Hello Friends 👋
We have a new episode of Journal Club this week. Lots of papers to review, many with serious clinical applications. A newly published NEJM study evaluates the effectiveness of antibiotics prophylaxis for babies with VUR in preventing UTI and kidney damage. New guidelines were released by ASPEN on the use on TPN in the NICU. We reveing an impressive meta analysis looking at perinatal risk factors for early onset sepsis and you might be surprised by how these risk factors rank against one another. We also look at the recently published NICHD paper in JAMA NET OPEN looking at NIRS and transfusion thresholds in patients enrolled in the TOP trial - fascinating stuff. There is a lot more - We hope you enjoy this episode.
The articles covered on today’s episode of the podcast can be found here 👇
Morello W, Baskin E, Jankauskiene A, Yalcinkaya F, Zurowska A, Puccio G, Serafinelli J, La Manna A, Krzemień G, Pennesi M, La Scola C, Becherucci F, Brugnara M, Yuksel S, Mekahli D, Chimenz R, De Palma D, Zucchetta P, Vajauskas D, Drozdz D, Szczepanska M, Caliskan S, Lombet J, Minoli DG, Guarino S, Gulleroglu K, Ruzgiene D, Szmigielska A, Barbi E, Ozcakar ZB, Kranz A, Pasini A, Materassi M, De Rechter S, Ariceta G, Weber LT, Marzuillo P, Alberici I, Taranta-Janusz K, Caldas Afonso A, Tkaczyk M, Català M, Cabrera Sevilla JE, Mehls O, Schaefer F, Montini G; PREDICT Study Group.N Engl J Med. 2023 Sep 14;389(11):987-997. doi: 10.1056/NEJMoa2300161. Epub 2023 Sep 12.PMID: 37702442 Clinical Trial.
Guo L, Han W, Su Y, Wang N, Chen X, Ma J, Liang J, Hao L, Ren C.J Matern Fetal Neonatal Med. 2023 Dec;36(2):2259049. doi: 10.1080/14767058.2023.2259049. Epub 2023 Sep 24.PMID: 37743349 Free article.
Robinson DT, Calkins KL, Chen Y, Cober MP, Falciglia GH, Church DD, Mey J, McKeever L, Sentongo T.JPEN J Parenter Enteral Nutr. 2023 Sep;47(7):830-858. doi: 10.1002/jpen.2550. Epub 2023 Aug 23.PMID: 37610837
Immeli L, Mäkelä PM, Leskinen M, Sund R, Andersson S, Luukkainen P.Acta Paediatr. 2023 Oct;112(10):2084-2092. doi: 10.1111/apa.16885. Epub 2023 Jun 28.PMID: 37341644
Lowe J, Bann CM, Dempsey AG, Fuller J, Taylor HG, Gustafson KE, Watson VE, Vohr BR, Das A, Shankaran S, Yolton K, Ball MB, Hintz SR; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.J Pediatr. 2023 Aug 26:113700. doi: 10.1016/j.jpeds.2023.113700. Online ahead of print.PMID: 37640232
Chock VY, Kirpalani H, Bell EF, Tan S, Hintz SR, Ball MB, Smith E, Das A, Loggins YC, Sood BG, Chalak LF, Wyckoff MH, Kicklighter SD, Kennedy KA, Patel RM, Carlo WA, Johnson KJ, Watterberg KL, Sánchez PJ, Laptook AR, Seabrook RB, Cotten CM, Mancini T, Sokol GM, Ohls RK, Hibbs AM, Poindexter BB, Reynolds AM, DeMauro SB, Chawla S, Baserga M, Walsh MC, Higgins RD, Van Meurs KP; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.JAMA Netw Open. 2023 Sep 5;6(9):e2334889. doi: 10.1001/jamanetworkopen.2023.34889.PMID: 37733345 Free PMC article. Clinical Trial.
de Boer A, De Proost L, de Vries M, Hogeveen M, Verweij EJTJ, Geurtzen R.Arch Dis Child Fetal Neonatal Ed. 2023 Sep 19:fetalneonatal-2023-325997. doi: 10.1136/archdischild-2023-325997. Online ahead of print.PMID: 37726159
Faison G, Chou FS, Feudtner C, Janvier A.Pediatrics. 2023 Sep 14:e2023061193. doi: 10.1542/peds.2023-061193. Online ahead of print.PMID: 37706240
Taylor GL, Joseph RM, Kuban KCK, Douglass LM, Laux J, Andrews B, Fry RC, Price WA, O'Shea TM.Pediatrics. 2021 May;147(5):e2020001040. doi: 10.1542/peds.2020-001040. Epub 2021 Apr 6.PMID: 33824183 Free PMC article.
Kuroda J, Okazaki K.J Perinatol. 2023 Sep;43(9):1179-1180. doi: 10.1038/s41372-023-01668-7. Epub 2023 Apr 5.PMID: 37019988 Free PMC article. No abstract available.
You can find Ben's notes below:
The transcript of today's episode can be found below 👇
Ben Courchia MD (00:00.558)
Hello everybody, welcome back to the Incubator. It is Sunday, it is Journal Club week. Daphna how it's going.
Daphna Yasova Barbeau, MD (she/her) (00:07.39)
I'm doing great. It took me, I was just thinking about this. I had a, not a tough call the other night, but like one of those calls that you're just up all night, you know? And it has taken me a full two days to recover. I'm just glad I'm not on tonight. You're on tonight.
Ben Courchia MD (00:21.914)
I mean, it kind of, I mean, it, I'm on tonight. But yeah, that was, I mean, I don't know if you're gonna share that story, but that was, that's, in the stories of Insane Calls, it is, it's up there. It's up there.
Daphna Yasova Barbeau, MD (she/her) (00:36.574)
Yeah, the story is, I mean, the call was busy, but in addition to the busy call, family members in the ER, everybody's fine.
Ben Courchia MD (00:44.13)
Now, because when you talk...
Ben Courchia MD (00:49.378)
Yeah, but I mean, yeah. So yeah, it involves a raccoon, it's nuts. So.
Daphna Yasova Barbeau, MD (she/her) (00:54.61)
It involves a raccoon. Well, okay. So dog walking in the middle of the night and the family member got attacked by a raccoon. I don't know. We live in a, we live in a highly populated South Florida suburb. So a raccoon was completely unexpected. And my lovely cute dog is apparently no hunter. So it's fine. But the dog is unscathed. Thanks to my.
Ben Courchia MD (01:13.454)
Ben Courchia MD (01:19.038)
Ben Courchia MD (01:23.035)
Daphna Yasova Barbeau, MD (she/her) (01:24.334)
quick thinking mother-in-law who got attacked by a raccoon while I was on call the other night. But you know you forget sometimes that like you're on call and stuff's going on at home, right? You just have to balance the two.
Ben Courchia MD (01:30.181)
That is nuts. That is.
Ben Courchia MD (01:37.128)
Daphna Yasova Barbeau, MD (she/her) (01:41.111)
Ben Courchia MD (01:42.124)
I have a bunch of articles too. I mean, this is nuts. That's why, when you said like, oh, I had a bad call, it's like, all right, like we've all had backup, but you sounded like it was worse than usual. I'm like, how could it be like, like we know, but we've all had, I mean, you're.
Daphna Yasova Barbeau, MD (she/her) (01:43.906)
Daphna Yasova Barbeau, MD (she/her) (01:53.004)
And you know I stay up most calls.
Ben Courchia MD (01:56.567)
Yeah, but you're a veteran, so you've had bad calls. It will take a lot to foster you. And then when you told me the story, I was like, yep, that is peculiar.
Daphna Yasova Barbeau, MD (she/her) (02:01.262)
to postpone her, yeah.
Daphna Yasova Barbeau, MD (she/her) (02:05.742)
We had a lot of follow ups with it, but we're all caught up now.
Ben Courchia MD (02:09.162)
Yeah, for sure. For sure. Yeah, there's a lot of articles to go over. I have six papers I want to mention. I'm going to try to do them relatively quickly, but they're all pretty big. Yeah.
Daphna Yasova Barbeau, MD (she/her) (02:19.638)
Six papers. Will I get to present any? Okay.
Ben Courchia MD (02:24.186)
For sure. It's gonna be a long one today.
Ben Courchia MD (02:29.042)
You know, I'm not going to waste too much time. I want to start with this New England Journal paper. So in the New England Journal of Medicine, there was a paper called Antibiotic Prophylaxis in Infants with Grade 3, 4, or 5 Vesico-Uritoral Reflex from the Predict Study Group. It's a European cohort of physicians. And what's interesting is that they're asking a very interesting question that is very pertinent to us in the NICU. They're saying...
does continuous antibiotic prophylaxis would be effective in preventing the occurrence of a first symptomatic UTI, and would avert secondary kidney damage in infants with grade three, four, or five, VUR. VUR is a physical ureteral reflux. I'm not gonna do that every single time, it's painful. And no previous UTIs, right? And so you can read the background, and you can read the discussion. I think I'm gonna go over the methods, and I'll tell you a little bit why they did what they did.
So this is a phase three multi-centered prospective randomized open label trial that was performed in 39 European centers. They included patients who were one to five months of age that had VUR grade three, four, or five assessed by VCUG or voiding ultrasonography. They had to have a gestational age of 35 weeks or more and an estimated GFR or of 15 mL per minute or more per one.
0.73 meter square of body surface area. But the key here is that they never had to have a UTI before. And they were trying to create a cohort that was representative of infants with high-grade VUR, with associated kidney and hypodysplasia, and no previous UTIs. They go over some of the history that's going behind that. A lot of the studies that have looked at antibiotic prophylaxis for VUR and how this was usually done in patients that were
screen and found to have an initial UTI, they said, we want to take the most at-risk population. So it's not like the ones that have a low-grade VUR, we want the highest grade VUR, as people who've never had a UTI, and we're going to see how good this prophylaxis is. And not having had a symptomatic UTI before is quite an interesting added variable there. They excluded infants with previous UTI with posterior rethral valve,
Ben Courchia MD (04:54.786)
So what did they do? The study participants were randomly assigned in a one-to-one fashion to either receive continuous antibiotic, meaning antibiotic every day, or no treatment for two years. And they looked at these infants for two years. The antibiotic choice were selected based on the local E. coli resistance pattern and included nitrofuranthione, moxicillin, clavulanic acid, cefixime, trimethoprim, sulfamethoxazole, Bactrim, and the doses are in the paper. They were not surprising.
The antibiotic is administered in a single daily dose with the option for the patient to change to a different antibiotic if there's like unacceptable side effects, obviously. After a first UTI, if a first UTI were to happen, the prophylaxis could be modified among one of the four possible options based on the sensitivities and really in order to prevent further growth of resistance organisms. They were monitored from baseline and then at 4, 8, 12, 18.
and 24 months. The primary outcome of this study is that the occurrence of a first symptomatic UTI, so will antibiotic prophylaxis prevent a UTI during the 24-month trial? The secondary outcome were how many UTIs you got in the 24-month period, whether they were kidney scarring. That's been a big topic of discussion. Does that prevent kidney injury? Then they looked at estimated GFR at 24 months. They looked at the causative organisms, the diabetic resistance of the UTI isolates and serious adverse events. The big question everybody's gonna have is
What is a symptomatic UTI, Ben? A symptomatic UTI is basically the concomitant presence of acute symptoms. So you have fever, you're not well, loss of appetite, and leukocyte esterates or nitrites on your analysis and a positive urine culture. People are gonna say, what is a positive urine culture, Ben? The positive urine culture is a growth from, so either any growth of anything on a suprapubic aspirate or...
Daphna Yasova Barbeau, MD (she/her) (06:47.394)
but super pubic, Asper. Yeah.
Ben Courchia MD (06:49.122)
Yeah, so they have, depending on how you got the urine, they'll give you different criteria. So if it's super pubic, any growth will be considered positive. If you are getting a catheter sample, then it is the growth of a single organism to at least 10,000 colony forming units per ml. If you are doing a midstream voided sample, then you need 100,000 CFU per millimeter. Bag specimens.
Daphna Yasova Barbeau, MD (she/her) (06:52.246)
Daphna Yasova Barbeau, MD (she/her) (07:14.135)
I love it when you ask yourself a question.
Ben Courchia MD (07:16.578)
Yeah, because I mean, just so you know, I'm making fun here. But these are the questions that, like, as you're reading through the methods.
Daphna Yasova Barbeau, MD (she/her) (07:21.511)
I know how you think, you're like, that would be my question. So.
Ben Courchia MD (07:24.086)
Yeah. As you read it, like they better define a positive. I know this is a bit of a big topic. The bagged specimens were not allowed. So from 2013 to 2020, 867 infants were screened, 292 underwent randomization, about 150 in each group. The...
Daphna Yasova Barbeau, MD (she/her) (07:29.026)
Daphna Yasova Barbeau, MD (she/her) (07:43.247)
Though, um, sorry, the midstream is an interesting collection method.
Ben Courchia MD (07:47.982)
Yeah, but you have to remember, that's true, but you have to remember that there are five months. And so I've seen it done. So like, if you have like, I know, but you know, I've seen like in, I've seen it done in the ER where, especially in boys, it's quite easy. And then you just let a bit of urine come out and then you catch it. You could catch it with a cup midstream if the baby is cooperative enough. So I don't see it as completely, but anyway. Well.
Daphna Yasova Barbeau, MD (she/her) (07:57.966)
Daphna Yasova Barbeau, MD (she/her) (08:11.498)
you know, five months old are known to be cooperative.
Ben Courchia MD (08:14.99)
You never know, if they're sick, it's the sad reality that, yeah, that's the first thing you learn as an intern in pediatrics is that the more cooperative the patient, the more scared you should be. So the infants were at recruitment, the median age was three and a half months. 80.5% of the participant had grade four or five VURs and 48.3% had bilateral VUR. Focal congenital defects were identified in about 28%.
Daphna Yasova Barbeau, MD (she/her) (08:23.851)
Ben Courchia MD (08:42.598)
of the population on baseline DMSA scan. Congenital kidney defects were not associated with the grade of reflux. And before enrollment, 51% had received previous antibiotic prophylaxis. They go over how much received which one. You can look into it. Like I said, we have a lot of papers to go over. In terms of the primary outcome, this is where we get into the interesting things. A first symptomatic UTI occurred in 21.2% of the patients who went.
on the WENDT prophylaxis and 35.6% in the untreated group. That was statistically significant difference. But pay attention as they do in the discussion about not just the difference, but that means that in the prophylaxis group, 80% never got a UTI. And in the control group, about 65 to 70%
never got a UTI. So not just the difference in the babies or children that got a UTI, but in the proportion of infants who really never developed a UTI. And the rule of thumb here is that despite these babies being, to be honest, the primed patients to be at the most risk, most of them never got a UTI in the 24 months after birth. So that's interesting. Urine cultures were collected by midstream in 59% of cases and by catheter in 41% of cases.
Daphna Yasova Barbeau, MD (she/her) (09:59.982)
Yeah, that's great news.
Ben Courchia MD (10:09.442)
UTI-free survival was not influenced by the type of antibiotic used. In terms of more stuff, sex was a strong predictor of the first UTI, with male patients having a hazard ratio of 0.46. And yet, when they controlled for sex, continuous antibiotic prophylaxis was still associated with the primary outcome. The number needed to treat to prevent one UTI within two years was seven. So it's not insignificant, you know.
seven patients have to be treated to prevent one UTI. Now let's look at some of these other outcomes because then this is really where it gets interesting. So the total number of UTIs, there were less UTIs during the 24 month trial in the group that received prophylaxis compared to the untreated group. The difference was 60 versus 79. And interestingly, for participants that had one or two UTIs, it was more common to see that in the untreated group. But when we were looking at the participant that had three or more,
then this was suddenly more prevalent in the group that received antibiotic prophylaxis. So for those kids that were receiving antibiotic prophylaxis, it almost looks like it did not matter because they kept getting those UTI. The one aspect that was interesting also was the new kidney scars. And so data at both baseline and 24 months was available in 84% of the study participants. And at 24 months, new kidney defects
were identified in 21 participants in the prophylaxis group compared to 17 in the untreated group. And that was not statistically significant. Interestingly enough, the number of new lesions was independent of the occurrence of UTIs during the trial period. New defects were seen in about 19% of the patient who had no UTI and 19% of patients who had at least one UTI. So it looks like the prevention of...
Like making sure that you prophylax these kits so that they don't get a UTI will make no difference as to whether they'll have renal scarring. So that's...
Daphna Yasova Barbeau, MD (she/her) (12:08.862)
Daphna Yasova Barbeau, MD (she/her) (12:14.058)
Yeah, and I didn't like that information. Even if they're prophylax, they get renal scarring. And how many, 20%, that's a lot.
Ben Courchia MD (12:23.882)
Yeah, I'm going to, well, 20% of the ones who had no UTI and 19% of the ones who had at least one. So yeah, very similar. I'm just going to finish quickly because I'm almost done. The estimated GFR, the data was available in 94% of 24 months and this was similar between the two groups. The antibiotic resistance, there was an interesting differences that were noted between the prophylaxis and the untreated group in the organisms that grew from the urine.
Daphna Yasova Barbeau, MD (she/her) (12:30.28)
Ben Courchia MD (12:49.354)
E. coli klebsiella species and proteus species were more commonly found in the ones that were untreated, but Pseudomonas infection. And an increase in non-E. coli isolates were observed in the patients who received prophylaxis. So definitely impacted your flora there. Resistance to at least two first-line antibiotics was present in 52% of the...
children who were received prophylaxis compared to only 17% in the untreated group. No serious adverse events really reported, no difference in the serious adverse event reported between the two groups. The conclusion is, are that they found a small but significant benefits of primary continuous antibiotic prophylaxis in preventing a first UTI in infants with VUR and without preceding UTIs. And the big question is, is it worth two years of antibiotic exposure to prevent
20% of a very high-risk population. So think about this, right? The kid who had mild reflux, so don't have too much, are you gonna prophylact them for the first two years considering the degree of antibiotic resistance? That is a fascinating question, and I'm curious to see how guidelines are gonna change with respect to that.
Daphna Yasova Barbeau, MD (she/her) (14:03.618)
Well, I didn't pull up the guidelines, but I think they already have changed.
Ben Courchia MD (14:07.662)
There's like so many, there's the pre, the pediatricians have their guidelines. The, the nephrologist have their guidelines. And everybody is bickering about this because well, the pediatricians don't care about renal scarring. The nephrologists care about renal scarring. And it's like, that's why I'm, I'm curious to see.
Daphna Yasova Barbeau, MD (she/her) (14:11.586)
That's true. There's not a lot of consensus, yeah, about...
Daphna Yasova Barbeau, MD (she/her) (14:22.303)
Yeah. And you know, we have this habit, and it happens in the ICU, right? That you're like, uh, antibiotics, no antibiotics, I'd rather prevent infection. But we're not thinking about, we do in the NICU, I think do a pretty balanced job of thinking about the long-term effects. But I'm finding in the community that is becoming less and less common, you know?
Ben Courchia MD (14:46.234)
I mean, when you think about not prophylaxis for patients who have grade three, four, or five reflux, and you're telling me that 70-something percent are never gonna have a UTI in the first two years, I would have not suspected that. I would have suspected the number to be much higher, and then it makes you wonder, do we even need to do this on a system-wide basis? Like, oh, you gotta grade four, we gotta give you prophylaxis for two years. I don't know. Does that change after two years? To be honest, I'm an urologist, that's not my problem.
Daphna Yasova Barbeau, MD (she/her) (14:57.31)
Daphna Yasova Barbeau, MD (she/her) (15:04.482)
Daphna Yasova Barbeau, MD (she/her) (15:12.246)
Hmm. That's somebody else's problem.
Ben Courchia MD (15:16.846)
There's like some, some adult doctors are going to work on that when they turn three years old.
Daphna Yasova Barbeau, MD (she/her) (15:21.45)
Yeah. And, you know, we say, oh, it's just low dose, but the, the sensitivities there, that was interesting, you know, about the resistance and then, you know, the, the things that we are really starting to talk about, like how does your microbiome shape the rest, the health for the rest of your life? And, you know, we haven't looked at the long-term effects of these children. We haven't looked at the long-term effects of getting your child to take it every day.
Ben Courchia MD (15:27.619)
Ben Courchia MD (15:44.482)
of very much. That's absolutely right.
Daphna Yasova Barbeau, MD (she/her) (15:49.106)
Very interesting. Thank you. I was very glad to see that you were going to share that paper. Okay. I have a paper. This was entitled Perinatal Risk Factors for Neonatal Early Onset Sepsis, a Meta Analysis of Observational Studies. The lead author, Lee Ann... Hello? From the Journal of Maternal, Fetal, and Neonatal Medicine. We always like to throw in papers from...
Ben Courchia MD (15:54.945)
Ben Courchia MD (16:10.726)
Daphna Yasova Barbeau, MD (she/her) (16:18.75)
more esoteric journals that we should be looking at. This is actually coming out of China. So what was their question? They were really looking for what are the perinatal risk factors for early onset neonatal sepsis? And you studied for the boards and you're like, we already know this. But can it change with our practice habits and societal habits? Are they changing? So I really like papers like this. It is a meta-analysis. They included case control and cohort studies on perinatal risk.
factors. They excluded animal studies, case reports, guidelines, reviews, repeat publications, articles without a control group, or the ratio number of samples in control group to case group greater than 10. So in their preliminary screening, they had 559 studies, but they actually only ended up using 17 studies, nine Chinese studies and eight English studies.
And I think what's interesting is it was 15 case controls and two cohorts, 1,987 cases in the case group and 4,814 cases in the control group. But the study area from where the papers hailed covered seven countries, China, the United States, the Netherlands, India, Bangladesh, Greece and Tanzania. So I thought that was interesting.
So risk factors were included if they were evaluated in greater than or equal to three articles and then, you know, selected for the meta-analysis. These included perinatal asphyxia or intrauterine distress, meconium contamination of amniotic fluid, GBS colonization in pregnant women, coriomyelitis, premature rupture of membranes, lower gestational age, maternal, urinary, or reproductive tract infection, perinatal fever,
very low birth weight and vaginal examination greater than or equal to three times, which actually I don't think we do a very good job of documenting, but. Interestingly, the results of heterogeneity tests showed that there was no heterogeneity in the four risk factors of perinatal asphyxia, intrauterine distress, maternal urinary or reproductive tract infection, perinatal fever, and this vaginal exam greater than or equal to three times.
Daphna Yasova Barbeau, MD (she/her) (18:42.21)
The remaining six risk factors had some heterogeneity. So the random effect model was selected to combine the effect size. And overall, the meta-analysis results showed that perinatal asphyxia or intrauterine distress had an odds ratio of three, meconium contamination, omniotic fluid, an odds ratio of 3.61, GBS colonization in pregnant women, an odds ratio of 3.45.
and odds ratio of 4.58. Premature rupture of membranes and odds ratio of 3.25. Lower gestational age and odds ratio of 1.55. Maternal urinary tract or reproductive tract infection and odds ratio of 3.61. Perinatal fever, which actually we've had in the last few months a number of cases. Odds ratio of 3.59.
very low birth weight and odds ratio of 3.79. And this vaginal examination greater than or equal to three times odds ratio of 7.95. All as perinatal risk factors for early onset neonatal sepsis. There was, as I said, significant heterogeneity in many variables. So they performed a sensitivity analysis to reduce this heterogeneity by kind of selective exclusion of studies. And this meta-analysis showed the final results.
Pretty similar. Perinatal asphyxia and tritium distress, odds ratio of 3. Amniotic fluid, meconium contamination and odds ratio increased to 4.51. GBS colonization and odds ratio of 2. Corio and odds ratio of 4.5. Premature rupture of men's brains, odds ratio of 2.6. Lower gestational age, odds ratio of 1.3. Maternal urinary or reproductive tract infection, odds ratio of 3.61. Perinatal fever, 3.59. Very low birth weight, 3.79.
Vaginal examination greater than or equal to three times odds ratio of 7.95.
Ben Courchia MD (20:43.467)
And what that means is that the OBs or the LND staff is just examining the mother more, like if there's multiple exams basically, right? Okay, okay.
Daphna Yasova Barbeau, MD (she/her) (20:46.274)
Daphna Yasova Barbeau, MD (she/her) (20:50.958)
Correct. Yeah. Which for, you know, maybe a prolonged labor is not uncommon, right? So yeah, three doesn't seem like that much. Yeah.
Ben Courchia MD (20:57.25)
I mean, we see that, like, oh, this patient's still closed. Still closed, right? When they tell you still closed, I mean, that's an exam.
Daphna Yasova Barbeau, MD (she/her) (21:05.322)
So I really thought this was interesting, right? Because there are obviously risk factors that we have historically worried about. Choreoamnionitis, the premature baby, why did you deliver prematurely? Was it infection or was it some anatomical problem? But I thought these were pretty high numbers. One for the vaginal exam, which obviously they try to reduce vaginal exams, but I didn't think three was that many.
And I think seeing this data about, you know, the entry in distress and meconium contamination, I thought was interesting. You know, you had that discussion all the time. You've got a kid, you're working them up for HIE, are you working up for them, working them up for infection simultaneously. So I thought that was interesting.
Ben Courchia MD (21:53.142)
Yeah, I think to me it really gave me pause because we, I remember the days where we thought, no, amniotic fluid is not a big deal because it's sterile, right? So, but you see that the OR that you mentioned is 4.5, probably one of the highest in this group, which I was, yeah, for meconium, absolutely. Then you look at GBS and it was lower. I think Choreo is very,
Daphna Yasova Barbeau, MD (she/her) (22:03.159)
Daphna Yasova Barbeau, MD (she/her) (22:07.358)
Yeah. For meconium contamination. Yeah, yeah.
Daphna Yasova Barbeau, MD (she/her) (22:15.422)
It was lower. You know, they didn't say, right, were they treated for GBS or untreated, so that may, but still.
Ben Courchia MD (22:22.466)
Right. But also, when you look at that, and you compare the fact that meconium and Corio are much higher than just premature rupture of membrane, technically. I mean, that's very, very interesting. And the UTI as well. I remember that we used to not pay too much attention to maternal UTI, but 3.6 still. So yeah, a very interesting paper. And you should definitely look at it. And all these ORs, by the way, are in the abstract, the second ones that you gave us after they did the correction and stuff.
Daphna Yasova Barbeau, MD (she/her) (22:36.054)
Ben Courchia MD (22:52.206)
You won't have to dig too much through the paper to see them. Yeah, agreed. OK. All right, so I'm going to go next to two different papers that I wanted to review. One of them is a short one, but it's someone is one that I've really, really liked. It's published in Acta Pediatrica. It's from Finland. And it's called Very Low Birth Weight Infants Receive Less Enteral Feeding Than What Is Prescribed. First author is Lotha Imeli. You're going to like this one.
Daphna Yasova Barbeau, MD (she/her) (22:52.426)
Yeah, too far.
Daphna Yasova Barbeau, MD (she/her) (23:19.029)
That feels like it checks out.
Ben Courchia MD (23:22.962)
Yeah. So the question is, how does a prescribed advanced of enteral feeding, is that how is it implemented during the first four weeks of life in VLBW infants and to what are the factors associated with the slow progression of enteral feeding? So they did a retrospective cohort study. They included all the VLBWs with a gestational age of 32 weeks or less who stayed in the NICU of the Helsinki University Children's Hospital for at least two weeks between
January 2005 and 2013. Now, the daily prescribed and administered nutrition for each infant in the first 14 to 20 days of life was retrieved from the EMR and depending on the total length of stay at the NICU. Now in the study, they focused on enteral nutrition, which means mothers on milk, donor milk or formulas. They had a feeding protocol that followed published guidelines and it was not really earth shadowing, pretty much what we all do.
protocol starts with immediate TPN. You stop the TPN when inter-roll feeds reach about 120 ml per kilo per day. Trophic feeds are started on day one, which is not the first day after birth, but the day, like 24 hours after birth. They advance their feeds by 10 to 20 ml per kilo per day, and they start fortifying at 100. So I know people have thoughts and opinions about that. But I mean, it's not controversial what they're doing. They defined, they viewed.
the admission in three phases. They said, let's look at trophic, which is phase one. Let's look at the transition when we're advancing the enteral feeds. And then, but you're still on TPN and let's look at the full enteral feeds where you're off TPN and you're just on milk. They had no guidelines on when to aspirate for residuals. They didn't want to do it, but they said it was often measured. So again, that checks out. They excluded babies that were outborn or weak, general anomalies.
They had 516 infants that were presented about 12,734 nutrition days. The infants were divided into three groups. They had 23 to 26-weekers. That was about 240 infants. They had the 27 to 29-weeker, 240 infants, and then the 30 to 31-weekers, 37 infants. The median time to reach full enteral feeds was 14 days. So they were a good unit. You know what I'm saying? They're not like...
Ben Courchia MD (25:38.646)
I mean, they match up with a lot of what the great centers in the US are doing. They're nothing too shy about from that standpoint. 43 infants did not reach full feed in the first month. And this was highest in the 30 to 31 group compared to the 23 to 26 and 27 to 29 group. Now, you may say like...
Daphna Yasova Barbeau, MD (she/her) (25:43.424)
Ben Courchia MD (26:03.494)
how that happened, the 30 to 31 week group had the highest prevalence of maternal preeclampsia and SGA, and we know how difficult it is to feed babies that are growth restricted. In the first two weeks of life, milk volume increased mainly slower than 10 ml per kilo per day, and the daily volume increase was slowest for the 23 to 26 week group. They have a great... I'm going to share my screen for you right now, but I'm going to post this on Twitter this week.
And you'll see how they have this great graph where they basically show you how the curve should be going up if you went up 20 ml per kilo per day. And actually it sort of felt more like 10 ml per kilo per day.
Daphna Yasova Barbeau, MD (she/her) (26:40.29)
Mm-hmm. It looks like a looks like the Billy Reuben curve really
Ben Courchia MD (26:46.606)
Almost. Yeah. Now, during the enteral nutrition phase, enteral nutrition was mainly implemented as prescribed, meaning once they were on full feeds of TPN, things went okay. 98% was of the prescribed nutrition was administered. During the early trophic feeding in the end in the parenteral nutrition phase, there was a discrepancy that was observed between the prescribed and administer nutrition. 71% of the prescribed feeds were administered and
The discrepancy was the largest for the 23 to 26 week group. When you look at that graph, you can see that the percentage of prescribed versus administer in the parenteral nutrition phase is very different for the smallest babies compared to the 27 weekers and onward. The full prescribed amount was less likely administered if a higher volume of gastric residual was aspirated or if the infant did not pass stool during the same day.
One last point, some of the factors that they found to be associated with this slow feeding advancement included the slower passage of the first meconium, the use of opioids. So definitely something that swayed the, that created that difference. The presence of a PDA and RDS associated with, and RDS were associated with the slower progression of enteral feeds. All these are basically factors that are affecting the GI function and motility of the immature gastrointestinal system.
So the conclusion of that, they found that the progression of enteral feeding in their population of VLBW infants was clearly slower than the recommended 10 to 20 ml per kilo per day. And that the implementation of enteral feeding differed from the planned feeding, especially during the parenteral nutrition phase. So in the very beginning, in the tiniest VLBW infants, this together with the cautious prescriptions made by the clinicians possibly plays a significant role in the slow progression of enteral feeding.
planning and evaluating enteral nutrition should be based on administered instead of prescribed amount. Further, besides having a feeding protocol and educating clinicians, education of the nursing personnel is also essential. Yeah, love that paper. Very, very nicely presenting something that we're all, I think, experiencing and showing that feeding protocols and nutrition does not stop at the EMR and that this is a joint effort with the whole team. So...
Daphna Yasova Barbeau, MD (she/her) (29:10.593)
Ben Courchia MD (29:12.55)
And nurses sometimes are very sharp in their assessment of the baby. And so maybe we are wishing an advancement and the nurses detect something. So I think that last point about making sure that everybody is involved in the education is paramount.
Daphna Yasova Barbeau, MD (she/her) (29:27.614)
Yeah, you know, I think it's an important point. And I think this is where, what's the word? Mistakes happen without people knowing it, right? Like you didn't, you thought the baby was getting one thing. That's not what the baby was getting. You made an advance. Nobody else knew that they thought, you know, and so the baby got more of an advance than you anticipated. So, you know, it's an important factor and feature.
Ben Courchia MD (29:38.211)
Ben Courchia MD (29:48.59)
Daphna Yasova Barbeau, MD (she/her) (29:54.71)
You know, I think it begs the question about would we be more successful with a nursing-driven feeding guidelines.
Ben Courchia MD (30:01.154)
Absolutely. So on that note, I just want to bring people's attention to another paper that was published this time in the Journal of Parentural Nutrition. And it's basically the guidelines for parental nutrition in preterm infants, the American Society for Parental and Enteral Nutrition. First author, Daniel Robinson, and this is from Aspen, from the, yeah, the American Association for American Society for Parental and Enteral Nutrition. So it's a big paper. And...
Daphna Yasova Barbeau, MD (she/her) (30:04.054)
Daphna Yasova Barbeau, MD (she/her) (30:09.671)
Ben Courchia MD (30:29.262)
Basically, what they tried to do is that they basically created a task force composed of interdisciplinary experts at of the Aspen group, and it included a neurologist, gastroenterologist, dieticians, pharmacist, and they had the methodologist and epidemiologist. And basically, the task force defined the literature search keywords that they needed to review. They developed 12 clinical questions that addressed the major practice themes, and they determined the period for the literature search.
target population and the outcomes. They researched the literature from 2001 to 2023. They graded all their stuff based on the grade system. And yeah, and that's pretty much it. So I just want to go over some of the questions and some of the recommendations. They have 12 questions. I'm not going to go over all of them. And I'm going to go over the recommendations. And obviously, each recommendation in the paper is supplemented by how they achieved
this recommendation, they tell you the papers that were included, what each paper found, how many babies they included. And so obviously, if we wanted to review this in depth, it would take us literally three hours. But I wanted to highlight a few. So question one that they addressed was in preterm infants compared with later initiation, does early initiation of parenteral nutrition macronutrients improve growth? And what they said is that they recommend the prompt initiation of parenteral nutrition after birth as soon as appropriate vascular access is obtained.
So you should never delay the administration of TPN. However, there's very few studies that evaluate the timing of parenteral nutrition initiation in preterm infants using growth outcomes that met definition for inclusion. So I think sometimes you wonder like, do I push the pharmacist to order me a TPN? Like we're right on the cusp of the deadline to order TPN. Like you should try to get that TPN. The quality of the evidence is very low for that point.
But again, as we saw with the seizure paper that we reviewed in the last journal club, the strength of the recommendation was strong. So the expert panel felt very strongly about this. Another important question, which was question two, is in preterm infants, compared with lower doses of parenteral amino acids, do higher doses improve growth outcomes? And their recommendation was that they advise against an initial dose of anything more than three grams per kilo per day, given that a single trial found
Ben Courchia MD (32:49.57)
an increased rate of sepsis in the infants who were prescribed an initiating amino acid dose of 3.5. Considering now the maximal target dose, they recommended providing parenteral amino acids at a minimum of three grams per kilo per day, and to not exceed 3.5 grams per kilo per day. The guidance accounts for growth outcomes, as well as neurodevelopmental outcomes associated with amino acid dose as addressed in question three. Also, they're saying that the current evidence remains limited.
in distinguishing any benefits, namely improved growth, comparing a maximum amino acid dose of 3.5 versus four. I often use four, which is interesting. And so they're saying there's really not much there. Again, the quality of the evidence is ranked as very low and the strength of that recommendation is listed as strong. Following up on amino acids, they say, in preterm infants compared with lower doses of parenteral amino acids, do higher doses improve neurodemental outcome. So again,
before we were talking about growth, now neurodemental outcome, they're saying in considering the maximal target dose, they recommend providing amino acids at a minimum of three without increasing beyond 3.5. The current evidence remains limited in distinguishing any benefits, namely improved neurodemental outcome, comparing a max dose of 3.5 versus four. And there is suggestion that exceeding 3.5 may not be without harm. So I'm definitely not ordering four anymore. I mean...
The strength of the recommendation is strong. The quality of the evidence is low. A few more questions. Question four asked, compared with lower intralipid doses, do higher intralipid doses improve growth outcomes? So they're saying that they recommend daily advancement of intralipids to a dose of three grams per kilo per day. If you're using soybean oil, intralipids or multi-component intralipids, they strongly emphasize the need for attention to intralipid composition when making decisions on the dose.
to ensure the provision of sufficient fatty acids for the purposes of preventing an essential fatty acid, for preventing essential fatty acid deficiency. Something our friend, Cami Martin, really tries to drill into, drilled into us and to many people that she's worked with. Providing suboptimal intralipid doses that are associated with a risk of essential fatty acid disease may impair growth, increase the risk of other adverse outcomes.
Ben Courchia MD (35:10.134)
And it also seems that the data is unclear as to where we should start with the intralipid dose. Again, the quality of the evidence is now ranked as very low, but the recommendation there is quite strong. I'm going to go through four more questions. These are shorter. They're asking, compared to intralipids containing 100% soybean oil as the soil oil source, man, try to say that 10 times, is altering the intralipid composition?
by reducing the proportion of soybean oil associated with growth outcomes. And they're saying, at this time, we do not recommend any specific composition for enhanced growth, given that there's no evidence for the benefit from any particular one. So they're not really taking a stand as to which composition is better. Question six asked that, compared with a higher dose of macronutrients, amino acids, dextrose, and interlipids, does a lower dose of macronutrients reduce the incidence of TPN-associated liver disease?
And they're saying that they do not recommend reducing the dose of either amino acids, dextrose, or lipids in order to prevent associated liver disease. Again, very low quality of the evidence, strength of the recommendation quite strong. Two more, maybe three more questions, sorry. They're asking, does reducing the dose of intralipid reduce the levels of unbound bilirubin? They're saying they're unable to recommend any specific intralipid dose for that purpose alone.
Question nine asked, does reducing the dose of intralipid reduce the risk of sepsis? That's something that I've worked in many hospitals and I've seen it done all different things. They recommend against dose reduction of intralipids to prevent sepsis. Quality of the evidence is again ranked as very low. So take that with a grain of salt. But the evidence, the expert panel says that the strongest is strong recommendation. So if you're worried about sepsis, don't turn down those lipids. I've done this before and.
I've done everything when it comes to that, because depending on where I worked, by which attending, I would have done different things. And then the last question that I was seeing is question 12 is, does the use of insulin improve growth outcomes? And they're saying that they recommend against the routine use of insulin for the purposes of improving growth outcomes in hospitalized preterm patients. The quality of the evidence is very low. The strength of the recommendation is quite strong. As you can see, this is a dense paper with a ton of great information. I hope that I piqued your interest.
Ben Courchia MD (37:28.814)
We will link this paper in the episode show notes. But a very important paper, I guess, that every division, I think, should review to at least make sure that you're in line with the recommendation, or at least not way out of line. So yeah. That's, yeah.
Daphna Yasova Barbeau, MD (she/her) (37:42.094)
And you know, we reviewed some papers recently about early protein use, and I'm just going to put a buzz for the hard work you did in our search feature on the website. So if people are like, have you guys reviewed the article? Can I listen to a podcast about something specific? You can either go in there, you can type in TPN, you can type in amino acids and see what we've reviewed recently. So, okay. Thank you.
Ben Courchia MD (38:07.062)
Yeah, appreciate that. Okay.
Daphna Yasova Barbeau, MD (she/her) (38:14.098)
I have an interesting paper. Do Bayley 3 composite scores at 18 to 22 months corrected age predict full scale IQ at 6 to 7 years in children born extremely preterm? A question that we've been pondering about. Leda.
Ben Courchia MD (38:31.669)
We spoke with Susan Hintz about that many times, I think. She's the senior at...
Daphna Yasova Barbeau, MD (she/her) (38:35.242)
Well, she is the senior author. So, so this is a question that has been on, on her mind, all of our minds, right? Because so many outcomes, so many, and so many neurodevelopmental outcomes, quote unquote, are based on this Bailey score because we know that longterm follow-up is so much work. Are you raising your hand?
Ben Courchia MD (38:58.198)
Can you lower your gain a little bit? Is it turned up? Okay. Yeah, because you're coming in very loud. Go ahead. Sorry about that.
Daphna Yasova Barbeau, MD (she/her) (39:02.266)
Yeah, that's better.
Daphna Yasova Barbeau, MD (she/her) (39:10.77)
So, lead author, Jean Lau, senior author Susan Hintz. This is in the Journal of Pediatrics. So this is a follow-up study of the neuro cohort, which is the neuroimaging and neurodevelopmental outcomes, which itself was a secondary study to the support surfactant positive area pressure and pulse oximetry trial, which of course looked at oxygenation strategies for babies born at 24.
and zero to 27 and six sevenths weeks. So they followed survivors from the support trial to school age and children were included for this study if they had both a Bailey three at 18 to 22 months and a WISC IQ, a full-scale IQ done at six to seven years. So at baseline, they had 531 babies in the support neuroimaging trial.
93% of those had Bailey's and among those with Bailey's, 84% or 415 had the school age follow-up and 377 had the WISC assessments. So they kind of just dive right into it. Both the Bailey 3 cognitive and language components were positively correlated with the full scale IQ at six to seven years. And the cognitive score
had an R of 0.33, the language had an R of 0.44. And importantly, they remained significantly correlated even when controlling for demographic factors. They also presented their weighted Kappa scores, which is of course a measure of agreement between two ordinarily scaled samples. They were 0.16 for cognitive and 0.28 for language. And these both signify a kind of a fair agreement.
But I think what's really valuable, I'd recommend everybody take a look at the tables because you say, okay, well, it's an agreement for this population, for this cohort, but what does it look like for individual babies? So they took the Bayley cognitive score, or both the cognitive and language scores, and they graphed them against the full-scale IQ scores.
Daphna Yasova Barbeau, MD (she/her) (41:29.95)
So what you see are these kind of quartiles of babies. And I think what's really valuable is I'm not gonna say outliers, but the babies on the extremes, right? So the babies who had a Bailey score of less than 70 were obviously very likely to have a full-scale IQ less than 70. And the babies who had Bailey scores greater than 100 were obviously the most likely to have a full-scale IQs greater than 100.
So the babies really on the either extreme kind of had the best correlation. And then these babies in the intermediate groups had less so, but you can definitely see the outcome. So I thought these tables were actually pretty helpful. And all in all, at least at six to seven years.
The Bailey scores do have some positive correlation.
Ben Courchia MD (42:34.466)
Yeah, I think that's an interesting thing. Something that I've been discussing with my late mentor about, because we did a lot of research on cognitive outcomes and we had such a large data set that spanned such a wide timeframe that we were able to work with Bayley ones, Bayley twos, and Bayley threes. And you could clearly see that the Bayley three, I guess, is quote unquote more generous. And so that despite the fact that you are below, you are one standard, one,
Daphna Yasova Barbeau, MD (she/her) (42:52.576)
Ben Courchia MD (43:03.566)
further away than one standard deviation. So 15 points is your standard deviation on the Bayley. Your median score should be about, your mean score should be about 100. So if you're past 85, technically you should have some form of, you're out of the norm now, and you should have some form of impairment. Less than 85, I'm sorry. But what we found was that actually, no, that was kind of true on the Bayley 2, even the Bayley 1, but on the Bayley 2, and then it really was.
Daphna Yasova Barbeau, MD (she/her) (43:17.646)
You mean less than 85, yeah. Yeah.
Ben Courchia MD (43:30.358)
you needed to be less than 70 to really start showing impairment because the, you, it was easy to, uh, the, just the, the Bailey three was, was just, yeah, a different kind of test. So I'm, I'm not surprised at all by the result. And I think that it was great that they did this study, uh, because that was something that was much needed, much, much needed. Yep. Uh, cause it's, yeah, cause when you say that babies who have a barely three of 84 and they're cognitively impaired, I don't believe that.
Daphna Yasova Barbeau, MD (she/her) (43:46.222)
Ben Courchia MD (43:59.874)
I mean, I think that these kids will catch up and that's not that's not severe at all. Okay. That has a 65 though. Yeah, that's very concerning, but the
Daphna Yasova Barbeau, MD (she/her) (44:07.658)
Yeah, and especially in this cohort of extremely preterm babies, right, that are basically less than two years at initial evaluation, right? So many of them have not, quote unquote, had the full opportunity to catch up yet.
Ben Courchia MD (44:15.471)
Ben Courchia MD (44:20.386)
Absolutely. And then again, it gives us a more narrowed range to actually put our babies on the scale, right? If I can only look at kids who have a score less than 70, it's tough. It's actually not very easy. And there was a paper in pediatrics, I forget when it was, I'll have to find it, but basically that looked at how do babies then evolve?
over time and how do they move from one category to another? And you could clearly see that these kids that were like in the mid 80s were eventually moving back up into the normal range. And they had like a very nice graph about how this was done. But again, maybe if I find the title before the end of the episode, I will try to read it out.
Daphna Yasova Barbeau, MD (she/her) (45:10.606)
I think that's a great, I'm gonna give a plug for a book I finished reading over the summer and we spoke about with Dr. Barbara Schmidt, The Boy Who Could Run But Not Walk by Dr. Karen Pape. I think is a good reminder about how our babies can have successes, babies and children can have developmental successes that we just totally miss on developmental screening. So I thought that was really cool for anybody who does.
follow-up, or who is working with high-risk babies and is trying to give prognostic information to families.
Ben Courchia MD (45:47.55)
The name of the paper I'm thinking of is a paper that was published in pediatrics in 2021 and it's called changes in neurodemental outcome from age 2 to 10 years for children born extremely preterm and the figure I'm thinking of is figure 2 which almost looks like I'll try to share my screen so that you can see it. So it almost looks like the brachial plexus When when you'll see it, you know what I mean
Daphna Yasova Barbeau, MD (she/her) (45:55.374)
Daphna Yasova Barbeau, MD (she/her) (46:09.338)
Ben Courchia MD (46:17.474)
Anyway, all right. Yeah, hold on. Let me show you right here. Do you see what I mean? Yeah, so basically you had.
Daphna Yasova Barbeau, MD (she/her) (46:27.822)
It does look like the break-up flexes, but it's kind of these overlapping highways.
Ben Courchia MD (46:32.85)
Exactly, exactly. Okay. All right. So where am I taking you guys next? Um, I have an important paper to review. It was something that, uh, Ravi Patel, um, did bring up on Twitter. It's called tissue oxygenation after transfusion and outcomes in preterm infant.
a secondary near-infrared spectroscopy study of the transfusion of premature randomized clinical trial, the top NIRS. First author is Chok and colleagues. It is published in JAMA, JAMA something. JAMA has too many affiliates. It is JAMA, I think, network open, but I will, JAMA network open, yeah, that's what it is. So, there's...
two large clinical trials that found that a higher hemoglobin threshold for transfusion did not improve survival without neurodemental impairment. And that now what we're thinking of is if we're using NIRS, can it be used to assess tissue saturation as an alternative to hemoglobin for determining transfusion needs, right? So as we are hooking up NIRS to our babies and we're seeing these values, what are we supposed to do, especially when it comes to perfusion? And what's interesting about this question is that...
when we're reading all these papers about anemia and transfusion thresholds, the core of the question is, does your baby need more oxygen carrying capacity? Do the tissues need oxygen? And it's true that making that decision based on a single value is very reductive to just say, oh, the hemoglobin is X, so then yes. But maybe NIRS can actually provide this information. So changes in tissue oxygen saturation following PRBC transfusion.
is my thing going, vary depending on factors like the degree of anemia and they may have long-term implications for the mental outcome. So this is a secondary prospective observational study of a subset of infants enrolled in the NICHD top trial. And what they're hypothesizing is that NIRS measures of the cerebral saturation and the mesenteric saturation would increase after a transfusion and corresponding tissue extraction of oxygen.
Ben Courchia MD (48:49.978)
for both the brain and the mesentery would decrease with greater change for those with a lower transfusion threshold. I'm just gonna go over this one more time. So when we're measuring NERS, we're measuring superficial sort of saturation and we can calculate the fraction of tissue oxygen extraction. And we don't want our tissues to be very efficient in how much oxygen they extract. If they are very efficient, if the...
tissue oxygen extraction is very high. It means that the tissue needs oxygen, is not getting enough, and is doing its best to get as much oxygen out of the passing red blood cells. So in an ideal world, we're giving so much oxygen to our tissue that the tissue itself doesn't have to be efficient in how much oxygen it pulls from circulation. So that's why we're hoping that the SAT goes up and that the tissue oxygen extraction goes down. So the top trial, which is the trial that they're using, that this is...
based out of is a randomized preterm infants of a birth weight 1000 grams or less, and gestational age between 22 and 28 and six weeks within 48 hours after birth to receive PRBC transfusion at either a higher or lower threshold. The patients for this particular study had to be concomitantly enrolled in the top trial. And I think we reviewed the top trial. There's a lot of, Keith Barrington has a great post on it. And basically, if you want to remember
The key to the top trial is that they had different thresholds based on how old you were and based on what kind of respiratory support you were on. So it was not just like a single digit that you just said, yes, no. Exclusion were that if babies had cyanotic congenital heart disease, if the neonatologist deemed the baby to be non-viable, if the baby had received in utero fetal transfusion, if there was twin-to-twin transfusion syndrome,
If there was isoimmune hemolytic disease, congenital conditions, et cetera, et cetera, it was quite long, and if the follow-up was not appropriate. So the sensors were applied to the right or left forehead and to the lower left abdominal quadrant for the first week of life, and then reapplied 48 hours during a subsequent PRBC transfusion to monitor cerebral and mesenteric saturation with near-infrared spectroscopy.
Ben Courchia MD (51:15.782)
Clinicians were masked to the measurement on the NIRS. The sensors were removed after seven days of life or 48 hours after completion of the transfusion. CSAT and MSAT, so the cerebral and mesenteric saturation and oxygen saturation measures were acquired every 30 second, pre-transfusion measures were averaged in the one hour prior to the start of the transfusion and post-transfusion measures were averaged in the one hour after completion of transfusion. Both periods...
required at least 10 minutes of consecutive data. The primary outcome of the study is the changes in NIRS measures. That is cerebral SAT, mesenteric SAT, tissue oxygen extraction for both the brain and the mesentery. And that was measured from pre to post-transfusion. The secondary outcomes was a composite of death or neurodemental impairment at 22.
to 26 months of age corrected for prematurity with neurodemental impairment defined as a barely three of less than 85. So I know we just discussed that, but sorry. Cerebral palsy with a gross motor function classification system level two or greater, or severe vision or hearing impairment. They also did a CART analysis to explore the infant level prognostic factors for death or NDI over the entire hospitalization period. So.
Let's talk about some of the results. Among the 16 participating centers, 179 infants with an ingestational age of about 26 weeks were enrolled and 140 of them had PRBC transfusion. When restricted to transfusions with both valid pre and post transfusion nearest data, there was 101 infants with a total of 237 transfusion events that were captured. The mean.
Pre-transfusion hemoglobin was 11 in the higher threshold and nine in the lower threshold group. There were no significant differences in demographic or perinatal variables between the different groups in their hemoglobin thresholds. Transfusion was significantly associated with an increase in both cerebral saturation, mesenteric saturation, but with no significant difference
Ben Courchia MD (53:41.774)
between the hemoglobin threshold groups. So I think that's very interesting, meaning that you would have expected that because the higher threshold group has more hemoglobin, maybe the change is not gonna be seen as significant. Maybe the cerebral SAT and the mesenteric SAT is not gonna jump up because, hey, the hemoglobin is a bit higher. But it turns out that
it was significantly associated with an increase in both cerebral SAT and mesenteric SAT, and no difference between the different groups. The mean cerebral saturation change in the lower hemoglobin threshold group was 4.8% compared to 2.7% in the higher hemoglobin threshold group, while the mean changes in the mesenteric SAT was 6.7% versus 5.6%.
Ben Courchia MD (54:42.35)
there was no significant changes in the oxygen saturation within either group. So again, if you're looking, it's interesting to see that the oxygen saturation does not have the sensitivity to detect much changes while the changes on the cerebral set and the mesenteric sets were detected. When it comes to cerebral fraction of tissue oxygenation extraction, tissue oxygen extraction, what they saw was that there was a decrease
4.2% in the lower hemoglobin group compared to 3.6% in the higher hemoglobin group when it comes to the brain and for the mesentery it was it decreased from 8.1% by 8.1% compared to 5.4% in the higher hemoglobin threshold group. Changes in NIRS measures based on chronological age at transfusions were also not significant.
over the first 28 days. Data on the secondary composite outcome of neurodemental impairment or death were available in 96% of the cohort. NDI or death occurred in 36 infants, which is 37% of the cohort. 30% survived with neurodemental impairment and 7% died. The number of transfusions with mean pre-transfusion cerebral saturation less than 50%.
was associated with neurodevelopmental impairment or death. So when the cerebral SAT goes below 50, that's a risk factor. So maybe that's a threshold that we should be using. The conclusions are that tissue oxygenation of the brain and mesenteric region improved after transfusion independent of the hemoglobin threshold group, while cerebral SAT below 50% may be associated with adverse outcome, future prospective investigation.
to compare the current hemoglobin threshold based transfusion practices to an individualized cerebral NEARS measures based transfusion guideline is warranted, they say. An improved precision medicine approach with cerebral oxygenation monitoring may facilitate a brain protective strategy for transfusion practices. I highly recommend people go through the discussion. We obviously do not have the time to do this here today, but I wanted to quote a few things that they mentioned. And they're saying,
Ben Courchia MD (57:04.482)
something I'm going to just read what I highlighted. They said infants in the lower hemoglobin threshold group tended to have lower pre-transfusion cerebral SAT compared to those in the higher hemoglobin threshold group. However, this was not always the case, underscoring the potential role of other factors contributing to cerebral hypoxia, including systemic hypoxia, cardiac output, and hypokarbia. The trajectory of pre-transfusion years measure over time is also consistent with literature describing
Daphna Yasova Barbeau, MD (she/her) (57:18.998)
Ben Courchia MD (57:31.45)
decreased cerebral saturation and compensatory increase in tissue oxygen extraction in infants with worse anemia. And so it's interesting to see that maybe the hemoglobin is a poor man's way of looking at tissue oxygenation. And they're saying that these findings support the idea that hemoglobin threshold may not be the best indicator of need for transfusion. As an adjunct to hemoglobin values, CSAT or FTOE tissue oxygen extraction could be considered for individualized determination.
Daphna Yasova Barbeau, MD (she/her) (57:51.286)
Ben Courchia MD (58:00.578)
of transfusion thresholds. So if you are like me and you just rolled out your transfusion protocol in your unit, you are quite depressed right now. Just another look, like re-deconstruct the whole thing. But yeah, because we have nears, because in our units we do have nears. So that's gonna be interesting.
Daphna Yasova Barbeau, MD (she/her) (58:06.306)
Daphna Yasova Barbeau, MD (she/her) (58:09.598)
You gotta take another look at...
Daphna Yasova Barbeau, MD (she/her) (58:21.23)
Yeah. I think it's exciting. I think, I mean, I think if you look at the pediatric population and the adult population and what hemoglobins they're letting people walk around with, you know, I think it's exciting. This is the future, right? Precision medicine, like what is going on with my individual patient is how I think we will get the best outcomes, obviously.
Ben Courchia MD (58:47.734)
Yeah, I mean, it reminds me of when people talked about when the oxygen saturation probes came in the unit. They're like, yeah, we used to say like, oh, baby looks blue. Maybe baby needs oxygen. Right. And it's like, oh my God, this was so archaic. And then you get the pulse ox. But then maybe we'll look in the future and says, oh my God, you just use a hemoglobin to decide whether it can needed more. It's like, yeah, maybe that's what it will be. Any well.
Daphna Yasova Barbeau, MD (she/her) (59:09.578)
Okay, I had this interesting paper. I'm not gonna go through the whole thing, but it was called Perspectives of Extremely Prematurely Born Adults on What to Consider in Prenatal Decision-Making Qualitative Focus Study Group. Lead author, Angrette de Boer, in the Archives of Disease coming out of the Netherlands. And it's a qualitative study entitled Tiny, Towards Individualized Care for the Youngest.
Ben Courchia MD (59:22.341)
Daphna Yasova Barbeau, MD (she/her) (59:38.894)
And so they had four focus groups between January and February, 2022, each with five to six participants born between 24 and zero and 30 and zero during the years of 1965 and 2002. So an interesting cohort. Participants were recruited through the Dutch Patient Organization and through social media. So it was a small group, N of 23, five men, 18 women.
Reborn at 24 to 25 and six, 13 born at 26 to 27 and six, and seven born at 28 to 30. And then to tell you more about the eras in which they were delivered, four were born between 1965 and 1985, nine were born between 1981 and 1990, and 10 were born between 1991 and 2002. So like this spans like the whole early days of neonatology.
In total, five completed secondary school or a vocational program, 10 had higher education and eight had a university level education. 15 out of the 23 had self-reported complications of prematurity. And I will tell you what those are because I thought they were interesting. So these are self-identified and reported long-term consequences of their extreme premature birth.
So cognitive, so cognitive learning disability or problems at school, brain injury or memory disorders in five of the 17 who reported long-term effects. Neuromotor function, so problems with moving due to hypo or hypertonia or a diagnosis of cerebral palsy, nine out of the 17. Remember 17 out of 23 who reported long-term effects.
in the psychosocial arena, concentration problems or ADHD, eat out of the 17, symptoms of autism spectrum disorder, two out of the 17, and quote unquote, other psychosocial problems, one out of the 17. Vision and hearing problems, seven. Respiratory problems, seven. Reduced immunity or susceptibility to infection, five. Easily fatigued, five. Growth restriction, five. Eating or feeding problems, four. Intestinal problems.
Daphna Yasova Barbeau, MD (she/her) (01:02:00.214)
Um, four, uh, no, sorry. Intestinal problems, three. And then other self-described consequences, feeling misunderstood, attachment problems, anxiety disorder, performance anxiety, insecurity, the need to prove themselves or, um, some stimuli processing problems, five.
And then they really wanted to talk to them about how do we counsel parents in the prenatal consult, given your experience with prematurity. And overall, not surprisingly, they agreed with a shared decision-making approach that both shared the factual risk information as well as feelings from the family. And they identified a number of themes that are probably related to the prenatal consult, which had been reported by families.
And for each one, I'll give kind of a synopsis of what they mentioned they thought should be discussed during that time. So the first anticipated regret or guilt that they sympathized with their parents for the decisions that they needed to make and thought that we needed to address that. This opportunity of looking at the child after birth. So.
They felt it would be prudent to look for infants, quote unquote, will to live. So were there distinguishing factors of the baby post-delivery that would help with the decision-making for deciding about early intensive care? So, uh, was there movement? Was there grimace? Uh, was the baby active? Um, so they felt that potentially that, um, could be taken into account as part of the decision-making. This concept of giving a chance at survival. So.
They emphasize that survival should not be pursued at all costs and that parents should be counseled regarding withdrawal of early intensive care if things change for the worse. Quality of life, they felt like this topic was very important, but even themselves difficult to define. But it came across on kind of a number of quotes that quality of life should not be determined based on the potential physical handicaps. Many of them noted that they had motor physical handicaps.
Daphna Yasova Barbeau, MD (she/her) (01:04:15.19)
but that they had full lives. This theme of consequences of early intensive care, they had concerns that the consequences of extreme prematurity were underestimated. And from their perspectives, more research needed to be done on long-term consequences in adulthood so adults can be better involved with this prognostication.
impact to the family, many described adverse effects that their hospitalization had on their siblings and that social support should be addressed during the prenatal consult. This concept of religion and spirituality, but not a lot of guidance on what to do about that topic. I thought it was interesting. I think anytime you've got a group of adults born preterm, we should be listening to our end stakeholders.
So I thought it was interesting to talk about.
You're muted, buddy.
Ben Courchia MD (01:05:17.806)
Yeah, there's some background noise, which is why I wanted to meet myself. Sorry about that. Yeah, it's an important paper that's going to, I think, be a reference as to, and adds itself to the library of testimonies from adults who were born preterm and getting information from their perspective and getting them to share their perspective. I think that's very important.
Daphna Yasova Barbeau, MD (she/her) (01:05:30.259)
Daphna Yasova Barbeau, MD (she/her) (01:05:42.442)
Yeah, and obviously these are self-recruited people who are, you know, and who can answer the questions in a focus group format. So it's...
Ben Courchia MD (01:05:48.646)
That's how it will continue to be. I think we are not gonna be able to force anybody to testify or share anything if they don't want to. So it will be people who wanna contribute. But I do think that as we've seen, as we've interviewed people who were born preterm on the podcast, they do wanna help their fellow, yeah, their fellow primis. And so yeah, that's for sure. Okay, so we're way over time. But, and I'm going to, I am going to...
Daphna Yasova Barbeau, MD (she/her) (01:06:07.162)
Daphna Yasova Barbeau, MD (she/her) (01:06:13.816)
Ben Courchia MD (01:06:18.742)
skip one paper that I wanted to review. I'll leave that for next time, but there's one that I really wanted to talk about. And it is published in Pediatrics, and it is called When the Unknown is Unknowable, Confronting Diagnostic Uncertainty. I'm gonna walk you through.
Daphna Yasova Barbeau, MD (she/her) (01:06:31.714)
I know, I needed to read this paper. So I'm glad you're reviewing it for the community. Ha ha ha.
Ben Courchia MD (01:06:34.507)
Ben Courchia MD (01:06:38.382)
No, for sure. First author is Julia Faison. And in the paper, we have really big names. Annie Janvier is on there as well. But I'm going to walk you through the paper. There's a case, so this will be more engaging and more interactive than our usual review of papers. So they make an early distinction between aleatory uncertainty, the knowable unknown, in which really probabilities are considered. So I know what I don't know. And I can tell you more information about
what our experiences have been. And then they talk about epistemic uncertainty, the unknowable unknown, in which there's really nothing I can provide to you in terms of data or anything like that to help you understand the problem. Now compared with aleatory uncertainty, epistemic uncertainty is met with considerably more angst because analytical thinking is rarely sufficient to mitigate the high emotional load. So they go through a case.
And they go through the case of this mother who had an unremarkable pregnancy. And she goes through what they quote, crash delivery at 35 weeks via C section for late decelerations.
The baby is in hypovolemic shock after birth and so is transferred to a level four NICU. The baby on exam is noted to have multiple dark red slash purple hemorrhagic masses on the head, in the mouth, in the right axilla and other sites. The cranial mass is bleeding profusely from a atrogenic laceration. The baby requires extensive volume and pressure support. She quote unquote codes twice before being transferred.
She's arriving to a level four, by the way, I say she, because I think they disclosed that there was a girl. And she's found to be encephalopathic. She's in URIC. She has a pH of 6.6. And you're thinking maybe they should cooling, but remember she has ongoing massive bleeding. So she's not a candidate for therapeutic hypothermia. She does receive nitric oxide for persistent pulmonary hypertension. And her differential includes multifocal lymph NGO.
Ben Courchia MD (01:08:47.85)
endotheliomatosis, it includes diffuse neonatal hemangiomatosis, it includes congenital vascular malformation of unknown etiology. She's too unstable for an MRI, she's too unstable for an MRI, DIC is preventing any form of biopsy, and they end up consulting 10 subspecialties, no diagnosis. The dilemma as presented in the paper is that the attending physician is conflicted about how to tell the parents, Nathalia and Daniel, how
the baby, her name is Evangelina, that the physician didn't think their infant daughter would live when they did not know the cause of her severe condition. So there's this conflict of how am I going to tell them, hey, your baby is not going to make it, but I don't know what they have. So how can I say that she's not going to live if I don't have much more information? And the question is, how would you advise the attending to proceed? So if you want to pause the podcast now and pick up afterwards, then that's a...
Maybe a good point to do that. And so then we're gonna get two perspectives. The first one is the one from Chris Fudner, who's a palliative care physician and ethicist. And I'm gonna mostly read some of the things that they've written, because I cannot paraphrase this well enough. But what he's saying is this situation, physicians feeling that they cannot render a prognosis for want.
of a unified underlying diagnosis is not uncommon. Despite how unique the case is, he's saying underneath this feeling of being stuck, there often seems to be a deeper feeling, namely the fear of potentially being wrong, sorry, of offering a fatal prognosis and having subsequent events show that death might not have been or was not inevitable. And I think that's very true, because it's like, what if I'm completely wrong? I don't know what the diagnosis is, so what if I'm completely wrong?
And so he asks the question, how to move forward. And so he says, with a combination of clinical and epidemiologic reasoning joined by clear communication, although not a panacea can help us to move forward. Start with thinking how any piece of information affects the prognosis of a patient. He talks about test prognostic values. He talks about how a diagnosis is important, but can also have a broad prognostic range, right? I mean, even if you have a diagnosis, diagnosis can sometimes be mild to very severe. And then he gives,
Ben Courchia MD (01:11:13.614)
the analogy of, it gives a story, an analogy of a person breaks into a person's home and hits them with a hammer on their head and the patient's brought to the ER. You could treat the head injury and you don't really need to know what exactly happened in the home to treat and know what's gonna happen for this patient with head trauma. So sometimes the situations you're faced with right there and then is enough information for you to provide consultation, to provide treatment recommendation and you don't necessarily need to know the details.
of the inciting event. And when he basically writes out how he would speak to this family, and he says, last, we should consider how to communicate not only our bottom line prognosis, but also the reasoning that led us to the parents in an appropriate manner. There are many ways to do so. And he says, I can imagine though I might offer to the parents, Daniel and Nathalia. So he says, and I quote, let me start by saying how much I wish your daughter was not ill.
I would probably pause here before continuing. I do not know what started the chain of events that led her to be so ill. What I do know is that one of those events was massive bleeding, which then led to what we call shock, where parts of the body did not get enough blood and the oxygen that the blood carries, and that this resulted in injury to the brain, to the kidneys, as well as to the heart, which you know stopped twice. I also know that all this injury is...
Continuing another pause. She is too sick to receive some of the treatments that could keep her body going longer. Although none of the treatments would stop the process that started this terrible chain of events. Another pause. I'm afraid that she simply cannot survive her extensive injuries. And his contribution to the paper stops here. And then we have the input of Annie Janvier who's a researcher.
a neonatologist, she's a nephesis, and most importantly, she's a NICU mom. So she says meeting Daniel and it's like, you can, you can hear Annie's perspective. And so it's kind of, it's kind of, it's kind of refreshing. So she says meeting Daniel and Nathalia in such a situation is no longer to discuss treatment option. The physician's role becomes one of supporting the parents during the death of their baby and helping them rewrite their story.
Ben Courchia MD (01:13:35.922)
I would unambiguously tell them that Evangeline is dying. She says, avoid euphemism. Just, we've done everything that we can to help her and are unable to keep Evangeline alive, she will die soon. She says, don't do the whole thing with, she's gonna be with the angels, she's gonna meet her maker. Just don't be ambiguous. Parents need to hear, there is nothing they could do.
Parents, sorry, I'm going to rephrase that. Parents need to hear that there is nothing they could have done to prevent what is happening to their baby. I would avoid, and again, I'm just citing mostly the paper here. When I say I, I mean, Dr. Jean-Vier says I. I would avoid describing everything we will not do, ECMO, MRI, nor would I ask for permission to withhold CPR or any other treatment that would not work for dying babies. CPR is a physiologically...
futile intervention that would not be offered nor discussed in many NICUs around the world. I would place the emphasis on everything we will do. Many parents are in such shock and so lost that they ask for recommendations. In this case, offering a plan is essential, naming, acknowledging, normalizing the emotions the parents feel. Anger, rage, sadness, despair, emptiness often helps families. Even if not evidence-based, in some circumstances when anger and injustice fills the room, I have used curse words.
and told parents life's a bitch. That was, that what was happening to their baby is unfair and that life makes no sense.
She says that I leave my email address with the families after the death. I send them a bereavement card. I stay in touch with them. Families have taught me a great deal over the years. They helped me become a better person and physician. She says, uncertainty about the diagnosis of a dying child is lesser but important problem. Parents of babies in the NICU often experience powerful emotion of inadequacy and guilt. That is something she's mentioned to us as well when we interviewed her for the podcast. We often...
Ben Courchia MD (01:15:38.51)
This guilt from the parents often goes unrecognized. Clinicians must be sensitive to the unintended harm they can cause, such as questioning the mother about her lifestyle, her health. With genetic diseases, either of the parents may feel guilt because they quote unquote, carried the bad genes. In this case, and in the vast majority of cases in neonatology, we know that the parents carry no personal responsibility for the infant's illness. Parents should be told, should be told so explicitly.
In the era of precision medicine, doctors feel like they need a diagnosis. Doctors are less willing to make a redirection of care decisions without a clear diagnosis, even when it is obvious that the clinical situation is extremely reserved. We have become dependent on precision tests and yearn for unambiguous answers. Lacking a diagnosis may make clinicians uneasy and may feel like a failure, especially in the face of death. For some parents also seeking a diagnosis is perhaps a way of coping. Knowing when to stop the diagnostic.
Odyssey and speak about life and death as an important skill physician should master So this is the end of dr. Jean-vius contribution and the case they do provide us with the case outcome. They Mentioned that the baby eventually and I continue to be an uric that she was not a candidate for dialysis She was not a candidate for ECMO and that after discussion between the team and the parents they agreed to redirect towards comfort care She passed away 37 minutes after being taken off the ventilator
and that the parent consented to an autopsy that confirmed a diagnosis of congenital rhabdoid tumor with placental spread and multi-organ metastasis inclusive of the central nervous system. Natalia and Daniels were appreciative of the care given to Evangelina and the support they received while she was admitted. So yeah, fascinating paper.
Daphna Yasova Barbeau, MD (she/her) (01:17:26.506)
Yeah, I mean, I have my thoughts, but you heard from the experts. So I, I know I, I mean, I think she does a very good job that if the team really feels like the baby is going to die, we ha we just have to tell parents like we're not doing them any favors by not telling them, you know? And
Ben Courchia MD (01:17:30.895)
What are your thoughts?
Ben Courchia MD (01:17:50.746)
Daphna Yasova Barbeau, MD (she/her) (01:17:55.662)
There are some things we just can't know. What a strange diagnosis, right? So, I mean, that exactly, you would have known that, yeah.
Ben Courchia MD (01:18:01.21)
But I think it was a great case to take because there's no way that this diagnosis, and they tell you, 10 subspecialists involved on the case. No one had this answer. And at the end of the day, when you look at the diagnosis, you're like, well, it wouldn't have mattered basically. Oh no, it would not have mattered. Exactly. Yeah.
Daphna Yasova Barbeau, MD (she/her) (01:18:11.042)
Daphna Yasova Barbeau, MD (she/her) (01:18:15.382)
That makes sense. Yeah, that makes sense. And the outcome wouldn't have been different. Yeah, if you had gotten the diagnosis. Yeah. And to get that diagnosis would have taken still weeks, probably, to some places months. And would the baby even have made it that long? I mean, not without.
Ben Courchia MD (01:18:35.33)
I don't think what was necessary to make the diagnosis would have probably killed this patient, right? I mean, the biopsy, anything like that. And I think, to me it was very interesting to actually put in writing the conflict of the physician when it comes to like, I'm so worried that this is something that I'm missing, and so that's why I'm afraid to say the baby's gonna die. When it's like, yeah, sometimes you're telling somebody's gonna come around and say, oh, this is just hyperbola or bulimia, you give them.
Daphna Yasova Barbeau, MD (she/her) (01:18:40.554)
Well, yes, the biopsies and yeah.
Ben Courchia MD (01:19:03.162)
this little pill and everything is better. And in truth, it's like, no, when we see it, we know what it is, we should talk to the families accordingly.
Daphna Yasova Barbeau, MD (she/her) (01:19:09.057)
And I think she underscores, we had this discussion with Erin at the Next Society and other parents that we've put on, that I mean, there's so much we can do for families in death and dying, and it is a part of our job. It's not just relegated to the social worker, the bedside nurse, or the palliative care team. Like, it's part of our job, I think, to sit and be with parents in...
Ben Courchia MD (01:19:33.87)
Daphna Yasova Barbeau, MD (she/her) (01:19:39.586)
death and dying and make that... It's a painful experience, but can we make it...
Ben Courchia MD (01:19:46.134)
Yeah. But like Ani is saying, you will become a better physician for it. It's, yeah, it's like me going to school. I did not enjoy it, but I needed it.
Daphna Yasova Barbeau, MD (she/her) (01:19:52.063)
And that's right, but you needed it. And for people who want to hear more from Dr. John B.A., who's obviously a wealth of information, we head around an episode 57 of the podcast.
Ben Courchia MD (01:20:07.97)
And if you are French speaking, she will be coming on the French podcast as well. So yeah, we love, we're big fans of hers. Um, yeah.
Daphna Yasova Barbeau, MD (she/her) (01:20:14.794)
Yeah. Okay. I don't really have a study. I was just going to mention this brief communication in the Journal of Perinatology. It's really a long abstract of this pilot study using an optical fiber light source to guide nasogastric orogastric tube insertion in neonates. Yeah. So I thought it was cool. I mean, they're basically just showing a proof of concept, kind of a safety profile, let's say, of using this.
Ben Courchia MD (01:20:28.598)
I saw that! I saw... How cool was that?
Daphna Yasova Barbeau, MD (she/her) (01:20:43.598)
NG tube that has an LED light at the end. So you can see exactly where it is in the patient. And I think this is interesting. I don't find that we have a lot of trouble with placing them in the NICU, but I wonder, my first thought was how will this help some families transition home with feeding tubes? I think it is a...
Ben Courchia MD (01:21:05.546)
I was thinking that and I was thinking like, what about ND tubes? Like the ND tubes, I need to get an X-ray. If I see the thing passing midline, then that's it. I'm good.
Daphna Yasova Barbeau, MD (she/her) (01:21:10.11)
Daphna Yasova Barbeau, MD (she/her) (01:21:15.734)
That's right, yeah, very, very cool.
Ben Courchia MD (01:21:18.906)
Yeah, very cool. And if you're not gonna read this paper because you're busy, they have pictures. Just look at the pictures, because you see the picture and you're like, yep, I get it, that makes total sense. So yeah, that was a great one as well. Okay, that was a dense journal club.
Daphna Yasova Barbeau, MD (she/her) (01:21:25.462)
Yeah, just look at the pictures.
Daphna Yasova Barbeau, MD (she/her) (01:21:35.062)
That's it. All right, everybody, have a good week.
Ben Courchia MD (01:21:39.278)
But we did it. Have a good weekend, everybody. Bye.