically platelet transfusion given at a dose of 50 milliliters per kilo, when the platelet count was either less than 25,000 versus less than 50,000 per cubic milliliter. 25 being the low threshold 50 being the high threshold. And then, of note, the protocol did permit additional platelet transfusion for clinically significant bleeding or surgery or invasive procedure. Fine. So how do they assess neurodevelopmental outcomes? So they were assessed at all the centers that participated. And ideally, they were done with the Bailey, three, and Griffith mental developmental skills extended, revised. So the GMDs er, scores more than two standard deviations below the mean, represented an unfavorable outcome. And what's interesting is that when these tests are when these tools were not available, basically what they did was that they contacted parents slash guardians directly by phone, to ask them to complete a patient reporting assessment. Specifically, the parent report of children's abilities revised the parka R. And that's basically a survey that is that is that has been evidence based to use parental reports to assess neurodevelopmental outcomes.
That's a lot of work, but they did.
I mean, I'm going to tell I'm going to tell you a little bit my opinion on the paper afterwards because I think it's a it's I mean, there's a lot of things to say, but yeah, I want to touch on that you're making a great point. So the favorable outcome was given if they could ascertain that a child was alive at the age of two years, corrected for gestation, and that they did not have any of the following cerebral palsy that impaired independent walking, Global Developmental Delay assessed by a healthcare professional as more than nine months behind expected for age, a pragmatic pragmatic clinical equivalent of more than two standard deviation below the mean severe seizure disorder hearing impairment not corrected by a hearing aid or bilateral view impairment with no useful vision, parentheses like perception only the primary outcome was death up to two years or an unfavorable an unfavorable outcome. And the secondary outcome included the components, the component parts of the composite long term rather metal outcome, analyzed separately using mixed logistic regression models. Now, another thing that they did is they looked at respiratory outcomes because in the original trial where they had found what that survival with BPD at 36 Weeks was clearly different between the groups. And the kids who got transfused at the higher threshold had a higher rate of BPD 63% versus 54%. And so they were like, we're going to try to look also at the long term pulmonary outcomes, since this is something that really came up in the original paper. So, a total of 660 infants were enrolled right between 2011 and 2016. In 43, centers in the UK, Ireland and the Netherlands. They had 59 infants that were excluded slash lost to follow up. In terms of the primary outcome data mortality data was available for 606 of the 653 infants and 93% 81 infants had died within 20 days of recruitment nine an additional 84 died before two years corrected age, five of the surviving children had insufficient data to assign a mental outcome leaving 436 children available for full neurodevelopmental analysis. Okay, so that's 666 650 babies, and then basically, about 450 left. For northern mental analysis. It's very important to make this point only 41% of children had formal neurodevelopmental assessment, meaning they were able to get an actual assessment done in person with the BS dsid Three, the belly three, and the rest had to go through this parental assessment form. What they found was that infant randomized to a higher platelet transfusion threshold of 50, compared to the lower 125 had higher rates of death or significant neurodevelopmental impairment of 296 infants assigned to the higher threshold 147 died or survived with an unfavorable outcome compared to 120 of 305. So the difference was 50% of the group on the higher threshold, died or had an with or survived with an unfavorable outcome compared to 39% in the lower threshold group with an odds ratio of 1.5 for looking at some of these respiratory outcomes. Of the 286 children who were in their higher threshold group 38% died or required respiratory support that two years of age compared to 28% assigned to the lower threshold group 22 children in the higher special group required respiratory support that two years corrected age compared with nine children in the lower threshold group, so that's quite different 22 verses verses nine. The conclusions of the paper is that the higher platelet count threshold for prophylactic transfusion in preterm infants less than 34 weeks at birth, increased the rate of death or Northern mental impairment at two years corrected age. There's no evidence to support to support a high prophylactic platelet transfusion threshold in preterm infants, and there's increasing evidence of harm persisting into childhood. As clinicians, we need to question whether a liberal approach to platelet transfusion can be justified on clinical or ethical grounds. So I guess this data obviously had to be reported. It does highlight the difficulty in performing we often we often commend other groups who are able to have very high follow up rates and are able to really evaluate infants at rates of like 90 plus percent to three years down the road. And I think, in this case, you see that only 41% was really able to get a formal northern mental assessment. And you may say, this invalidates the data for me, I'm not going to rely on this data. I don't think it could be used. That's up to you. But it does it. First of all, it should not obscure the fact that the other 60% of the patient populations were followed in a way through a parental survey. So that should not eclipse that but also it highlights how difficult it is to perform northern metal follow up two years after birth. It is extremely, extremely difficult. And so So yeah, so the data I think is interesting. I think it reinforces what was published early on in the first paper but but definitely highlights some of the issues that we all run into when it comes to performing northern mental follow up.
What it what this kind of highlighted for me, I agree with you entirely on all things. But what it highlighted for me was when a baby is that sick, right They're so thrombocytopenic Gosh, just how at risk they are for both the short term mortality, but long term morbidity. And, you know, we've been talking about this a lot in our unit about prognosticating outcomes for families, when these other you know, what we have is like, you know, the head ultrasound, but what, but when we have these other factors that are additive, right, infection, inflammation, you know, that, that it's hard to quantify, but we know impacts neurodevelopment. And secondly, that, you know, none of our treatments are without risk. Right. And I wonder if there, maybe we have to, like go back to the basics of like storing blood and transfusing blood. And is there a way that we can make it like, less inflammatory? I don't know. But
you want to read that? Yeah. Reinventing the wheelchair.
I just feel like that's something in medicine that we're like, Well, this is how we do it. But maybe there's a way to do it better. I don't know.
Someone get get cracking Yeah, right
on that. Not that's not it's not a study, I will do somebody. Okay, well, thank you. I wanted to do this paper, or to get go. I guess I will do all my papers eventually. So I'll start with this one. And the title is hind milk as a rescue therapy in very preterm infants with sub optimal growth philosophy, philosophy, lead author below, I'll shake and trailing author crystal wood. This is in the journal nutrients. And it's coming to us from Canada. So this was a prospective cohort study in a level three NICU between January 2019 And June 2022. The inclusion criteria was quite stringent, infants born less than 30 weeks and less than 1500 grams born and two parents two with enough quote unquote enough milk supply. So greater than 150% of infant needs, which is no small feat. Infants needed to be on full enteral feeds of 140 mL per kilo per day of exclusively milk diet greater than two weeks with slow weight gain and their parameter for slow weight gain is less than 15 grams per kilo per day. inclusion criteria I'm sorry, the exclusion criteria was small for gestational age, or chromosomal anomalies. So obviously two major factors in slow postnatal growth. So the intervention they used was they had mothers separate their milk, so they started pumping, and then after the flow is initiated for that pump, the first three minutes were set aside that was considered for milk and the remainder to empty was considered the high milk. The primary outcome was the rate of weight gain, while consuming hind milk as compared to the two weeks prior. And the secondary outcomes were the changes in the anthropometric, anthropometric Z scores and changes in the fatty acid profiles. So the baseline characteristics they had 552 infants born during that time period 163 With identified a slow growth, philosophy, velocity, unfortunately, they were only able to enroll 34 infants. And I just thought this was interesting. We review so many papers, most 82 of the remaining infants did not meet the inclusion criteria, which again, it we have, it is hard to have an exclusive milk diet, it's a lot of work. And there are so many factors that go into preventing an exclusive milk diet. But they go ahead.
No, and it's the it's the dilemma that every researcher faces, right. It's like you want to you want to get power versus high quality data, right. And so as as stringent your inclusion criteria as stringent as your cleansing criteria become, then you get a much narrower sample size, but a much cleaner sample. But it's right, but it makes the performance of the study so much more difficult,
for sure. And I do think it was important in this study to be clear about, you know, like you said, to have the cleanest the cleanest data, so 27 refusal to participate, we still have a large refusal to participate, and I actually think that number is climbing, and then 21, quote unquote, other reasons. The average gestational age for the group is 26 and a half weeks average birth weight of 855 grams, and the majority of the infants were on non invasive respiratory support. And, interestingly, I thought their unit must do a great job with nutrition they had enteral support initiated on a median day of life one day In the median day of initiation of hind milk, so for the babies selected to participate with 33 and a half weeks, hind milk and composite milk differed significantly, so when they looked at the milk that is pumped normally, so the composite milk versus just the hind milk differed significantly and that and total calories, there were no differences in protein or carbohydrate. So for the primary outcome, there was a significant increase in weight gain in the two weeks after initiation of high milk compared with the two weeks prior to using composite milk. The mean difference in weight gain was 3.8 grams per kilo per day. The weights the scores were significantly higher at two, three and four weeks of high milk. Interestingly, and they have these beautiful graphical depictions, but the z scores make kind of a peak at three weeks and then begin to taper off. The head circumference scores were larger at three and four weeks, and the length Z scores remained unchanged. All were adjusted for protein content, gestational age, sex, and exposure to postnatal steroids, and BPD. So they did try to evaluate for some of the other con founders with poor weaking. The secondary outcomes they looked at were that all the fatty acids were higher in the hind milk. But only linoleic acid reached statistical significance. There were no differences in arachidonic acid, or DHA. So the takeaways are, was that the hind milk did increase the weight gain some people may say, but is that enough? But you know, I mean, for some of our babies who really have stagnant weight gain, I do think it's a potential. So potentially, clinically important.
I'm thinking maybe some people are not familiar with because I mean, we've we've done we've done high milk in our in our mouths in the past, but like, what if somebody says, Well, I don't understand like, isn't that baby getting the hind milk anymore? Like, what are you giving? Exactly? Can you? Can you explain to us what it means to feed? Like, what is the difference in in just? Well, I
think if you take the overall in that we had, this is sometimes complicated to explain to parents. So if you take the overall feeding volume, basically, a higher proportion is going to be of hind milk, I actually thought it was interesting that they only pumped off the first three minutes after the flow is initiated, because the counter argument is, isn't there good stuff in the four milk that babies need. And so I actually think this is still not, quote unquote, exclusively hind milk. But a higher proportion of the milk that the babies are getting are his hind milk,
right. So instead of basically having hind milk with other, just you just want to just want to use the hind milk alone and feed that to the baby with whatever additional calories, supplements and so on so forth, that you're otherwise giving them.
Right? That's right. So it has a higher caloric density, just like they showed here at high, it has a higher fat content. There's more water content in the in the for milk as compared to hind milk. But that's why I thought that was, I think, actually, they only pumped off the first three minutes. And for people who have pumped before or watching mom's bumped photometry. It's arbitrary, right? You know, sometimes sessions can range from five minutes to 20 minutes, right. But I think what I would have liked to have seen is more nutritional data on the composite versus the hind milk, because obviously, that's different for every individual. But I thought it was an interesting study, especially when we're talking about putting so many different other kinds of additives to fortify milk and increase the caloric density, when you have a milk product that you can manipulate to change the nutritional value, I think is is interesting. What does it mean to give more fat as caloric density versus say, protein as caloric density? You know, I think that's a question that has to be asked. And, you know, what does that mean for long term growth and development of the metabolic syndrome and things like that, but I think for babies who's who's, you know, mother's producing a lot of milk, which is hard to find it to begin with, and whose weekend is not good, it's something to consider. I also think there are some moms who are pumping so much milk that some of that milk can be have a low caloric density, so that's something that we have to not all milk is the same, right? So we have to be knowing And what kind of milk production families are are bringing in?
All right. My turn. So the next paper I want to look at is a paper that was, I guess, also published in the Archives. Yep, the in archives of disease in childhood, fetal and neonatal edition. And the paper is called threshold for surfactant use in preterm neonates network meta analysis. First author is a ofii brand again, and it's paper coming out of Ireland. So, I mean, it's a meta analysis. So it's not like a study was conducted there, right there. And then but anyway, so I thought this was an interesting question, right? I mean, the initial introduction of the first part of the introduction talks about how surfactant is a key component of the management of IDs, which we all know, we know that surfactant can be either given prophylactically, or selectively and you can and that means, either in the delivery room, you give it to all your kids who meet certain criteria, or you say, No, I'm going to first stabilize them on nasal CPAP. And then if they reach a certain threshold of vfio, to then I'll give them a dose of surfactant. And the question they ask is like, what is what is the threshold. And they're mentioning that despite a large body of work, assessing the best use of surfactant, there's really little data that is out there to assess what the proper fit threshold is, or should be. And there's tremendous variability. So they quote that the European consensus guidelines suggest a 30% threshold, both the American Academy of Pediatrics and the National Institute for Health and Care Excellence, and that's in the UK state that surfactant should be selectively given to infants on nasal CPAP. But they actually just shy away from even giving you an FAO two thresholds. The Canadian Pediatric Society says 50% should be the number. And so the value of a fire to in isolation as a measure of IDs severity, and surfactant requirements has been very much disputed, as a failure to as we know can be influenced by a myriad of other factors. And so what the authors are trying to do in this study is to perform a systematic review and network a network meta analysis comparing different thresholds of FAO to for surfactant treatment in infants under 32 weeks of gestation. So they included studies that were randomized control trials, the patients had to be neonates born before 32 weeks of gestation managed on non invasive ventilation and patient managed on nasal CPAP. I'm sorry. The primary outcome they looked at was mortality. secondary outcomes included BPD pneumothorax. The number of surfactant doses that they'd be required. They had a category defined as major morbidity, defined as at least one of the following severe ivh PVL, necrotizing enterocolitis, grade stage two a or above ROP, retinopathy of prematurity, greater than stage two, or bronchopulmonary dysplasia. They also wanted to see if any study looked at Northern metal outcomes at two years of corrected gestational age. And they wanted to see if anybody also looked at high health related quality of life. So 26 References describing 14 trials were included. And this ended up including about 5300 infants approximately the mean gestational age range from 27 to 30 weeks, and a threshold of a failure to for provision of selective surfactant ranged from either 30% In three studies all the way up to 60%. In three studies, five studies provided surfactant at 40%. And three studies provide a surfactant at 50%. So right there, we're seeing we're seeing already some some variation really going from 30 to 60%, is quite, it's quite a quite a range. In terms of the primary outcome of mortality, each of the 14 studied of the 14 studies I'm sorry, measured mortality, and the including these 5300 patients, and none of the estimates reach the statistical significance, with 30% threshold having the highest odds ratio for the outcome of mortality with an O R of 1.8. And a 95% confidence interval of one to 3.44. So not statistically significant, but probably the one with the highest degree of difference in terms of the of the secondary outcomes BPD, they found no difference regarding BPD, or chronic lung disease alone, in terms of the use of surfactant. That was surprising and also not very surprising, meaning less those were given for higher thresholds. So if you were having a threshold of 60%, then obviously you got less doses of surfactant. However, it was not a dose dependent response. So the 60% threshold had the least doses make sense? 30 percent was the second threshold and then 50% Third 40% last. So it did not really follow the did not really follow a straight A straight line. In terms of complications of prematurity, there were no significant differences in the incidence of AVH PVL neck or BPD 60% fit to threshold had a higher incidence on ROP on direct comparison with prophylaxis, which is not really surprising, obviously. neurodevelopmental outcomes are two years one trial reported this outcome and 43 of 480 in the prophylactic group and 55 out of 511, in a selective group developed neurodevelopmental impairment, so not statistically significant. And then they did a sensitivity analysis of infants treated treated in the era of antenatal steroids and the use of nasal continuous positive airway pressure as initial modes of respiratory support. And it showed no difference in mortality rds, or ivh. Alone, but suggested an increase of combined outcome of major morbidity in the 60% threshold. So it really clearly seems that you're waiting until 60%, you're probably waiting a little bit too long. The study then goes on to conclude that the meta analysis of these 14 studies 5290 infants suggests no statistically significant difference between a range of 30 to 50%. If I were to, for the provision of surfactant to infants, regarding mortality, respiratory outcomes, or complications of prematurity, they do mention as we just said that a 60% threshold may result in more major morbidities. Despite the low quality of evidence and limitations of indirect comparison, this review provides the strongest evidence currently available supporting the judicious use of surfactant in preterm infants. The reason I was You may be wondering, like, why are we even so like, so like, so like, no change, basically, we don't really have better information. But I think this, these are some of the things that are ingrained in you in in your fellowship, or in the whatever institution you train in, like this, when this number hits, I give surfactants. And it's kind of nice to have a paper reminding you that, you know, if you wait until 40%, you're not like, not killing the patient. It's I mean, it's like you there's there's no like the evidence is not very much. It's not super clear cut. And so I think sometimes you, for me, the way I read this paper was that, you know, sometimes the baby's fit does cross a certain threshold, when I trained, it was 30%. And you're like, Oh, my God, it's 35%. And I haven't given surfactant? Well, it's nice to have data that says, well, actually, the Canadians waiting until 50%. And so if you look, and so that's something that they mentioned in the discussion, actually, that I should bring up, which is, maybe we should have a more comprehensive approach to these things and not just look at a single number. And I was like, You know what, that's probably very true. So I really like this paper.
Yeah, I totally agree. Right. And I mean, it's there, like different patients also, right, like the pre term, the surfactant deficiency from, I don't know, the conium and activation or congenital pneumonia, or, you know, the, the infant of diabetic Mother, you know, there's so many reasons is the baby distress, like, are the co2 is normal, like, we aren't talking about those things, you know, and individualizing care in that way. We just had a twitter poll about it. Right. So what's the threshold? And the truth is that we're using different thresholds.
Yes. Am I on Twitter for the past few weeks, I have to say, I missed that.
You'll get caught up, don't worry.
I think what's the conference is behind us. I'll be I'll be more accurate. But my notification badge on my iPhone keeps climbing and I'm like, Ah, and I definitely have reached the tweeter notification threshold where I'm like, It's too many.
I can't even catch. But I think it's interesting. You're right. There are some things that are dogma when you're coming out of fellowship, which are not true everywhere.
Yeah, and as a fellow I remember, like, I remember as a fellow especially, it's like, it's like the kids on 40. You know, the kids been on 30% the entire night. And then as you round or you sign up in the morning, suddenly the kids on 40% People like he's on 40% You haven't given surfactin is like, Oh my god. Oh my god, I'm so sorry. I'm so sorry.
That you come back with your equipment and the nurses like oh, it was touch time. I just wanted the baby back down to 27 28% We're good. You're like, great. Man.
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Okay, my next paper is a kind of a respiratory paper also so title the effect of changing respiratory rate settings on co2 During nasal intermittent positive pressure ventilation and premature infants. Something else that I learned is dogma. Lead author Ori Hawk, Wald, senior author, Amir kugelman. This is from the Journal of Perinatology is coming to us from Israel. So the study design is a prospective controlled crossover study. The inclusion criteria were infants that were 24 and Oh to 32 and six weeks gestational age, on non invasive support from the gecko or for post extubation support, having been stable on at least six hours of non invasive positive pressure ventilation settings. And of note, they use the RAM cannula. So what was the intervention. So they basically took the infants in their baseline situation, an IP fee rate, non invasive positive pressure ventilation rate of 10, or if the baby was on 30. And they watched them for an hour using end tidal co2 measurements. Or I'm sorry, not entitled, because they're not invasive using Transcutaneous co2 measurements. And then for the subsequent hour, they either bumped a baby who was at 10, breaths to 30, or baby who's at 30, breaths to 10. And they watched the Transcutaneous co2 levels during that time period for the third hour, then they put the baby back to whatever the baseline was. So either 10 or 30. So nifty, started as high or low, then change to low to high, low versus high and then switched back. So their primary outcome was to look at the mean change in Transcutaneous co2 When changing the rate, and then they also wanted to look at the type of histogram spontaneous respiratory rates de saturations, bradycardia, is apneas. Did any of those things change during that time period? So pretty simple study, but I think an important question to ask. So the primary outcome overall was that the mean change in Transcutaneous, co2 was negative 1.1, when increasing the rate from 10 to 30 breaths per minute, so it decreased the Transcutaneous co2 measurements by about 1.1. And when decreasing the rate from 30 to 10 breaths per minute, it the overall change in Transcutaneous, co2 measurements was an increase of point four, six. So nominal, there were only two cases where the Transcutaneous co2 increased or changed had a Delta of more than five. And that happened once with increasing the rate and once with decreasing the rate. And then interestingly, there were no differences in histogram type, spontaneous respiratory rate, number of D saturations of bradycardia, or apnea for any of the babies, they did see a difference in mean airway pressure, I thought this was interesting of 7.1, and 8.1. So 7.1, on a rate of 10, and 8.1, on a rate of 30. And this was statistically significant. They also found a statistically significant difference in mean SPO 290 3%, on 10 versus 94%, on 30. And so a quick, quick overview, but I thought it was an interesting paper, because we bump up and down these kids all the time, sometimes based on gas is not in our unit, but we've practice places where where that was happening a lot. And it doesn't seem to make a difference from that perspective. There are obviously babies that seem to need more rate than others, for different reasons, and maybe one of the reasons is just this increase in mean airway pressure. I thought that was interesting. I do think that the one hour interval is short, and maybe some of these babies will declare themselves if we left them on for longer. But an interesting paper nonetheless. Your thoughts respiratory guy.
I think I think you have to take this paper with a grain of salt and be very careful because you could easily be tempted to think Oh, making big swing changes on your rate on non invasive ventilation doesn't mean that you
know, you I'm I creep. When I make rate changes, I don't certainly don't go for 30 to 200
I am very comfortable with those changes. I am very comfortable with going from 30 to 1030 to office if that's needed, but I think but I think the you could eat has really misconstrued the paper and say, oh, like if I go from 30 to 10. It's not a big deal. And there's a lot of physiologic reason as to why that is. We know that. It's not like when you're intubated, those changes, there's so much leakage. There's so much already spontaneous breathing effort, that, that it's not surprising that the changes would not make such a drastic impact. I think what to me, it says is it's interesting, because I was thinking about the one hour and I was like, you know, the one hour is nothing like it's not helpful to me. But it what's interesting is that if you look at the data from the standpoint of, we make a change on the event, and there's always this sort of automatic one hour post, one hour post event change, you're like, oh, We'll reevaluate in an hour. Well, the paper shows you that this is not going to be helpful. Like if you make event change of this significance to a baby on non invasive, give yourself six hours, give yourself until the end of the shift, because you're going to come back in one hour. And if you get yourself a guess and be like, Go eautiful. It's the same. Well, maybe we know it's not meant to be changing that quickly. And like you said, maybe your your your change is actually a good one, and the baby will do well, or like you said, maybe the baby will start becoming ticket, Nick, three, four hours later, and you should just like be around when that happens. Yeah, yeah. Yeah.
Yeah. Okay, go do it with a longer, a longer time span
that you have to be you have to be ballsy to that. Alright, I'm going to talk about neck for the next two papers, I have two papers. And they're kind of interesting. So the first one is published in pediatric research. It's called current pain management practices for preterm infants with necrotizing enterocolitis. A European survey. Judith 10. barge is the first author. And I love these papers, I loved survey papers. And there's like so many cool graphs on this paper. I just loved it. So the background state starts with NEC is pretty bad. Okay, that's like probably their first two, three statements. And we're like, okay, we can all get on board. It's exactly right. It's like I can get on board with that NEC is bad. But they're mentioning how the excessive inflammation and ischemia in the intestine caused severe visceral pain. That's something that I think in our profession can easily be overlooked. Because patients don't really talk to us. If our baby said, Hey, Doc, like I'm in pain, we will probably treat them differently. Up to optimal pain treatment in patients with neck is not only needed to protect from the burden of pain, but also to promote recovery and outcomes. They even also talk about the negative long term effects of pain and neonates, and we all know that so, in the Netherlands, acetaminophen and opioids such as morphine and fentanyl are the most commonly used for treating patients with neck who are experiencing pain. And they mentioned this retrospective study that has shown that despite analgesic therapy during neck most patients still experience episodes of pain and a quarter 25% of patients experienced persisting periods of pain with a median duration of seven hours. This is inhumane if we thought about that. If a patient in an adult floor was complaining of pain for seven hours, you would get an incident report. Right? Yeah, it
makes me it makes me like sick to my stomach. You know, when I come on. So what's what's the what's the analgesia they're like, and nothing the baby's been okay, that's not taka Karthik and I was like, but what do you mean,
right? Seven hours. They're saying and I quote to our knowledge, international guidelines for pain management for patients with neck have not been developed yet. And so the study aims to describe the current pain management practices with neck in European NICUs, including pain assessment, non pharmacological therapy with the ultimate goal, right. This is as a first step in the ultimately developing European consensus, consensus guidelines for the management of pain in patients with neck. So this was a cross sectional study that was conducted to assess pain management practices, through a web based survey. And the final version of the survey included 39 Questions about NICU demographics, protocols for analgesic therapy, pain assessment, non pharmacological interventions, use of IV analgesic dosing regiment and the response and the respondent, the respondents expert opinion on current pain management in his or her NICU. It's kind of cool because they have this graph about like, how many NICUs they were able to capture in each country, and it's sort of we're a small field man, like you. You look back at some of these countries, and you like they're pretty big countries. So like, the UK 12 They were able to get 12 out of 44 NICUs. And it's like, I would have said hundreds of niches. I think Iceland has one. Wow. It's it's Yeah. And then and it's not what you would expect. So For example, in Italy, which is on the surface area, not the biggest country has like 118 NICUs. So anyway, interesting stuff. Interesting stuff that just would pique your curiosity. Okay, so let's talk about some of the results. The total number of 306 responses were submitted. 288 actually came from European NICUs 63% of NICU representative characterize the level of care provided by their NICU as level four. So high acuity, the median number of annual neonatal admission to the NICU was 400. So pretty large NICU, including a median number of 65 vl BW admissions, over half of the NICU is treated one to 10 patients with neck yearly, and approximately a third, treated more than 10 neck patients per year, Nicu representative from 36 out of 44 European countries, so 82% of European countries are represented. So it's not really skewed the data of the 259, unique European NICUs 61% had a written protocol for analgesic therapy in neonates, first of all, just as just that sink in, right. So just over half have a protocol for pain management, not a neck, just regular pain management in the NICU in 64%. Of these NICUs. This protocol included clear definitions for starting stopping and adjusting analgesic, only 7% of NICUs with a protocol for analgesic therapy, had a specific neck pain management protocol. So even out of these quote unquote, good students, if you want to call them Where did you have the protocol, they didn't really have a specific approach to neck. The level of adherence to the protocol as rated by the respondent was high in 25% of the NICUs. I'm sorry, it was very high and 25%, high and 43%, intermediate and 27% and low in 5% of NICUs. In terms of pain assessment, there's a variety of pain assessment tools that have been reported to be used. They mentioned the comfort new score the issue of doula, doula and confer the new Vinay in French, the neonatal infant pain scale, the neonatal pain, agitation and sedation scale, the impasse and the premature infant profile. The pain assessors, I thought that was always interesting, included nurses in 96%, physicians in 31%, and parents in 5.3%. I think this is such a critical overview of the importance of the entirety of the staff in in following these babies, right. The number of pain assessments per day was one to two in 7% of NICU three to four and 42%, five to six and 22% and more than six in 25% of NICUs. In terms of pain management practices, non pharmacological intervention, sucrose IV analgesic and epidural analgesic were used in 58%. So non pharmacological 15% of the time, sucrose 39% of the time, IV analgesic 92% of the time, and epidural analgesic and 2% of the time, I've never seen that done as pain management for any see. But yeah, in terms of pharmacological treatment out of the 225 NICUs, using IV analgesic for patients with neck 53 NICUs initiated analgesic therapy preemptively. So so as soon as the diagnosis was made, and then 44% of NICUs, the therapy was different, whether you were ventilated or not. And I think that's something that really highlights how there's a need for some protocols, because obviously, many people are saying, well, if the baby is not on the ventilator, they're less comfortable with some of these other analgesic like fentanyl and so on and they're very afraid of depressing the respiratory drive. The most commonly used and Joe sedative for initial analgesic therapy were acetaminophen 70% of NICUs using IV acetaminophen which by the way is very interesting because I don't know how it is for our audience members it is a pain in the ass to get IV acetaminophen in the US every time you order it so you can I used to have this this game with my co fellows where we would put in the order start the timer until pharmacy called you you know, and it would be like yeah, let's see how quick they call
and and I mean that is just a nod to the our healthcare system like opiates, no problem. Send them right up. But acetaminophen, which costs more IV acetaminophen, very expensive.
What are you using for
what do you reduce the amount of opiate needed significantly? That's a great, it's wild.
It's wild, right? And then and then I'm just gonna go on my soapbox here. And you've all experienced this where they're like, well, I'll approve it for like 24 hours and it's like, no, like, this kid. This kid may need more than 24 hours. Have a via cinnamon oven. Anyway, so that was very interesting. Fentanyl was next 56% Morphine 49% midazolam, 25% sufentanil 11% and ketamine 6.7%. I've never used ketamine. I've never used the fentanyl either, but I've used fentanyl obviously. Acetaminophen, fentanyl and or morphine were often used in combination of two or three of these analgesic. Acetaminophen is always used intermittently, fentanyl and morphine were mainly administered continuously and intermittently and midazolam and sufentanil. were administered continuously. A few more notes that I have on this paper in case of pain despite initially started analgesic therapy 92% of the NICUs intensified analgesic therapy by increasing the dose, and then 53% by adding another medication, and 23% by just switching to just going to another medication. The last thing I wanted to mention was the opinions of the different respondents to the pain management in their NICU 39% identified pain assessment as a target to improve pain management, with 40 of them mentioning that better tools for pain assessments are needed. I think that's a very astute point, obviously, it's it will become much easier to manage and address pain if we can assess it better. In the future, incorporating physiological parameters was something that was mentioned as well. And 12 mentioning that pain should be assessed more frequently. I mean, obviously, their response does show that in terms of pain protocols, 31% of respondents expressed a need for more standardization in pain management for patients with neck by establishing protocols slash guidelines, a good lead point, I think, for them to continue this work. 11 of them remarked that these protocols should be specific for neck and for people remark that they should be evidence based. Thank you. And object therapy, according to 43 NICU, Representative 27% of the respondents better analgesic therapy was needed to improve in pain management for patients with neck this most commonly until using another analgesic administering preemptively analgesic therapy, or more aggressive analgesic therapy and five respondents. So the conclusion is that there's large variability in the use of pain protocol, pain scales and allergies, therapy for preterm infants with neck across European NICUs. And that data from the current study may provide a basis for development of a consensus guideline, I will post the picture of I'm going to show this to you right now. Definitely, this is actually quite cool of the European of the European map with basically all the different countries and which medication is most used. And it's quite just cool to see where more things it's very interesting. Anyway, but yeah, very interesting paper.
Yeah, I mean, I love I love papers like this just because it highlights I mean, like so many things in neonatology. You really have a wide variation in practice. But it's important just to be talking about, you know, pain management. Did you want to do your second neck paper do you want me to go?
I can do the second neck paper. It's a very quick paper that I saw. I signed the archives of these in childhood, and it's called mucus fistula. refeeding in neonates, a systematic review and meta analysis. Ideally, we'd like it, the first author is Gonzalo Solis, Garcia, and it's coming out of Canada. I mean, the the first part of the introduction reiterates the fact that NEC is not good. And they're saying how the majority of neonates undergoing bowel resection and ostomy will have fragile physiological status with risk of fluid and electrolyte imbalance feeding intolerance, suboptimal growth requiring long term TPN that may be associated with sepsis, colas, stasis and other complications, leading to increased length of hospital stay and cost. Over the last few decades, there's been an increasing number of surgical centers that have initiated the use of mucus fistula refeeding in neonates with the intention to maximize bowel function when the ostomy is active. This is a technique that I didn't know was introduced in the 1980s and involves basically introducing proximal ostomy effluent into the distal mucous fistula to maintain the physiologic route of intestinal content if you've never done so sorry, if you've never done this before, like basically you have ostomy output and whatever comes out of the ostomy. You push it into the fistula and you're trying to keep the distal gut active. We've done this many times ourselves, the surgical groups that we've worked with, recommend that very frequently, especially
Well, it's interesting. We even in the same surgical group, they're not all on the same page.
I found that this is something that is often more consistently recommended. For these high ostomies, where you do have a significant distal bowel that's there, but, and it's always made technical sense to me, right? It's like, sure, like, yeah, that's where the poop would have gone if you had the ostomy and the fistula connected, so why not? And so what they're saying is that although the technique has been known for more than four decades, there's no published RCTs in neonates and to evaluate the impact on cholestasis duration of TPN feeding tolerance. And most of the evidence comes from case reports and case series. And so what they're trying to do is saying maybe we should do a systematic review and meta analysis. Just study the effectiveness and complications of mucus fistula. refeeding in neonates after abdominal surgery, so they included studies that had infants receiving surgery at less than 28 days after birth, or less than 42 weeks corrected, and that involved mucus fistula refeeding they only included human studies and mucous fistula. refeeding was defined as the delivery of proximal ostomy output into the distal mucous fistula. Other non traditional refeeding techniques such as triple catheter or rectal refeeding, were excluded. I don't know what triple catheter was to be honest with you. But anyway, those were excluded. If you're familiar with triple catheter that was excluded. The primary outcome was the duration of TPN duration of parenteral. Nutrition in days, when secondary outcome were time to enter or feed both from the stomach creation and from the RE anastomosis rates of cholestasis peak bilirubin levels of rates of sepsis, time to reassess the Moses and length of hospital stay. So I'll go quickly through the results. It's a short paper, the literature Retrieved 411 potential article, the screen 410 There's no RCTs in any of them, they were able to include 16 observational studies, including 623 infants, out of which 10 had a comparison group. And so these were the ones that were included in the meta analysis and most of the studies were retrospective cohort studies. So the most common indication for abdominal surgery preceding ostomy and mucus visual refeeding where intestinal atresia neck and meconium alias they used there's a variety of different catheters that were used, whether it follies or others, and most of the studies used intermittent mucus Fischler refeeding technique, refilling it, with the assistance of pump between three and eight times a day, right? Meaning it's not a continuous, you don't have it on a continuous loop, which I'm not exactly sure how you would do that. But basically, the nurse like empties the bag a couple of times a day. In terms of the primary outcome, pulled analysis from five observational studies, including 244 neonates show that infants with ostomy, who underwent mucus fistula refeeding had reduced duration of parenteral nutrition compared with infants with ostomy creation but no refeeding and the difference was of 37 days. So that's, that's pretty significant. The grade of the evidence was low, but nonetheless, quite quite impressive. In terms of the secondary outcomes, pulled analysis showed that the rates of COVID stasis time to reach for feeds after stomach creation, duration from RE anastomosis to full feeds and the duration of hospitals, they were lower in the mucus fishery feeding group compared with the comparator group. In those studies, no differences were found between the mucous fistula, refeeding group versus comparator group with regard to the peak belly level time from laparotomy to re anastomosis and rates of sepsis. And I think the peak bilirubin level are quite slow to to to rise, and so on and so forth. And I think our surgeons usually are pretty quick, pretty quick to go to re anastomosis. And they just have usually a few weeks of they'd like to baby to not go through back to back procedures too quickly. So I think maybe that that played a role. In terms of feasibility. They mentioned how some studies have reported complications such as stricture, local infection, but it's basically summarizing that it's feasible and safe, considered safe by all the studies that they looked at. And so the conclusion was that this systematic review and meta analysis of these observational studies found low quality data that showed that mucus visual refeeding may be safe and feasible, could improve nutritional and gastrointestinal outcomes in neonates undergoing laparotomy with ostomy and mucus fistula and that results of ongoing RCTs will help corroborate whether it is safe or not so interesting to see how something that we do very frequently he has not much basis in evidence a
lot of hand waving Okay, well good to know. Good to know because it's a it's a lot of work right to do
for our nurses Yeah. burners. Yes,
we are right for me it's not that much work for the system. I'm just another that just another line I have to put for output and for it Oh, Hey, well, thank you. I have my last article for the day is entitled neonatal mortality and disparities within the Military Health System. This is brought our attention brought to this article by Dr. Matthew Harrell, who, as you say, is a friend of the podcast. And so I'm always giving us great suggestions. So thank you. Thank you. Thank you. And the lead author Rasheeda, Vereen, and senior author Caitlin drum, this is in the Journal of Perinatology, we should try to Rashida
who, if you remember, was on the EB Neo campaign episode. So right, so she has been on the podcast before Rashida congratulations and hello,
hello. And so this the quote unquote location so the authors are joining us from Fort Hood, Texas, and Walter Reed in Bethesda. But it's a use of the Military Health System Data Repository. And just a little background, if you're not familiar with the military health care system, which I was not. The reason they wrote this paper is that socioeconomic status and access to care is often kind of been an excuse for racial disparities in health outcomes. And this article is using data from the Military Health System Data Repository, which collects data from 260 military health care facilities that end and in addition, civilian facilities that reimbursed the TRICARE program. But in general, it's felt to be as close to universal health care coverage as you can get in the states and demonstrates overall excellent access to care, and includes 9.6 million beneficiaries, including active military personnel, retirees and their dependents. And in general, they have over 100,000 live births per year. So totally a reasonable place to study this. So it was an observational query of the MHS MHS data from all LIBOR neonates between 2013 and 2015 200,000. Uh huh. That's a lot. That's a lot. That's good for that. And so a little bit about the terminology, because sometimes I'm not familiar with the terminology. So they do use sponsor rank as a sponsor is, I think, whoever the healthcare falls under the military personnel, and then rank as a surrogate for socioeconomic status. So they use the quote unquote, junior enlisted rank as a surrogate for low lower SES. And that has been done in other military studies. neonatal mortality is death within the first really 28 days day of life zero through 27. And of note in terms of the race and ethnicity data, this was self reported. So the baseline characteristics, so during the time period, they had 320,283 live births, they had 588 neonatal deaths within the first 27 days of life. So this should be noted that this report represents a neonatal death rate of 1.84 out of 1000 live births, which is less than half the US death rate 4.04 out of 1000 live births from 2013. And I think that's an interesting point to make that potentially, potentially could our overall nation national birth rate be different if we had universal health care and better access to care, the branch of service, there was no relationship with mortality. And then when they looked at the officer versus the enlisted rank, so again, a surrogate for socioeconomic status, there was actually no difference in neonatal mortality. When analyzed by rank and race, there was a higher rank conferred no decreased risk of neonatal mortality. The preterm rate overall, for all births was 7.2%, which again, is less than the US overall rate. However, black non Hispanics sponsors had an increased rate of prematurity of 9% compared to the overall rate of 7.2%. The lowest rates were actually an American Indian Alaskan infants of 6.6%. This is also another interesting point, because we know there's a huge disparities in American Indian and Alaskan neonates, but again, is potentially very much related to access to care. Extremely preterm neonates not surprisingly accounted for 59.9% of deaths overall, except there was a much there was a higher percentage of black non Hispanic neonates who are delivering prematurity, the rate was 210 per 1000 compared to extremely preterm white, non Hispanic neonate A 204 per 1000 sponsor race and ethnicity and neonate. Preterm status, like I said were significantly associated with neonatal mortality. The highest mortality rate was for black non Hispanic sponsors 3.41 out of 1000. compared to white, non Hispanic neonates, the black man has been in neonate had a two fold increased risk of death. And this was significant. when adjusted for preterm status, it was no longer significant, but again, the black non Hispanic group had much higher rates of premature delivery. Interestingly, American Indian or Alaskan Native group had the lowest mortality rate 1.11 of 1000. And for all races and ethnicities, the MHA s rate was mortality rate was lower, and the prematurity rate was lower than the corresponding us right. So the study takeaways, I'll read this just line for line from the study. The results indicate persistent racial disparity and worse outcomes for black infants. Despite universal coverage, access to care and stable employment. These results further support the need for anti racist research resources and policies to eliminate disparities. So, I mean, overall, the data shows that pregnant people in the military have improved preterm labor rates compared to civilians, they have improved neonatal mortality rates compared to civilians. However, black pregnancies in the military are still more likely to end in preterm labor, even after controlling for socio economic variables. I thought it was a really interesting study, and an interesting way to parse out some of those confounding variables.
Agreed. Hold on the light fixture in the studios are falling,
like getting in a fight with sorry,
but no, I think I think it's a very interesting conclusion. Because it's a good it's a good reminder of a complex problem. Because sometimes you may be tempted to think, Oh, if we had universal health care, then all our problems would be solved. And it's not true. Like it would solve a significant ones. Yeah, it would solve but it would not solve everything. And I think it's it there's still room for work to be done in many other areas. And it's the statistical concept of overfitting. We cannot say, oh, that solution would fix all our problems. No, there's there's more system, systematic systemic work that needs to be done to sort of, and I think both universal health care and our relationship with work in the US is something we could talk about. Because people, yeah, so anyway, interesting. Very interesting. Very interesting. Yeah. And also, it's nice that the military exists so that it can actually provide this outlook of saying, well, actually, here's here's a case set.
We do have a system. Exactly, exactly. Yeah. All right.
Well, we go over that bad today. This was not better than usual, other than usual, and we've covered a lot of good papers. So this is fun. Daphna, thank you for making the time today. Thank you for everybody who is contributing to this great literature and,
and telling us about papers that interest you.
100% 100% Alright, guys, I'll see you. I'll see you for review very soon. Okay, bye. 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 podcast, 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 email@example.com. You can also message the show on Instagram or Twitter, at NICU podcast or through our website at WWW dot d 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
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