#346 - CPAP with Purpose: Supporting Babies in the Delivery Room and the NICU (Part 1)

Hello friends 👋

In this episode of The Incubator Podcast, we welcome Dr. Cindy McEvoy, Professor of Pediatrics and Director of Neonatal Research at OHSU, to discuss her work on the use of extended CPAP in preterm infants. CPAP has long been a cornerstone of neonatal care, but how long should stable infants remain on support? Dr. McEvoy shares findings from two randomized controlled trials that explored whether an additional two weeks of CPAP could promote lung growth and improve longer-term outcomes.

We review the physiologic rationale behind extended CPAP, including the role of mechanical stretch in stimulating alveolar and vascular development. Dr. McEvoy explains the stability criteria used to determine eligibility for extended CPAP and how her team measured pulmonary function in neonates. Results from her studies showed significant improvements in lung volume, diffusion capacity, and expiratory flows, with early signals of reduced wheezing at one year of age.

The conversation also touches on feeding tolerance, the practicalities of implementing extended CPAP in the NICU, and the need for larger multicenter studies to confirm these findings. This episode offers an evidence-based look at how a simple extension of an existing therapy might reshape respiratory outcomes for preterm infants.

----

This episode is part of a special three-part series on the use of CPAP, supported by Fisher & Paykel Healthcare. Their sponsorship makes possible the logistical production of this podcast series but does not involve curation, moderation, or influence over the content of the discussions.

Fisher & Paykel Healthcare offer a full neonatal care continuum which helps provide the best start possible to our precious babies worldwide.

Watch the design matters video series and discover what drives the innovation behind their neonatal interfaces https://www.fphcare.com/hospital/infant-respiratory/support/design-matters/

----

Short Bio: Dr. Cindy McEvoy is a neonatologist and physician-scientist whose work centers on in-utero and early-life interventions designed to optimize fetal lung development and long-term childhood pulmonary function, particularly in the setting of adverse exposures such as maternal nicotine use, maternal obesity, and prematurity. She is widely recognized as an expert in neonatal and infant pulmonary function testing, the conduct of randomized clinical trials, and the retention of high-risk cohorts in longitudinal studies.

Dr. McEvoy earned her medical degree from Loyola University in 1995, followed by a pediatric residency at Kaiser Foundation Hospital in Los Angeles. She then completed a fellowship in neonatal-perinatal medicine at LAC-USC Medical Center. Early in her career, during her husband’s military service in Pensacola, Florida, she practiced in private neonatology and served as Medical Director of the Children’s Hospital at Sacred Heart Hospital.

Since joining Oregon Health & Science University (OHSU) in 2000, Dr. McEvoy has been an active clinician, educator, and leader in research. She currently serves as Director of Child Health Research for the Department of Pediatrics and Director of Neonatal Research in the Division of Neonatology at OHSU, while maintaining her clinical practice as a neonatologist.

----

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

Extended Continuous Positive Airway Pressure in Preterm Infants Increases Lung Growth at 6 Months: A Randomized Controlled Trial.

McEvoy CT, MacDonald KD, Go MA, Milner K, Harris J, Schilling D, Olson M, Tiller C, Slaven JE, Bjerregaard J, Vu A, Martin A, Mamidi R, Schelonka RL, Morris CD, Tepper RS.Am J Respir Crit Care Med. 2025 Apr;211(4):610-618. doi: 10.1164/rccm.202411-2169OC.PMID: 39977011 Free PMC article. Clinical Trial.

Extending CPAP in stable preterm infants to increase lung growth and development as measured by pulmonary function testing.

Mamidi RR, McEvoy CT.Semin Perinatol. 2025 Aug;49(5):152059. doi: 10.1016/j.semperi.2025.152059. Epub 2025 Feb 28.PMID: 40023691 Review.

----

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

Ben (00:00)

Hello, everybody. Welcome back to the incubator podcast. We are back this Sunday with a special interview and we are joined in the incubator studio by Dr. Cindy McEvoy. Dr. McEvoy, thank you for being on the podcast and joining us today.

Cindy Mcevoy (00:12)

Thank you so much for having me. think this is a great opportunity to talk a little bit about CPAP and one of my recent studies.

Ben (00:22)

I agree. Daphna is here with us as well. Daphna, good morning. How are you today?

Daphna (00:26)

doing well. We've both been looking forward to this episode, but I know in particular you have been looking forward to this episode.

Ben (00:32)

Yeah, I've been looking forward to this episode number one because Dr. McAvoy has been on my short list of guests that I wanted to have on. then Hot Topics, think, was the catalyst when we were able to sit down with you and talk a little bit about this. This was sort of ⁓ the activation energy that I needed to send these emails and say, OK, let's make this happen. ⁓ Dr. McAvoy, for people who are not familiar with who you are, you're a practicing neonatologist. You serve as the director of child health research in the Department of Pediatrics, as well as the director of neonatal research.

within the neonatology division at OHSU. Your focus on ⁓ in utero and early life intervention is designed to maximize ⁓ fetal lung volume, childhood pulmonary function, especially in the context of ⁓ maternal ⁓ substance ⁓ use, maternal obesity, and prematurity. ⁓ You have brought a wealth of expertise in neonatal and infant pulmonary function testing ⁓ about conducting a randomized control trial and ⁓

We're excited to delve into your work about extending CPAP use in the NICU and its broader implication for neonatal care. You've written extensively about this particular topic. One of the earliest papers that you wrote was published in 2020 and was published in the Journal of Pediatrics and is called The Effect of Extended Continuous Positive Airway Pressure on Changes in Long Volumes in Stable Premature Infants.

You recently published in ⁓ the ATS journal another new study called Extended Continuous Positive Airway Pressure and Preterm Inference Increasing Lung Growth at Six Months, a randomized controlled trial. Before we begin diving into the studies themselves, can you tell us a little bit what is the rationale for considering extending

any in this intervention in particular. think that in the medicine, we're always, if we can stop something, we feel like, my God, we should stop it. So the idea to extend C-PAP for a little bit longer can seem to go counter to everything we were taught. Can you tell us what is the physiologic reason behind this? Because there is one.

Cindy Mcevoy (02:47)

Yeah, that is a great question. ⁓ And I agree as neonatologist, when we come in on service, we're always looking as to how can we simplify care? How can we feel like we've made progress with our preterm infants? ⁓

But if you really delve into it, it's very like the even the history of CPAP is very interesting. So, you know, this started way back with Dr. Gregory in the 1970s for preterm infants. And we know that putting patients on CPAP right after delivery is one of the most effective therapies we have to support their lung volume, to improve their oxygenation and to decrease apnean and avoids intubation and decreases ⁓ bronchopulmonary dysplasia.

And this is pretty well established, but the question of how long we should keep patients on CPAP is one that we became very interested in probably about 10 years ago at OHSU when we reviewed our practices and realized, we're all doing things differently as to how we're taking patients off CPAP. And as we delved into this more, we discovered really a vast ⁓ amount of literature already available on

the potential physiologic benefit of keeping a patient on CPAP and giving them this mechanical distension and how that's been shown in various animal models to promote lung growth and also blood vessel growth and capillary growth. And that really was the impetus for the first study that we did in 20, that we published in 2020 that

You know, if a baby's in, there's also much evidence, you know, we know if a baby's in utero, they're going to have fluid filled lungs that causes mechanical distension, you know, all the way up to delivery. And the importance of that in the face of let's say oligohydramnios or patients with congenital diaphragmatic hernias, where there's an encroachment on the lungs early on and it impairs lung growth and lung development. So again, there's quite a bit of physiologic literature supporting

mechanical stretch and its importance to promoting long growth and development.

Ben (05:05)

Yeah, in a recent article you published in seminars in perinatology called Extending CPAP in stable preterm infant to increase lung growth, you mentioned an example that should resonate with most of us, which is the prenatal management of congenital diaphragmatic hernia, where by just keeping amniotic fluid in the lungs, preventing the collapse of the alveoli will lead to better lung development. And so the idea of fostering, nurturing these mechanical receptors, these mechanical stretch receptors,

throughout distension is a mechanism that we know has worked in other settings as well.

Cindy Mcevoy (05:40)

Yes, and after let's say a pneumonectomy, there's also an increase in lung volume that can occur in compensation. So we know again, the mechanical stretch forces are very powerful.

Ben (05:53)

So this original study that you published in 2020 was the results of patients you had recruited between 2014 and 2016. Can you tell us a little bit about the idea of extending CPAP, I think makes sense. But one of the big questions that people can have is while a patient is being maintained on CPAP,

What are some of the stability criteria? What are some of the ways in which we can assess that they're doing okay on CPAP? And how were you guys deciding about who goes in which category and is CPAP the adequate modality for their support?

Cindy Mcevoy (06:37)

When we did that study, we reviewed the literature and used respiratory stability criteria that had previously been published in other studies that had looked at weaning patients off of CPAP. So we looked at the infant's respiratory rate. We wanted them to be on CPAP of five and Rumeir consistently. They had to be tolerating cares, which we did every three to four hours when we take the patients off of their CPAP and make sure that there's no nasal trauma that's occurring.

⁓ Also, their rate of retractions, if they had any retractions. So we had ⁓ a of respiratory stability criteria that we used to decide when these infants were ready to be stable and ready to be randomized in that initial trial. And that's actually the stability criteria we used in our subsequent study also.

Ben (07:28)

That's right. these stability criteria were that we're using a CPAP of four to five centimeters of water, no oxygen requirement, you mentioned, a respiratory rate less than 70, retraction score of one or less, less than three self-resolving apneic episodes and or bradycardia and or desaturation per hour for the last six hours. An average saturation above 86 % for at least 90 % of the time over the past 24 hours and not being treated for PDA or sepsis and tolerating

time off CPAP during routine care for up to 15 minutes. And while these might sound like stringent care criteria, I think that what it highlights is that when we're talking about extended CPAP, we're really not talking about babies that need the support, right? mean, because obviously that is not really a question about providing the best level of support to the babies that need it. We're talking about babies in which weaning is definitely on the table in which we make the conscious decision of extending the care for an additional two weeks.

Cindy Mcevoy (08:23)

Correct, we're talking about stable preterm infants who are basically convalescing where in times past or depending on what your unit paradigm is, you would be considering taking these patients off of CPAP. Because at this point in their care, when we put CPAP on, let's say in the delivery room or immediately after birth, we're really trying to support their FRC and stabilize the infants. When we're looking at how long we're gonna keep the infants on CPAP, they meet these stability criteria.

but we want to extend the therapy more to promote lung growth. Stay with us. We'll be right back.

Ben (09:01)

This episode is proudly sponsored by Reckitt Mead Johnson. Reckitt Mead Johnson is dedicated to the research and development of nutrition products that help support baby development at every stage, including an extensive and female portfolio for premature and low birth weight infants. To learn more, visit hcp.meadjohnson.com.

And one of the aspects in which you have a lot of expertise and which is related to the outcomes of ⁓ these two studies is the measurement of pulmonary function testing ⁓ in these infants. And so for those of us, I mean, I have asthma, so I've gone through pulmonary function testing. I think it's very different. ⁓ I mean, it's not very different. That's not really what I meant to say, but the way ⁓ we measure the same things, just the way adults would undergo pulmonary function testing is very different from the way a baby would undergo pulmonary function testing. Can you tell us a little bit about

What does that look like and how do we actually measure pulmonary function in a neonate in the NICU?

Cindy Mcevoy (10:00)

Yeah, great question. So I became interested in this when I did my fellowship. I was lucky enough to have a mentor that was a trained neonatologist and pediatric pulmonologist. So I had access to a pulmonary function machine and that's where I first learned how to do a pulmonary function test in the nursery. And as I progressed in my career, now I've learned how to do a pulmonary function test in infants, which is also very challenging and now preschool and school age. So I'm going the whole spectrum because

very interested in looking at pulmonary function trajectories, which is important. And so in the nursery, obviously, and in infants and even preschool kids, you can't tell them, take a deep breath and blow out as fast as you can to measure their force expiratory flows. So particularly in the nursery, all of the techniques are based on passive techniques. And up to about 44 weeks of corrected age, we can usually get the baby in a quiet sleep. We want them in a quiet sleep. We want very

⁓ control conditions as much as possible in the nursery. We want them supplied when we're doing the testing. And so the measurements we primarily make in the nursery, you look at their flow volume loops, which sounds very simple, but actually can give you a lot of ⁓ very important information and also are very difficult to do because you want them to be quiet. You want them to be consistent. You can look at

The full volume loops are respiratory and expiratory shape except for looking for obstruction and what their tidal volume is. Then we can also measure their passive mechanics so we can measure their passive respiratory compliance and their passive respiratory resistance. Again, they need to be quiet and ⁓ not be extremely tequipnic to be able to get this test done. And that gives us an idea of how compliant or ⁓ how much volume we get.

of per change in pressure and that gives us also very important information. And then we also measure their lung volume. ⁓ And in the nursery, we do that measuring their functional residual capacity, which is the amount of air in the baby's lungs at the end of a normal expiration. And we do that with the nitrogen washout technique ⁓ where we give them ⁓ supplemental oxygen for a very short period of time where that washes out their nitrogen and then we're able to measure their lung volume.

have done this for a long time, so we get very reproducible numbers. With that, ⁓ we find very useful, so we do lung function testing in the nursery both for research, but also for clinical care.

Daphna (12:28)

Thank you for ⁓ highlighting those parameters. I was also very interested in the respiratory questionnaires that you're administering. I think in the NICU at the bedside, we have this sense ⁓ that these babies have like a reactive airway type of phenotype. so it was interesting to see how you all were assessing that over the first year, if I'm not mistaken.

Cindy Mcevoy (12:55)

Yeah, we did actually monthly questionnaires in our most recent study. ⁓ and we based our questions on the Isaac, ⁓ child and adult respiratory questionnaire. And so basically asked about, the parent about any, ⁓ new episodes of wheeze, any costs or calls, whether there was a healthcare provider diagnosis of diagnosis of wheeze, whether they were actually prescribed any medication. So bronchodilator.

or corticosteroid, whether they actually went into the emergency room for visits. We also try, as you're mentioning, the phenotypes and the endotypes of premature babies, I think is still a very active area of investigation. And we know all preterm infants, even babies just less than 37 weeks, so I always laugh that, when I'm rounding in the nursery, those babies are doing great.

But all preterm infants have altered lung development and are at risk for subsequent respiratory disease as they age. And there's pretty good evidence that being preterm is a risk factor for the development of chronic obstructive pulmonary disease as these children age and become older. And I think looking at the phenotypes and trying to determine, is there an atopic element, which we also ask about ⁓ ATP and allergies in our respiratory questionnaire.

⁓ And trying to really fine-tune what the phenotype is ⁓ of the premature infant is still a very active area of investigation.

Ben (14:24)

And so ⁓ talking a little bit about ⁓ the intervention itself, ⁓ you randomized babies ⁓ over these two studies to either discontinuation of CPAP or extension of CPAP support for a duration of two weeks. And obviously before, up to before discharge. I want to make sure that we clarify something, obviously that these two studies that we're talking about.

may somehow sound like the continuation of one another, but there are actually two separate studies. so the baby studied in the original paper of 2020 in Journal of Pediatrics is one cohort and the study published more recently a couple of weeks ago in the ATS journal represents a separate cohort. Can you tell us a little bit about was that just done out of necessity or was it just...

to tweak maybe some things in the protocol or why not just continue to study the population you had originally looked at.

Cindy Mcevoy (15:27)

Yeah, great question. So our first study was more of a pilot study feasibility study to see if we were able to consent the subjects into the study and to randomize them to the two extra weeks, which we based on actually ⁓ an animal study in ferrets that had randomized ferrets to two weeks of CPAP versus ⁓ two weeks of basically no CPAP and shown.

that at the end of one and two weeks of therapy ⁓ in this animal study, there was significantly increased lung volume or total lung capacity in the animals who had gotten the two extra weeks of CPAP. But when they looked at the ⁓ other lung function tests, they looked at the compliance and the resistance, there was not any change between the extra CPAP and the no CPAP, which seemed to indicate that there was actually lung growth and parenchymal remodeling.

So that's how we picked the two weeks ⁓ of CPAP for our first study, which we also did in our second study. And we were really excited when we showed that ⁓ when we randomized the infants, we did a measurement of lung volume in the nursery. So functional residual capacity, FRC. And so we measured that right when we randomized them, then at the end of the two weeks of treatment. And then we measured again before they went home.

And we were able to demonstrate that the infants who were randomized to the extra two weeks had significantly increased FRC at the end of the two weeks. And then at the end of the two weeks of treatment, everybody came, was off their CPAP then. But then when we measured them again at the, before discharge, and so it was probably about two weeks after everyone was off CPAP, the patients who had gotten the extra CPAP had an even greater FRC compared to those that came off. So it seemed like that the, it seemed like those effects

persisted just from that extra two weeks of CPAP that were initially given. So we were really excited about that, but unfortunately we're unable to follow these patients after discharge because I had a pilot study, a pilot grant. And as we thought more about it, we really wanted to see like the lungs were bigger, but did it persist number one through six months of age. And ⁓ in the nursery, we can't measure, do measurements of lung, of ⁓

lung diffusion capacity, DLCO. So were the lungs bigger and did they work better and did it persist after discharge? So that is, ⁓ at that point we put in for another NIH grant, for an NIH grant to randomize another cohort of patients to do a very similar protocol in the nursery, but be able to follow the patients after discharge and actually measure alveolar volume and lung diffusion capacity and also

force expiratory flows, which is a measurement of how the airways are working when these patients were infants at six months of age. And then also get our respiratory questionnaires through 12 months of age.

Daphna (18:27)

And then I actually have a question about in that the first cohort, it wasn't that like they had more lung growth and it stayed proportionally bigger than the group who, you know, had a discontinuation early. It's almost like it continued to grow even off of the CPAP, which is really cool.

Cindy Mcevoy (18:49)

Yeah, I mean, that is a great observation that you're mentioning also. So we were one, so that also made us wonder like, there genes that are also being turned on during this time? And was it, you know, another question is, is it just two extra weeks of CPAP or is there a critical post menstrual age when we're administering this extra mechanical stretch that is really stimulating not only lung growth and development, but potentially other epigenetic changes, et cetera, that might be.

affecting other organ systems.

Ben (19:20)

The difference was actually quite striking at two weeks. It's about 50 % increase in FRC. If we're looking right at the time of discharge, it's now 60 % increase. So definitely something pronounced. I want to ask you a little bit about the practicalities of this approach and the translation at the bedside. Speaking to colleagues, I mean, think that it's one of these interventions where it seems that there's

an appetite for this particular intervention. I see a lot of colleagues, both locally down here in the US or even abroad who are picking up on this and extending their use of CPAP in babies that are at high risk of chronic lung disease. And for most of us, ⁓ think what I've seen is that it looks like people keeping babies on CPAP until about 32 weeks of gestation corrected. ⁓ what I wanted to ask you was that in the studies themselves,

the ⁓ post-menstrual age at the treatment allocation is usually on average 32 weeks. And so my question to you is, what is your perspective on the practice that, for example, Daphna and I in our unit currently have where we keep babies on until 32 weeks versus potentially even looking beyond that and say, well, maybe we should keep babies on CPAP until let's say 34 weeks. And what are some of your thoughts specifically also on

feeding because I think that this is a big issue. know that you've looked at that through these two studies.

Cindy Mcevoy (20:53)

Yeah, great question. So in both of these studies, the patients met our predefined respiratory stability criteria. In the first study, it was about 32 weeks post-menstrual age, and the second study was a little bit more, 32.4. So at that point, we randomized them. So half of them stayed on the CPAP for two more weeks, till about 34 weeks and a few days.

⁓ And so I can only speak to the results of this study, which was a single center trial because we did very sophisticated pulmonary function testing as our physiologic outcome. And ⁓ so in this study that improved their pulmonary function, we did not see any differences in the time to first feeding or in the time to full feeds or in the length of stay in either of these studies between these two groups. And of course, know, CPAP is a very common therapy and it's very important to

do it well, whatever system you use, and we use bubble CPAP. So part of the results also could be due to the very specific system we used, as well as to the fact that we use chin straps to optimize the delivery of the CPAP and increase the transpulmonary pressure basically that the CPAP is giving. In our experience, when the patients were randomized to the two extra weeks and came off at about 34 weeks in a few days,

The infants, our infants were not showing a readiness score to start, you know, effective suck and swallow and nippling. But of course, this is always something that needs to be considered if it's going to affect when the babies first start nippling and their ability to get to full feeds. But we didn't see any differences in these two studies in those outcomes. I should also mention that we did a ⁓ study out, we have a primate research center here.

in Oregon, so I collaborate a lot with one of my ⁓ mentors out there, Dr. Spindle, and we actually did a study randomizing preterm non-human primates to CPAP versus sham CPAP. And we administered the CPAP to the patients out there, and it was just like a mini NICU out at the primate center. And we administered ⁓ the CPAP with Hudson prongs, and it was bubble CPAP.

so half of the primates got the bubble CPAP, for 12 hours a day for nine days. And half of them had the prongs in place, but did not get any CPAP. And we can only do it for 12 hours a day because unlike our little preterm babies, the preterm primates have long arms for a reason, which is that they were always pulling the CPAP out no matter how we tried to swaddle.

Daphna (23:31)

And we thought we struggled to keep CPAP

Ben (23:35)

Yeah.

Cindy Mcevoy (23:36)

And so we had to sedate them. so, you know, ethically, we know we only would sedate them for 12 hours a day. But we did this ⁓ out there for 12 hours a day for 10 days. And we were able to demonstrate that CPAP administration to the preterm primates significantly increased the number of alveoli we were able to count on stereology. And there was also a trend for improved pulmonary function in those primates that got the extra CPAP.

which didn't meet significance because of the numbers, but again, like a very strong translational premise, again, supporting the fact that ⁓ CPAP ⁓ improves lung growth and development.

Daphna (24:19)

⁓ Thank you for that. wanted, before we get too far away, ⁓ to ask some more feeding-related questions because I can anticipate there are people sitting in their car saying, about this? And ⁓ my first question, I have two questions. My first is you talked about how you guys use a chin strap kind of routinely. And you do talk about in that seminar's paper about one of the potential adverse effects of CPAP is this phenomenon of CPAP.

belly and does it, is it interfering with our feeding tolerance? ⁓ What was the experience like for you in that regard?

Cindy Mcevoy (24:59)

So in both studies, monitored for any adverse events, looking for feeds being stopped because of feeding intolerance. And we didn't show any differences between the two groups. And I actually have a ⁓ former fellow, now junior faculty here, who looked at our last 30 patients in our most recent randomized study. And during the 14 days of therapy, we had a second pulse oximeter that we would put on the patients, which would collect

the pulse oximetry data very granularly, every seconds. And we had the face covered for the nurses and the alarm off of the second pulse oximeter, so they didn't see what it was picking up. And we were able to really quantify very carefully the episodes of hypoxemia that the patients were having between the two groups.

When she looked at the last 30 patients looking at these episodes before feeds, during feeds, and after feeds between the two groups of patients. And interestingly enough, the patients who stayed on CPAP during and after their feeds actually had less of the episodes of intramet and hypoxemia to less than, we picked 90 because that's, saturation is less than 90 for at least 10 seconds because that was the primary outcome from the pre-vent study that.

correlated with subsequent neurodevelopmental outcomes. And so we were very interested to see that staying on CPAP, patients who stayed on CPAP actually had less of these episodes. So I think ⁓ that dismisses kind of one of the old wives tales that it increases episodes of intermittent hypoxemia or desaturations.

Daphna (26:40)

interesting.

And you ⁓ indicated that you guys use a feeding readiness scale. I wonder in your unit if babies are still on CPAP and they are showing signs of feeding readiness if you're feeding on CPAP.

Cindy Mcevoy (26:54)

We are not currently feeding on CPAP and that of course is a great question. I know there are some units that do feed on CPAP. So we're currently discussing whether we would consider feeding on CPAP. But again, if the infant is on extended CPAP for lung promotion and the infant is really showing feeding readiness ⁓ signs, we're also going to attempt to... ⁓

So when the patient's doing CPAP care, they can go ahead and try to do feeding.

Ben (27:29)

Very interesting. ⁓ Dr. McEvoy, looking at the paper that is recently published in ⁓ the ATS journal, I'm wondering about if you could tell us a little bit about what you ended up, what are the main takeaways from the findings of this specific study, considering that it now includes a pretty much you've doubled each arm of the study here, going from about 20 plus.

babies in each arm in the original 2020 study to close to 50 plus babies in each arm for this follow-up study. When you are looking at some of the pulmonary function testing longer into the future for these infants that are randomized to Extend CPAP.

Cindy Mcevoy (28:14)

Yeah. Well, thanks for that question. think I'm really proud of this study because we did it during COVID. And so it was very challenging, ⁓ you know, for the parents and, and for my staff, et cetera. So we met our sample size and, know, have a very positive results in terms of the physiologic findings of, the patients who got the extra C-FAP for the two weeks have increased alveolar volume. They have increased lung diffusion capacity.

And they also have improved force expiratory flows. So we improved their parenchymal function, but we also improved their airway function. And when we did our respiratory questionnaires through 12 months of age, there was also less wheeze reported in the patients who got the extended CPAP, even though it was not significant, but we weren't powered for that ⁓ outcome. And so with this group of patients, I think it's very important to continue to follow them to see if the results still persist.

So I'm very interested in looking at lung function trajectories and early interventions we can do to help improve where an infant sits on their pulmonary function curve. Because if you start lower, you tend to stay lower on your pulmonary function curve, and you tend to be more prone to respiratory disease as you age. So if we can bump that up initially, hopefully we can improve their lifelong lung function outcomes and respiratory outcomes.

So importantly, I'm hoping to continue to follow these patients so we can do continued follow-up of their pulmonary function so we can see if these benefits persist in terms of their force expiratory blows. So take a deep breath in and breathe out as fast as you can, which is definitely linked to wheeze and ⁓ potentially subsequent chronic obstructive pulmonary disease.

And then also we're very interested not only in getting a physiologic outcome, but potentially doing a very low dose CT scan so we can actually quantify their airways and quantify their lung vime. Cause we always say a picture is worth a thousand words. And I think that would be again, very supportive of where we're actually able to show structural improvements. And then looking at whether in these patients trying to really endotype them to see if we can determine

As we, as we had touched upon earlier, you know, do they have reactive airway disease or what is their endotype that causes them to have increased respiratory disease? So we could come up with a more personalized approach. So that's the thought we have with this current cohort, but of course this is a single center study. And, you know, we're very optimistic about these initial results, but I think a larger pragmatic study is needed to.

⁓ see if these results are generalizable. And also we wanted to have about 50 % of our patients be less than 29 weeks that were randomized and half be 29 to less than 33 weeks. But the smaller patients didn't meet the respiratory stability criteria we had outlined before our cutoff, which we had set at, ⁓ 35 weeks of post-memorial age. So I think a larger study where that would be able to recruit potentially smaller patients.

to also see the impact of extended CPAP on their course in the nursery, but also longer term is needed.

Ben (31:39)

Talking about a picture being worth a thousand words, think I want to commend you for the figures in both papers and even in that seminars in perinatology. are amazing and they are very... ⁓

Daphna (31:52)

And a wonderful background, I think, for people to really go and learn. I hope everybody will go and take a look at that.

Ben (31:59)

So I wanted to ask you very practical question because I have the benefit of, have worked in two places where we've practiced this, we've had this practice of extending CPAP. The first place it was already adopted before I even got there. So I had, I just took it on and it was great. And the first and the second one where we're at now has been very well received by the staff. But what is your advice when it comes to implementation?

What would be your approach in order to be collaborative and do this in a multidisciplinary way so that you can calm the potential critics that might say, oh, why are we doing that? And what is this now?

Cindy Mcevoy (32:43)

Yeah. I think it goes back to the physiology and, and, ⁓ presenting the literature on the benefits of mechanical stretch on lung development, the in utero benefits, you know, whenever I was talking to parents to, ⁓ potentially enroll their, their infant in the study, that was always very powerful to talk to them about, if your child was still in utero, your, your, your baby would have fluid filled lungs and their

you know, that promotes lung development. So that's what we're mimicking with this therapy of extending, extending CPAP. And of course, you have so many shareholders or shareholders basically involved in making ⁓ a clinical study or translational study successful. have, you know, you have your own research staff who has to understand and be

excited about the study. have the parents, but you also have obviously all of the physicians taking care of the patients, neonatologists, and the bedside caretakers. I think just a lot of education ⁓ and encouragement and really rolling out the study well ⁓ will promote success in doing a larger trial.

Daphna (33:56)

Yeah, and speaking to how well the study was done, I think you have such an array of respiratory parameters. I think that's really valuable for the community, especially as a future jumping off point as we move forward. And I guess that brings me to my one of my last questions is, two weeks enough? Where do we see the, is there anything in the animal data about the fall off where we're no longer getting benefit?

Cindy Mcevoy (34:26)

Great question, I'm not sure we know. I think that that requires more study about the duration and maybe the optimal post-menstrual age that it's administered. And again, endotyping the patients who might respond, again, best to the therapy and the intervention and what the duration would be.

Ben (34:46)

Dr. McEvoy, thank you so much for joining us and for sharing your thoughts on these beautifully designed and executed studies. ⁓ Any parting thoughts for our listeners as we conclude this interview?

Cindy Mcevoy (34:59)

Oh, I just encourage everyone to find a passion. You know, I really enjoy clinical translational research and I think so important to take things from the bench to the bedside so we can really directly impact patient care and creating the paradigm in your nursery or wherever your healthcare setting is of involving the parents, you know, as shareholders in the study and getting them excited about participating in

in these type of trials so we can make progress.

Ben (35:30)

Yeah, what a nice piece of advice because I think that sometimes we read a lot of the clinical studies, but it's by going back to the physiology that sometimes we can identify mechanisms that can lead to a pretty much of a breakthrough on the clinical side.

Cindy Mcevoy (35:42)

I think sometimes the simple breakthroughs are the best. Just extending a therapy we're already using is very exciting.

Ben (35:50)

I agree. I agree. Thank you so much for making the time to be on with us. This was a great conversation and congratulations on this body of work.