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PNG Conference: The post surgical neonatal: to feed or not to feed. An update of ongoing randomized trials

Results and outcomes described are anecdotal and specific to the institution and its protocol. For a list of published studies of EHMD, click here.

Learning Objectives:

  • To understand current feeding approach for infants with abdominal wall defects and intestinal disease
  • To review current evidence in nutritional management for infants with congenital heart disease and diaphragmatic hernia
  • To learn about on-going randomized trials and cutting-edge research for the management of surgical neonates

Speaker:

Cynthia Blanco, MD
Professsor of Pediatrics and Chief, Division of Neonatology
Director, Neonatal Nutrition and Bone Institute
UT Health San Antonio, University Health System


TRANSCRIPT:

I would like to thank the organizers for inviting me today to speak about the postsurgical neonate and how to feed these infants. I am honored to be here today.

I have some disclosures: I have received some financial support from Prolacta Bioscience to conduct a randomized control trial and infants with single ventricle physiology. And I'll be speaking a little bit about that trial. And I do not receive any other financial support as a speaker and do not belong to any speaker bureau.

So the objectives of today will be to understand some of the current feeding approaches for infants with abdominal wall defects and intestinal disease. We're also going to review the evidence in nutritional management for infants with congenital heart disease and diaphragmatic hernia, and we're going to learn about some of the ongoing randomized control trials.

So abdominal wall defects continue to affect many infants every year on ompaloceles and gastroschisis are the most common defects that we encounter. With now gastroschisis being the most common defect with a data show in about one and 6000 births.

The complications from gastroschisis, we all have seen those bowel loops are thickened, adherent, or shortened sometimes. A lot of the times the main issue will be that they are inversed or atresias. And those are common and need to be taken into account for these activities in the future. We have to understand that that intestinal dysfunction will take much longer to normalize, if it's in combination with atresia or infarcted areas. And normally, it will take about six weeks, but it could take up to several months. There's really not a lot of data on how to predict which one of the infants will develop more dysfunction than others. And unfortunately, it's more of a trial/error. And you have to try to feed those babies and later you're going to learn if the baby's going to have significant complications or not. With the exception, of course, as I mentioned, if they have atresias, you also have to take into account other complications. For example, if your baby has IUGR, prematurity, is SGA, or has other associated anomalies. Of course, those are going to complicate the course of any baby with gastroschisis.

Omphalocele: you know the rupture of the defect will be increased the risk of complications because then that intestine would have been exposed to a amniotic fluid. But also, as we know, omphalocele runs with a lot of other complications, like they can be IUGR, they can have prematurity, but they can have a lot of other anomalies. And some of the most important one will be cardiac anomalies, but also genetic syndromes. So those are the complications that are going to occur in omphalocele more frequently than with gastroschisis.

And the survival of the babies with these kinds of defects has increased significantly since the 60s to over 90% currently. And of course, it's probably secondary to the improvement in management in the NICU care. And the long-term morbidities continue to be related mostly with intestinal dysfunction. So in your program, you have to take into account if you have a shortcut program, or intestinal transplant in order for you to truly evaluate those babies are the sickest of the sick is that come to your center and how do they do with long-term morbidity.

The intestinal inflammation may incur with either one of the defects. And, again, the degree of normal appearance is dependent on the extent of inflammation, but that really, you know, the way that it looks like in general is not going to be very accurate on how that baby's going to do long term. You can look at histology after, you know the surgeries repaired the defect. But the atrophy of the myenteric ganglion cells may be patchy and maybe in different areas and not completely and the entire intestine. And that's going to play a role into the dysmotility and the transit time. But then also you have to take into account that babies that have intestinal disease will have potentially decreased absorption capacity. So if your baby's not growing despite of providing a good amount of enteral calories and you have to start thinking about doing additional testing to evaluate the absorption of carbohydrates, fat, and protein.

So when do you usually start the feeds on this baby's? Sometimes I just say, easy when intestinal motility returns. But how do you determine that? In general, you can initiate trophic feed as soon as the gastric output decreases, because then that tells you that those babies are able to tolerate passing that gastric juices down to the rest of the intestine without the gravity suction. Because if you can't even do that, then you're not going to be able to even get your trophic feeds pass the stomach or the jejunum.

The omphalocele patients usually start feeds as soon as possible, and especially if they're not ruptured. But just think about, you know, starting feeds and minimal enteral feeds should always be, you know, consider every day in half the questions like is there a reason why I cannot feed this baby today. If you don't have any motility established whatsoever, for example, you have not had a single stool. If you have emesis, or you continue to have a lot of gastric output, it's going to be counterproductive if you're trying to push those feeds. So you have to take those three main things into account in order for you to be able to be successful with feeding.

In regards to what type of feedings Of course, mom's milk will always be the best. And that's what I will recommend to start all babies. And if that is not available, you can utilize regular formula. Or you can decide to go to semi-elemental or elemental formulas, depending on your practice, because about 20% of the babies will have protein milk allergy. In our institution, we if we don't have enough breastmilk, then we will do a regular formula to make sure that if that baby's on the 80% that can be tolerated in a normal formula, then that will be a good trial. And but if the baby has like short bowel, lost a lot of the bowel, or has atresias in significant segments of the bowel that were lost or had to be salvaged in re-estimates, then we will probably go to donor human milk if the breastmilk, mom's milk, is not available. And why is that? There's some retrospective data that has been identified where babies that were fed exclusive human milk had shorter time to full enteral feeds.

And this article that I'm going to show you some of the data. You know, they look at the different percentage of human milk, you see from the columns left to right. And the babies that receive 100% of human milk, regardless if it was moms or combination moms had similar characteristics and the other babies received less amount on the columns towards the right. And I'm going to look through just mainly the vaginal delivery or the primary closures. That has not been shown that it really affects intestinal motility anyway, but you can see there that they're pretty similar in between all the different groups. Where it was a little different is the birth weight, you can see that the babies that were receiving more than 50% of human milk were a little larger than the ones that were receiving less than 50%. And the age of initiation of feeds was sooner on the babies that were receiving mostly human milk, like 100%, it was 14 days versus those that were not receiving a human milk were initiating feeds at 22 days.

And then lastly, you can see the outcome measures that they had those babies that were receiving more than 50% of human milk had less days to get to full feeds, decreased length of stay, and their median days to discharge was sooner. This is like of course first attempt, right? Those babies that were on this spectrum of the best outcomes. This was not taking into account those babies that failed and had multiple episodes feeding intolerance.

So there were some other studies recently that have looked at like, you know how fast we advance baby's postoperatively. And they had some implementation of guidelines. And it's always good to just have a guideline in your unit, with infants with a primary diagnosis of atresias, gastroschisis, NEC, and volvulus. And again, this study was also looking at the first surgery and the first attempt of feeds to provide guidance.

So what did they implement in this study? The feeding guideline, you know, implemented at greater initial post of enteral nutrition volume, that we're doing less than 15 mL per kilo per day, and they implemented to go to 15 to 20. And the rate of feeding advancement if there was no science of intolerance, to continue to go by 15 to 20 mL per kilo per day. The type of milk and the guideline was breastmilk to include donor milk and was the preferred type, but formula can be used.

And what they've found is that the proportion of infants with intestinal failure after the implementation was actually improved. And you can see on the graph that weeks to resolution on those babies before and after the guidelines, and you can see on the lighter grayed, shaded area, they had less proportion of infants with intestinal failure over time. And again, this happens quite a bit when you introduce a guideline. And it might be the guideline itself, that is the one that produces the effect of getting, you know, shorter time to acquire for feeds or that there's less variability in between physicians and providers to get to the goal of ensuring a full volume feeds.

So what about this very, the severe be the biggest with severe intestinal failure? There's really minimal guidance of what to do once these initial steps fail. And that usually happens on babies that have ultra-short gut, pseudo-obstructions, intestinal failure, which usually is define of greater than eight weeks of inability to advance to full feeds. And those babies that fail to attain full-volume feeds after two trials, by a team with intestinal failure or short bowel syndrome.

So in our institution, we adopted this definition. So then we can go by and once we defined these babies, then we have a multidisciplinary team approach and protocol for these babies. So if an infant has intestinal failure, in general, those babies don't have a history of GI surgery. And the main event will be this motility or feeding tolerance. If they do have surgery, then they have lost minimum and about and those babies that have short-bowel syndrome are the finest those that have GI surgery with a significant portion of the bowel was resected. And those babies that are less than 20 centimeters of bowel left are classified as ultra-short.

So our protocol when we were in the process of submitting for publication, is that we developed this bowel rehab protocol in 2016. And it was based on data collected from within 43 patients that we had in our unit with short-bowel syndrome and intestinal failure. And we have a guideline on when to initiate enteral feeds, how to do oral care, the feeding time, the approach, if somebody uses bacterial overgrowth or not, defeating advancement regimen, the PR advancement, how do you transition from continuous to policy to if you're using continuous? And how do you transition to formula if you need to? So having a protocol as such in your unit is key. So then everybody knows on these particular babies that are very, very difficult to manage, what are the next steps? How are we going to do this as a group and try to agree on an approach to include the surgical team, the GI team, the neonatal team, and the dietary team. And so then it decreases also what I call the schizophrenia of like feeding difficulties in the unit and that also provides a guidance for our parents of this very difficult babies.

So I'm going to share a few of the babies that we have been very successful on feeding with this type of multidisciplinary approach and guidelines. On the top, on the photo that is labeled A, you can see a baby whose charm with pseudo obstruction. At the start of the protocol, you can see how dilated that bowel is, the patient is intubated. And at this charge, this took months to rehab that bowel. But you can see that that bowel can be rehabbed, even though they had significant pseudo-obstruction. And this baby had been told by multiple facilities that the baby was not going to survive. The baby ended up with a trade because of like lung disease, but bowel was able to eventually be completely rehabbed. And then other baby that we have on the bottom left, it's a term baby with gastroschisis, multiple intestinal surgeries, no ICV valve, IVC valve present. And the bowel length was less than 40 cm with severe dysmotility. And this baby had dilation of the bowel, which you can see on film number c, and are labeled as C. And then you can see on D, the baby's bowel is much more decompressed. And the baby at that time was tolerating larger amounts of feeds.

So those are the type of babies I'm talking about with severe intestinal disease and short-bowel syndrome. And even though this looks very complex, it kind of like you know, in our multidisciplinary meeting, having this guideline, and going through and going back and you know, when we're deciding what to do with the babies going back to what did we say we were going to do. And looking at the initiation, the feeling tired, the feeling approach, the feeling protocol, the bacterial overgrowth, the initiation of feeds, and reviewing the literature constantly and updating this protocol. It's something that has led us to have a better approach for these babies and being able to rehab babies that are very difficult.

So in regard to initiation of trophies, and we're just going to go through some of those boxes that I showed you in a larger slide, so we can see it better. Usually, we have to wait until the bowel dilation improves, and until the output decreases, usually weight is less than 20 mL per kilo. In some cases, some of the babies that have a hypersecretory face, we may start even if they're like a 30 mL per kilo of OG output, but usually we wait until they decrease significantly and that is non-bilious. So then you can actually ensure that that feeding is going to go down in the intestinal tract. Usually we wait for at least 24 hours of having that orogastric tube in gravity. And if tolerated, then we initiate the intro feeds.

And sometimes we just have to be patient to wait until that happens. The feeding type again, we initiate with breastmilk and donor milk. And we do not use any dilution of any of the feeding types. So and that's why I underlined that non-diluted elemental formula because it seems that in some areas, there's still some practice of dilute diluting the formulas or even the breastmilk, which does not ensure you a better tolerance be just decrease the amount of calories which is something that I do not recommend. The feeding approach, so in the babies that have significant feeding difficulties, and they already failed multiple times, we go for drip feedings, but a modified drip feeding to try to allow at least 30 minutes of 30 minutes to an hour of not having a feeding in that intestine to promote secretion of gastric content and to promote a more like normal GI tract health by not having a constant refeeding. And then the part of venting the G tube is critical for those babies that have zero obstructions or that has significant bowel dilation. Because over time, it seems that with that approach, we've been able to get that bowel slowly to decompress and we continue with this regimen until the bowel dilation improves. And we can drip for like you know a longer period of time. But always have a period of time where you don't have that drip feeding when you clamp the G tube and 30 minutes of venting that G tube if your bowel continues to be dilated.

And the feeding advancement would have several different approaches if the baby has significant intestinal failure versus if it's short-bowel syndrome, or if the baby has ultra-short, we will always feed but the amount of feeding, it's lower on those babies with ultra-short. But by going with lower volumes and smaller advancement on those babies, we've been able to rehab some of those infants to get to be independent of TPN, or at least get 50% of the enteral feeds that they were supposed to get on babies that have, I'm talking about babies with only jejunum or babies that have seven centimeters of bowel, 10 centimeters of bowel.

And when do we initiate the PO fees or the PO intake and to make sure that those babies do not have severe oral version, it's almost impossible to not have any oral aversion. This baby said you haven't fed for months. But we try to initiate it once they have achieved a certain amount of volume. And we try to go by the amount of bowel that is remaining. Why? Because we believe that having that extra bolus of feed, if you have an ultra-short bowel, and you provide on top of the under feet of bolus feed for the pill and it's very large, then you're probably going to cause some dumping and you're not going to get up on your total volume that you're trying to achieve. So these are like the guidelines that we have made for our own place. And it's usually kind of like one hour's worth of volume that we initiate for the PO intake in general. And we just wait until that volume is, you know significant that you can actually have a PO feed with that with that one hour's worth of volume. And again, on those babies that have significant dilation that we wait until they're tolerating a larger amount of volume to start the PO feeds, like about 10 miles per hour.

So again, just another patient that I would like to share with you this baby had 17 seven centimeters of dilated jejunum that was sent to us for bowel rehab and had had months of attempts of feedings and were not able to decompress that dilated bowel. And with the feeding regimen that I just talked about, we were able to decompress that loop about and able to feed this infant slowly, but we got to almost full enteral feeds.

So what else do we have problems with these babies as they continue to survive? And we have seen vertical itis percent in these babies in the present late in the disease process not as early as we would think. So again, there's new issues that are arising in this population.

And I will go through this severe allergic colitis, which it's more related to the use of eosinophilic infiltration at the local level in the lamina propria in this surface of the epithelium and also on the crypts. So a lot of the times we think about it as it will cause like generalize using affiliate and that's not the case it will be local in the intestinal area.

So the traditional approach that we've had for allergic colitis is that we only think about protein milk allergy, which is the first approach and that's completely appropriate and we will go from semi-elemental to elemental formulas, or if we we’re on breastmilk, then if they still develop allergic colitis will end up with elemental formulas. But again, that allergy is not considered very frequently, and I would like to talk about that today.

Just to pay attention on the different formulas. The lipid source comes from various areas, and it is thought that all of them could be potentially allergenic and one of the ones that it's the least allergenic, it's probably canola oil. So pay attention into which ones are you providing and how much of each does each one of your formulas have. And perhaps taking into account if you have a patient that develops allergic colitis. And we've had several babies with severe intestinal failure who developed this disease, while receiving feeding with elemental formulas, because we got to the point where breastmilk was no longer available, and we have to transition to elemental formulas, or they It was never available, and we ended up with elemental formulas. These babies were evaluated for IV fish oil. At that point, because of the severity of the liver and intestinal disease. That was when we could not use it as widely available as we can right now, we had to go through an IND. And these patients were confirmed between 2011 and 2015.

So one of the patients with a term baby with malrotation and volvulus and had a resection that resulted in only eight centimeters of viable intestine. So the baby tolerated like about 100 days of human donor milk at half volume before switching to eldercare in preparation for this charge. Because we were not able to provide donor milk as outpatient. And then the baby developed bodies tools.

You can see on the left, we did a colonoscopy, and you can see all that patchy red areas. And it was confirmed by histology that this baby had allergic colitis. And after discontinuing the formula, and we made custom made formula with a different type or with no fat, then you can see how those patchy areas of redness resolved. And the bloody stools, of course, clinically, they resolve as well.

Another Baby, you know an ex-29 weeker with NEC with resection that left only 32 minutes 37 centimeters of viable bowel, the baby tolerated about 95 days of human milk. And then we transition again up and close to this charge on bloody stools started thereafter, which was something that you know we had not seen on elemental formulas.

And as you can see, again, on the left the patchy redness and the infiltrates and we discontinued Neocate. At that point, we switched to tolerance. And we looked at the resulting colitis. And if there's any dietitians, listening to this talk, I'm sure they're not going to be very happy about talking about tolerance, because it does not have that much. It has mostly carbohydrates and does not have almost any fat. And it's not something that I will recommend to go right away because he has I believe less than 1% fat. But if it takes care of the allergy, then you can introduce your fat thereafter,

which is something that we did in another patient. This baby. Patient number three was a 34 week or develop NEC on the 15th day of life and failed with elementum neocate and had bloody stools.

And again, had patchy moderately to severe colitis. We discontinued tolerX and then resolving colitis.

So I'm just taking into account that plant-based lipids should be considered as a potential allergen. And again, though canola oil is plant-based and is thought to have a lot of potential for allergenicity compared to the other derived oils, and you could eventually added into the treatment or you can slowly transition toward a different formula and not remain, of course, on TolerX or the custom made formula without fat. But that is something that you just need to consider and have in the back of your mind that allergy to the fat could happen to the enteral fat.

And these are just a pictures of a couple of the patients that the parents have allowed me to share both of them hand ultra-shorts and have been able to grow and grow well over time and eventually got independent of TPN. And, and I'm very happy that we've been able to rehab patients with very, very short bowel.

So other treatment options is the step procedure. Um, there's plenty of case series that have been reported with pre-step bowel length. If you're unable to feed these babies on how 30 centimeters bowel, they can increase it by 42%. And the enteral tolerance increases from 20 to 60%. But usually the intervention is formed around one year of age. And you have to have a good selection of patients and a comprehensive multidisciplinary rehab team, because we've been able to decrease the number of babies that require these step procedure. Because over time, these babies have been able to tolerate more enteral feeds closer to 60 to 70%, which is the same as the outcome step procedure without having to go back to surgery. So we still do step procedures, but way less than before, and it's less intervention for the infants.

Another thing that, you know, it's very interesting is the de GLP-2 axes. And there's been some recent studies looking at GLP to assess secreted in the terminal ileum. It does slow motility, which that increases the amount of time that you have in especially those babies have that small bowel to increase the time to digest and to absorb. It increases also the messenger blood flow and reduces the enteric secretions. And there's been no thought that the critical innovations of GOP to stimulate the intestinal surface area, what they did in this series is that they look at several babies that had gastroschisis and they drew blood samples at the beginning of their enteral feeds wasn't until feed reached 50% of the calories once they got to 100% of the calories in at the clinic visit at one year of age.

And what they found is that the babies that had less, you know GLP-2 levels or was the word, it took them longer to adapt and to be able to tolerate feeds. So and they those that had a higher level were weaned from parental nutrition faster. They did take samples at the intestinal level for GLP-2 receptors, and the distribution remained the same in between the different patients. So that needs to continue to be studied.

But then, based on this theoretical effect of GLP-2, there's a potential for GLP-2 treatment with tougaloo tide, which there has been a multicenter study published recently, they involved 59 infants, and they had 24-week treatment with two different doses of GLP-2, and the main, you know, purpose of this study was to evaluate safety, efficacy, and pharmacokinetics. And the primary outcome was the percent decrease of TPN at 24 months. So what they found is that the percent decrease in 24 months from two different doses that they utilized was significantly different than standard of care, as you can see on that graph. So that's something that is coming up and that we may have another tool to improve outcomes on these babies. But still, we need to do it in a investigational and prospective study, to see if this is a good aid into improving outcomes of this babies.

Now, I'm going to move on to the cardiac defects. So the main issue with cardiac defects is not as much intestinal dysmotility, but its growth failure. And I've been dedicating, you know, the last five to seven years of my career yo understand why a lot of these babies develop a growth failure. Up to 50% of the single ventricles have this problem in particular, those that have HLH. They have feeding sound challenges, but I think a lot of it, it's also because of the way we approach the feeding treatments for these babies. The feeding type prior to surgical repair is trending more toward human milk (BFPO), and if the baby wants to be old, we allow them to do so. But after the surgical repair, we continue to have sub-optimal caloric intake and also fluid restriction is problem. So there's been some algorithms that have been developed and have been well published. For example, this one is how to feed like pre-op, how to take into account like your hemodynamics is a safety feed and the feed your options that you have.

And this article also they have, you know, an algorithm for feeding PO post-op. And I think that it's very important for us to have these guidelines again, because then it again provides us with a pathway on how to feed this infants. So there's also others that have recently published a consensus-based nutritional approach approach pathway for this infants. As you can see, for example, that the nutrition Care Plan A on the top, the babies are growing well, they're tracking well in the birth percentiles. And basically, they suggest to provide the normal requirements that we'll always do if we have normal fluid allowance, and breastfeeding, etc. But then if you are not growing, well, then you go to the plank here B, or C, depending on what centers you are, depending on what kind of fluid restriction you have. And then you start reviewing these patients a lot more closely. And then you start being very proactive about giving extra energy and extra protein early on, before you start developing growth earlier. And the same thing for like the nutritional care plan C. And this was something that they implement this is a study from Europe. And what they did is that then they looked at before they implemented the pathway, and after they implemented the pathway. And as you can see, on the graph, on the left, you can see the change on weight and z scores, before the pathway on the open white boxes. And after the pathway into dotted boxes, and at four months then it significantly decreased the change on the z score are the negative change, which is good and 12 months, that negative change improve significantly as well. And then on the graph on the right, you can see the babies that you know after the pathway, the event today's decrease significantly, and the PICU length of stay as well. And this is just by implementation, of a pathway and nutrition care, which, again, we should strive for bringing our own pathways into implementation.

What about utilizing human milk preoperatively? I'm Dr Hair, and then look at a retrospective cohort, which is very large of over 500 babies with congenital heart defects. And they hypothesis was that exposure to cow's milk preoperatively would increase the risk of NEC. And they look at all the risk factors if the babies received any feeds, if they went fast on the feeding volumes, if they received any fortification, the cap formula, any that were feeding with a UACs in place.

And what they found in the multivariate regression analysis is that the major factor that decreased the risk of NEC was to provide that exclusive or fortifier human milk diet prior to surgery. And then also the cardiac lesion had an effect of increasing the risk of NEC. But the rest of the other risk factors that they took into account did not seem to have an effect.

So a few years ago, we, it was probably about six or seven years ago, we thought about randomizing babies to evaluate the growth velocity, especially those that had the highest risk of growth failure, which were the single ventricle babies, and to provide them prospectively an exclusive human nutrition, with early food fortification to try to get to the maximum calorie intake that they will require in order for them to grow. So the primary objective of this trial that we started four years ago, a little over four years, is to evaluate again the growth velocity and we'd z scores 30 days after the initiation of feed post-surgery. In those babies that were fed that human milk diet, I'm going to go through the details of this study.

Our hypothesis was that those babies that can receive exclusive human milk diet throughout the pre-op and post-operative period will have short term and long-term benefits with improved growth and neurodevelopment, while reducing episodes of feeding intolerance and NEC.

It was a randomized blinded, controlled trial, the population was babies less than seven days old with single ventricle physiology that will require surgical repair within the first month of life. And we will attempt to enroll about 100 babies to have 84 completers. And it was investigator-initiated. But industry sponsor, we had several investigators, I am the PI for this study. But we all got together to try to get this study design. And what we decided is that physicians, residents, all the providers will be blinded. But the dietitians and the dietary techs will not be blinded, since they had to mix the formulations every day.

And we could not keep them completely blinded. The inclusion and exclusion criteria are listed here, basically term baby so then we could get prematurity out of the confounding factors. And also, we excluded those very, very sick babies that you know, require CPR or have had anomalies and required CPR before the surgery. In those anomalies there will potentially cause and effect on growth. And if they require ECMO, pre op or if they had an A grade three iVh because of the long-term outcomes that we're really looking at as a primary outcome as well.

So this is what happened we enroll within the first seven days if you go into the human milk arm, we were hoping to enroll 42 on that arm and 42 on the other arm for fine. We will always provide a mom's own milk first. And if there's not enough pre-enrollment then donor milk was utilized no formula. But after randomization, if there was not enough mom's milk, then the human milk arm will get donor milk and the bovine arm will get formula. And at about 60 mLs per kilo on the human milk arm the babies will get fortified versus at 100 mLs per kilo in the standard arm with bovine, those babies will get fortified. We believe that babies needed to be fortified early but most of the center's would not have fortified early with bovine formula, we did not feel comfortable. But since it was comfort or comfort on fortifying early with a human milk fortifier that was exclusively designed for this term babies. We believe that since you know preterm babies had been tolerating human milk derived fortifiers at 40 or 60 mL per kilo, then probably these babies will tolerate it as well. And that decision was made to fortify these babies early.

So this is the bulk of the study on how the postdoc feeding protocol was. And we divided by step so that the physicians could go back on steps but not know which babies were on which arm. So then let's say the baby was on step four, everybody fully fortified, but the baby developed feeding intolerance. And they didn't know which group the baby was on, they could say oh, go back to step one. And we'll just go back to like plain human milk unfortified at a small volume. And that's how that how we started right we will start on step one with trrophic feeds up to 20 mL per kilo per day and we did not advance for 24 hours. The step two after one to three days will advance by 20 to 40 mL per kilo per day. But the ones on the human milk will be automatically fortified at 60 per kilo to 24 calories per ounce and a 100 per kilo to 26 calories per ounce and on the other arm on the bovine arm there will be automatically fortified at 100 per kilo with the standard formula use at that center. And then after going to after that and after 24 hours that will be automatically fortified to 26 calories on the human milk arm and advance to goal have suggested 130 240 mL per kilo per day and then automatically get 45 to 28 calories versus the other group will not get 45 until 24 hours later have after tolerating it 24 calories for down to 45 26 and then they'll stop right there, because that's what the majority of the centers were doing at that time. On the human milk arm after tolerance up to 28 calories per ounce, and we'll go to 30. Because that will be the goal of getting at least 130 kcals per kilo per day on those on those babies without waiting for poor weight gain versus the other arm, we will follow this tender of care of waiting several days, if there was poor weight gain, then we will increase the 28 or 30 calories per ounce as the regular practice on that institution.

So the subject enrollment was completed in December and of this past 2020. And we enrolled 107 infants in total, to have the 84 completers that we needed.

So adverse events that we were looking for. It's NEC, sepsis, if we had feeding intolerance, and the DSMB analysis were completed 33% and after 66% of the enrollment, and they had no concerns. And right now we're looking at data. And we're doing the analysis and we will be presenting this data at PAS. So stay tuned for the results of this study.

And last, I will talk briefly about congenital diaphragmatic hernia. And these babies have mostly complications and records of reflux and for gut this motility. Allah lot of them will have acquired an anti-reflux procedure. There's a lot of anatomical part parts that will contribute to this reflux. And they're all listed in there. But you know, it's something that unfortunately we do, we have to deal with it after the fact.

But the feeding management after surgical repair, a lot of a lot of places, you know, go very slow there, but these infants are do not feed. But we have seen that if we initiate the trophic feeds, as soon as possible. As soon as there's return about function, there's actually improvements in tolerance. And we still advance cautiously because the BBC had in general impairment of blood flow or hypoxia. And we take into account that they had like you know, prolonged periods of hypoxia. But in a lot of the places they antenatal diagnosis had been confirmed. And there is a pretty standard or aggressive approach in the delivery room to not let those babies have significant periods of hypoxia. So that is no longer a huge factor, they still have a risk of NEC. But again, just look at the baby and see if they require quite a bit of CPR or had a lot of potential time with decreased intestinal perfusion. In general, it is rare that these babies will have NEC with the newer approaches and early placement on ECMO of some of the babies instead of waiting until they have significant hypoxic episodes. The issues that we're seeing is, you know sometimes intestinal obstruction secondary to additions if the intestine was manipulated a lot. And a lot of these babies will have mal rotations, they can have volvulus. But in general, and you know this gets repaired as the defect gets repaired. And to tell the truth, the most common problem right now besides reflux is probably failure to thrive so we have to really be cognizant about it and be proactive about providing enough calories early on.

So in conclusion, initiate feeds on any post-surgical neonate as soon as possible. When the motility is established. We can initiate the traffic feeds sooner with our advancing and the PO feeds in the pre-surgical neonate with cardiac defects, you can initiate it if they're able to PO, and in terms that have intestinal disease, you can figure it out if the baby is able to tolerate PO and in small volumes if the intestine is able to tolerate that's more volume, you're probably going to be okay as well. And emphasize the use of human milk, and may use donor milk if mom's milk is not available, although we need more prospective trials, specifically in babies with gastroschisis, or intestinal disease, more than just the anecdotal or the retrospective analysis. And as I show you, we're having more prospective studies in the cardiac babies coming out soon. And again, avoid diluting any milk because it does not work. And it just prevents you from providing enough calories.

Implement multidisciplinary teams, I cannot emphasize that enough. That has been a big game changer in our unit, and in many other facilities. Design your feeding guidelines based on evidence, but also on consensus, have a consensus with your team with their surgeons with your GI team, and maximize your calories early on via TPN if you need to. And watch for your optimal growth velocities and be proactive and not reactive and track your long-term outcomes.

And I would like to finish with a beautiful picture of this; one of my favorite patients that remained in our unit for a whole year, and we had a one-year party in there. But she's doing great. And I'll be happy to take any questions at this time.