Specialists with the UCSF Fetal Treatment Center share the latest on prenatal techniques for detecting, evaluating and treating diaphragmatic hernias to optimize lung development and prevent deadly pulmonary hypertension. They also present intensive care strategies for newborns and long-term developmental care plans for kids.
Refer to Fetal Treatment Center
Hi, my name is Aaron Matsuda and I am the director for the fetal treatment center here in san Francisco and in Oakland. I just want to thank each and everyone of you for joining us today and I just wanted to reassure everyone. We are here and we are open and we are here to partner with you and serve our patients together. Um Thank you for joining us today. We will be talking about CDH and optimizing care from prenatal diagnosis to adulthood. I'd like to introduce dr Haman lee. He is our medical director for the fetal treatment center and surgeon in chief for UCSF Hospital. Many of Children's hospitals. Thank you Dr li for joining us. Thank you and and thank you to everybody for attending. Um we're presenting this from our fetal treatment center virtually and uh really it's been just such a great pleasure in my 20 year career at UCSF to be involved in the fetal treatment center and taking care of all the many patients and uh and uh one of the very uh focused areas of interest and expertise that UCSF in the fatal treatment center uh is treatment of patients with congenital diaphragmatic hernia. So I'm gonna just provide a brief overview and then talk about tracheal occlusion for congenital diaphragmatic hernia. So uh in our C. D. H. Center which is a virtual center we have many areas of expertise uh that really all provide support to our patients with congenital diaphragmatic hernia. So uh we have expertise in imaging prenatally uh in particular. Um uh and Dr Feldstein is going to talk about that biomarkers that uh dr Mackenzie has led the effort. Uh uh congenital diaphragmatic hernia. Um uh We also are one of the few centers in the first in the world to do tracheal occlusion to promote long growth for um congenital diaphragmatic hernia, notably our delivery center uh is immediately adjacent or intensive care nursery, which allows our neonatologists and mfs and pediatric surgeons and other specialists to all congregated the delivery and uh not to need transport with our uh severe congenital diaphragmatic hernia babies. Um Dr Keller's gonna uh talk also about the pulmonary hypertension Center of excellence, which was the first on the west Coast, the second in the country uh here at U. C. S. F. Uh and the doctor who is going to talk about long term outcomes in our techniques for repairing congenital diaphragmatic hernia uh notably uh California. Children's Services awarded us the very first um and and perhaps still only uh CCs designated multi specialty, multi um uh diagnosis um uh award for our joint pulmonary hypertension and long term follow up patients of which congenital diaphragmatic hernia was really the lead uh diagnosis that led to this were immensely proud of that. So um uh this is all centered around the fetal treatment center. So next slide. Mhm. Um So I think if you scroll. So really the problem with uh congenital diaphragmatic hernia is that it's a simple an atomic problem which is a hole in the diaphragm but it leads to disastrous. And if you keep scrolling their disastrous physiologic consequences which include pulmonary hyper pleasure and pulmonary hypertension and the pulmonary hyperplasia and pulmonary hypertension. Obviously make respiratory um uh compromise after birth. And so that is really the key problem with congenital diaphragmatic hernia. In fact the home that I frame is relatively easy to fix. Next slide please. So one of the issues with congenital diaphragmatic hernia is uh worldwide there's about a one third mortality. So it's a severe disease. But it's hard to know which patients uh are severe enough that we might need to uh do something different either before birth or after birth. And obviously families also want to know the prognosis the potential prognosis for their Children as well as possible before birth. And Dr Feldstein is going to talk about a lot of this but has to do with ultrasound and MRI uh prognosis and eco prognosis before birth. Next slide please. So as far as our experience, the first fetal surgery clinical trial started in the early 1990s with Dr. Michael Harrison is widely considered the father of fetal stud surgery. And what we found was that in the decade of the 90s the improvements in care of congenital diaphragmatic hernia were improving. rapidly. And for liver down CDH the operation was successful but not necessary and led to a fair amount of morbidity. Next slide please. So uh then looking to try to take care of the ones that were most more severe. We came across uh in our experience, patients with congenital high airway obstruction syndrome, which basically means that there's either Lawrenceville or treasure still necessary. Tree asia. And um these uh infants had huge, these neon eights in fetuses had huge lungs because the trachea or lyrics was blocked and it prevented the egress of lung fluid from the lungs and it resulted in over expanded lungs or hyper plastic lungs. Next slide, please. So, a lot of work was done in our lab uh in the 90s, uh and it showed that uh in animal models that we could get lung growth by uh including the trachea ourselves. Next slide, please. And this led to a technique of tracheal occlusion via a balloon catheter device. Uh this could be done minimally invasively under ultrasound and fetus coptic guidance, and it prevented the aggressive lung fluid to promote lung growth. Next slide please. So, prospective randomized controlled trial was performed uh And this was published in the early two thousands in the new England Journal of Medicine with Mike Harrison leading the study. Uh This was done with a maternal uh laparotomy, no history to me, a single 4 to 5 millimeter port site through the uterus. Uh And then the scope was placed into the fetal trachea balloon was inflated. Uh The Catherine was detached and then uh exit delivery was planned um uh to deliver the baby because obviously we had to remove the balloon at delivery as well unfortunately. Or fortunately depending on how you look at it because the immense progress that dr Keller and her colleagues made in the care of congenital diaphragmatic hernia here and nationally. Survival in the control arm of this prospective randomized controlled trial was 75%. Which was the same as in the tracheal occlusion arm. And you see many luminaries including dr Harrison, dr Keller. Uh Dr Hawgood who is our chancellor now, dr Farmer who's the chair of surgery U. C. Davis dr filly, widely considered really one of the fathers of uh fetal imaging. Um So at this point uh we really couldn't offer tracheal occlusion uh in the same way that we could and we thought that the reason for the lack of difference was that we thought that there was some lung growth but the group that had tracheal occlusion delivered earlier than the standard post NATO group. And so perhaps the benefits of lung growth were offset by the complications of prematurity. Next slide please. So um Fast forward a few years and really uh lots of credit goes to dr john depressed in Belgium who uh had access to smaller devices and different balloons. Uh, and he uh pioneered doing the entire tracheal occlusion without a maternal apparatus. Me, uh, and obviously therefore no history to me with a single three millimeter port and he could both place the balloon and then remove the balloon, which would also allow for vaginal delivery rather than an exit so that there was no big maternal pissed arata me. Currently, multiple centers around the world are involved in this. There's a moderate group in a severe group. The centers in the United States are only participating in the severe group and the reason for that is survival in the United States has historically been higher than in the rest of the world. And there didn't seem to be rationale for doing this in the severe group. And Dr Feldstein is going to talk about what the severe group is. We are awaiting results. We are doing trade conclusions here at UCSF and similar to the world experience. Although this is not a prospective randomized control trial, our survival for tracheal occlusion using this most minimally invasive technique is about 50%. Whereas our survival in the control group seems to be about 5-10%. But keep in mind that this is not a prospective randomized control trial and our experience, but rather what the families decided for their treatment. So, next slide please. So the uh some of the inclusion exclusion criteria for tracheal occlusion via this most minimally invasive approach, which also includes taking it out at a second. Photography is 18 plus years of age. Normal carry a type liver up with an O. D. E. L. H. R less than 25% between 18 and 29 weeks. Uh MRI prior to tracheal occlusion, we place the balloons at 27 to 30 weeks and we're removing in the 34th week, if the fetus coptic reversal is not possible, then we'll do an exit procedure. So we are, as I said, continuing to offer this here at UCSF. So next slide, I think that is my last slide and I will introduce Dr Vickie Feldstein, who is professor of radiology and really one of the world's leaders in ultrasound imaging of fetuses. And she, I've had the immense fortune as I have with almost everybody in this panel of working with her for 20 years here at UCSF. So dr Feldstein, thank you. Uh Thank you, honey, I want to make sure you can see and hear me. Yeah. Your great, great, great, thank you. So yes, I'm Vicky felt seen, I'm a member of the radiology department here at UCSF and have been for almost 30 years and have been part of these projects that um I'm in reference from really honored to be part of this panel and given this opportunity to speak with you um the minutes I have I'm going to talk a little bit about the ultrasound assessment of patients referred for suspected diaphragmatic hernia. Most are left sided and will address um in particular targeted ways the position of the stomach and of the liver. We pay particular attention to any additional findings as part of our morphological assessment and I will address in more detail the metrics than american planners. Used to identify patients at greatest risk. Well referenced. The use of M. R. And R. Role in assessing candidacy and assisting with intervention. When there routine obstetric sonography identifies over 70% of cases and many of the cases we've seen are detected on routine scans closer to home, 85% or left sided and forth, paying particular attention to cite us typically there detective because the fluid filled stomach is herniated and seen in the left hemothorax. Occasionally we'll see what's referred to as a bowel only C. V. H. The stomach is down as well as the liver. Those are not candidates for intervention. What the stomach is often up and what we were talking about is the presence of liver up meaning a portion of liver. It's usually a portion of the left lobe and severe CDH is and the outcomes can be predicted by prenatal imaging. And so that's sort of our purpose in doing this. An axial view of a symbolic fetus shows the fluid filled stomach in the chest next to the heart and two more examples with more significant degrees of rightward displacement of the heart, larger hernias, more content and in particular more liver herniated. That's the solid tissue anterior to the foods that stomach and the left checks. Sometimes we send patients for whom there's a diagnostic dilemma. This case was referred for dexter position. You can see that the heart, it's subtle and a really good pickup at the heart is situated to the right and the um stomach was where it belongs at the left, upper quadrant of the abdomen. And the differential included a cardiac abnormality or some other chest lesion. But there's new technology and all our fields including improved imaging quality and by changing technique and in particular higher frequency transducer. We could appreciate that in the left chest was collapsed foul so this was a TBH but about will only had started down. I reference the need to look for additional structural anomalies. And the list is long and you can see the frequency of other organ systems which can be involved in the setting of a C. D. H. In particular. There is a significant risk of associated cardiac abnormalities and they're listed here. So a fetal echocardiogram is part of the routine evaluation of patients found to have diaphragmatic hernias. In this recent case there was a large left sided hernia with a lot of rightward shift. Um And you can see it's subtle but there's a small amount of food in the right hemothorax and on this corona image of very small amount of the city's small amount of real findings and not expected in the setting. In addition the fetal profile looked abnormal. And the assessment includes sort of cookie genetic evaluation and you can see the ultimate diagnosis in this case was Palace Trick. Again, not a patient for him and a little intervention is warranted. So I mentioned that we pay attention to the position of the stomach and the liver. The presence of liver herniation and its degree influence how much shift and therefore how much room is available for the lungs, particularly the right want to go to grow. And this portends degrees of preliminary hyperplasia and resulted mortality will reference the L. H. R. Which stands for lung to head ratio. It was first described by colleagues here at UCSF in 1996 and found to be an independent predictor of survival and short term morbidity. The lung to head ratios obtained on an axial view through the chest. And it's uh the formula is an area um millimeters squared of right lung divided by head circumference and Melanie. And I just want to make the point in imaging, we almost always measure legions directly and the bigger the number. The worst things are. In this instance we're measuring the right lung and the more lung we see, the less shift and the better the prognosis so high LHR is a better prognosticator. And in general and our experience over one pretended better outcomes and we targeted interventions for numbers below one. Over the course of this year of the studies done over the years, the L. H. R. Has been adapted by other investigators and other centres. It takes some familiarity. We have used the anterior posterior diameter method when it's first described that was used, but these diagrams show other ways to take that image and place calendars on the right lung. Uh In terms of reproducibility, most centers are finding that the trace method works to. The other revelation over the years is that even though the denominator is just head circumference, it doesn't fully control for gestational age and LHR increases as gestation advances. So to address that, a newer parameter has been introduced to the literature and that's observed to expected LHR. And there are reference values for these numbers and it has been found to be an independent predictor of outcomes. I just want to include here a new reference boy Philly who hangman uh mentioned has taught his study this um this uh entity for years and been very involved in much of the discovery and he introduced LHR to the literature and more recently wrote about just using stomach position. It's a sort of quicker, dirty or proxy for how bad the degree of uh of shift is. And simply by looking at where the fluid foot stomach is located, that sort of portends how bad the hernia is and in this case it's a severe one would be confirmed with a lo O. D. E. L. H. R. Because the stomach is situated all the way on the right floor racks behind the, Yeah here are some colonial images um uh from an M. R. In a fetus with left sided diaphragmatic hernia. One of the advantages of M. R. Is it distinguishes lung single intensity from liver, single intensity from bowel, which can be hard on ultrasound. In this case you can see the fluid filled stomach is herniated as is a portion of the left lung. We do M. R. Not as a matter of your team though for enrollment in the trial it's necessary and the patients we see if there's an indication M. R. Is done and these are the kinds of energies obtained. One advantage is you can see both lungs, both the contra lateral right lung and the it's the lateral left lung up near the apex and calculate total lung formulas and compared to reference values going back to a case of an isolated left sided C. B. H. With liver up and worrisome, numeric parameters low LHR, low observed to a suspected LHR. This patient would be counseled and considered for fetal intervention and Hammond mentioned the trials that um have been instituted including the total trial for which we've seen patients who qualify as severe. There's the website is referenced there and I just want to mention briefly and show you what we see. Ultrasound is involved with identifying a safe place for introduction of the endoscope because we need to avoid the placenta to do this appropriately and safely following deployment of the fluid filled balloon. We serially assess the fetuses by ultrasound, and Mark can be done to mostly to look for a change in one science. So I'll close just by reinforcing the notion that ultrasound can reliably make the diagnosis of CB agents often detected elsewhere. And we confirm the findings. We've established that the lesions isolated looking for any additional structural abnormalities. Use prognostic features including stomach and liver position. The measurements as I showed of the contra lateral lung LHR in its different forms. And this assessment has become one of the widely accepted tools used to counsel patients um and inform decisions of around potential intervention. And with that all close and introduce our colleague to be. Mackenzie will be next speaking about biomarkers. Thank you Vicky. Great. So um I'm going to speak to you about some work we're doing to try to predict the prognosis and and fetuses with C. D. H. Uh and some other anomalies By looking at biomarkers in addition to um prenatal ultrasound and m our findings. So I think here's the crux of the problem. Which is that um what we measure prenatally is the lung size. And although pulmonary hyperplasia does relate to and contribute to pulmonary hypertension, what we see in the niCU is that these babies with severe CDH die of pulmonary hypertension. And we know from looking at the literature on c. Pans that the size of a lesion doesn't necessarily predict how bad your pulmonary hypertension is going to be. So sometimes we'll have a patient with an intermediate LHR who has very severe more than predicted pulmonary hypertension post natally. Uh And sometimes the patients that we predict would have a very severe course end up doing better than we expected next. So are there some other surrogates of pulmonary hypertension that we can measure prenatally? So one surrogate it turns out is the diameter of the pulmonary artery. Uh And this is measured by echocardiogram. Uh And it's you can imagine it's a pretty tricky measurements. Uh And here we're lucky to have dr Anita Grady and her colleagues who have gotten very good at measuring both the right and the left pulmonary artery diameter. Uh And as Vicky mentioned, what we measure with the L. H. R. Is the size of the good lung because the of course on the affected side, which is usually the left side. Uh that line is quite small and that pulmonary artery is also quite small but measuring the size of the right lung to measure the LHR and measuring the size of the pulmonary artery to measure the um uh If you can go back to the previous line to measure the pulmonary artery, can predict severity. So what you see here is a study where we looked at the pulmonary artery diameters and looked at the Z. Score uh which is uh which is a statistical score for whether you're smaller or larger than the uh two standard deviations. And you can see that most of the non survivors had a Z. Score below predicted. Whereas the survivors all had Z. Scores had predicted. So it's not a test that we're using uh clinically to grade prognosis now, but we're definitely doing echoes on all comers with C. D. H. Uh and using it as part of the the counseling of the affected families next slide. And it sort of gets us to the subject of precision medicine. And what we mean when we talk about precision medicine in in fetal therapy. So when you think about the routine prenatal testing that we do today, we of course rely on radiologic findings such as ultrasound and MRI. Uh And in some cases were also doing genetics studies. But we don't have all the multiple layers that we do after birth. That can help us guide prognosis and develop better therapies next slide. So post natally we have in addition to those studies, of course we can look at environmental exposures and laboratory tests and other biomarkers that can really allow us to see how patients doing. It's sort of the equivalent of do you make clinical decisions based on X ray or cT or do you also uh look at you know, cbc LFTs and you know the whole slew of other laboratory tests that you have next line. Next. So uh we have done a research study and we're conducting multiple research studies uh to try to predict biomarkers. And the first thing we've done of course we don't want to draw blood on fetuses. As and so the first test that we've done is to simply collect the cord blood at birth. Uh and see to what extent that predicts the pulmonary hypertension that you see after birth. Uh And dr Keller. We'll talk about this in the next bit. But she has done a lot of work showing that the echocardiogram that you get at two weeks is a very accurate predictor of the baby's course and the amount of pulmonary hypertension that they would have. Uh And so we did one study that. I'll tell you about where we measured the biomarkers and the cord blood at birth and then correlated that to the degree of pulmonary hypertension that each baby had at two weeks next. Uh And so we collected blood from 19 fetuses with our 19 babies, newborns with C. D. H. And you can see that the majority were left sided and the majority were liver up kind of the kind of severe population that we tend to see here at UCSF. Three had had prenatal Shakeel inclusions, three required ECMO. Um And about a third of them had neonatal demise. And in terms of the pulmonary hypertension that we measured by echo, about a third of them had mild, and two thirds of them had moderate to severe pulmonary hypertension. Next And we compare these biomarkers to healthy term controls. 23 we have them next. The first thing we looked at is kind of an interesting biomarker which is the number of the mother cells that traffic into the fetus. And we see that this happens more in sick feet. This is and those who have a fetal intervention. And you can see here that the amount of maternal cells that we found in the cord blood was significantly increased in the fetuses that had severe CDH compared to those who have mild or two controls. Next. And then we looked at a whole array of different biomarkers. Some of these are growth factors and chemokines. And what you're looking at here is the light grey is control. The medium gray is mild C. D. H. And the dark grey is moderate to severe C. D. H. And you can see that a biomarkers such as E. G. F. Shows a very nice pattern of increase between the controls and the severe CDH is next. And we saw a similar pattern when we looked at inflammatory biomarkers uh seen here for example, interferon alpha or I. L. Six next. So this was interesting to us because the dogma of course is that pulmonary hypertension doesn't start in utero because the baby isn't using their lungs in utero. But it does definitely suggested that because we saw these markers in the cord blood that the pulmonary hypertension starts in utero and potentially should be treated in utero. And obviously some of these pro inflammatory molecules that we identified could be therapeutic targets for fetal intervention. Next some of the current projects that we're doing. Now our whole exam sequencing of patients with C. D. H. And actually um here we have a program that's led by my colleague mary Norton. Uh many of you know of course um who's doing a whole exam sequencing of fetuses with a number of congenital anomalies. And we have a specific program on idiopathic high drops. Actually that's run by Teresa Sparks. Uh And in doing even just the first couple of patients that we looked at with C. D. H. We have already found a specific mutation that's associated with a more severe prognosis. So really hoping that understanding the nuances of the genetic disease in CDH can also add a second layer of to that layered uh prognosticator that I showed you. We're also looking at micro Arnie's which are messenger RNA is found in in in in blood. Um And we are seeing some correlations between the specific micro RNA profiles uh and the severity of disease next. And so our goal is really to uh add to the L. H. R. And O. T. Ratios and the pulmonary artery diameters that we are using so far uh to really create a precision score for pulmonary hypertension based on multiple parameters so that we can better counsel families and develop new therapies for C. D. H. And with that I'd like to actually one more. Um And so a few years ago we started kind of the research arm of the fetal treatment center, just the uh center for maternal fetal matter. Listen for single gene disorders such as a clinical trial on stem cell transplantation for thalassemia, as well as working on pregnancy complications. So we'd like to move the field uh sort of expand the scope of fetal therapy, birthday for pregnancies. And with that I'd like to um introduce dr roberta Keller, um who is the vice chair of research in the department of pediatrics and a professor of pediatrics uh and probably the world's most talented clinician in taking care of these six CDH babies and keeping them off ECMO and getting them out of the hospital. Thanks roberta. Thank you tippy for that kind introduction and pick every thanks everyone for for joining us today. Um You can go to the next slide there. Um So this is I have to kind of starting flights that I start all of my toxin CDH with. And so this is the first one And uh I think the other speakers have have helped us with kicking this off here. So really the path of physiology of congenital diaphragmatic hernia is path of physiology of lung hyperplasia. And um the lung peron coma and vasculature actually developed together both in italy and post in italy. And so this is a disorder both practical and vascular hyperplasia. And with respect to the lung Brinkema. Specifically we see decreased branching which results in decreased Asami um And therefore decreased numbers of LV. Lie. And when you have to when you have lower numbers of villa you have forced lung compliance and therefore problems with clearing your CO. Two or ventilation. Um And you also have decreased area for gas exchange, the lung level as well as at the vascular level. So this is a disorder of restrictive lung disease. And we also see a restrictive vascular bed along with that because of the way the lung development proceeds in Abra. And that restrictive vascular bed therefore needs to accommodate a full cardiac output or divert the blood away from um from the vascular bed, which is a problem with transition or persistent pulmonary hypertension of the newborn. Um As tippy. Instead, we've also seen persistence of pulmonary hypertension. I'll show you some of that data later on. Um In addition to this problem with the restrictive vascular bed, however, we have pulmonary vascular disease, abnormal vascular reactivity and we have remodeling of the vascular bed. Um some of which probably occurs prior to delivery, but much of it which also occurs after delivery related to the um insults and and challenges with caring for this. Um Good that newborns. So as everyone has um nicely demonstrated there's varying severity of this disorder. But these babies are of course are required to have post natal lung vascular growth for their survival just as every baby is. Um And as I mentioned, the uh interventions we take to support these babies actually impedes that growth and can actually not just impeded because an arrest and therefore lack of ability to survive next slide erin. Um so this like shows you data from three centers that have published their outcome survival over the course of about 20-25 years. So starting in the early 1980s and ending in the early 2000. Um and I believe the slide out looking at the different strategies that they use to care for babies with that dramatic cornea and the care the strategy, the consistency of employing that strategy is critically important, caring for this population because human mentioned, um you know, we are in close proximity in the intensive care nursery through set of double doors to Labour and delivery. So we are we have a full team of people there who are able to care for these patients right from delivery. And we also have a healthy volume of patients averages about 17 year. Um so we can employ good consistency with our strategies across all of our patients. And let's not just at the level of the providers, the physicians or the nurse practitioners, but also the nurses at the bedside and arrested for therapists because of course there's lots of intervention happens when the physicians aren't around. Um So in this slide you can see in this early era where which is labelled as emergent repair. Um the teams were using essentially a strategy of trying to maximally Visa dilate the pulmonary circulation and they did that by hyperventilating the patients to get there. So remember I said that ventilation is poor and restrictive one disease. Instead, the approach was to try to hyperventilate the patients in order to make them alfa logic and to try and dilate their pulmonary vascular bed and also to hyper oxygenate them with the concept that of course oxygen is also a cold winter days, a dilator. And you can see that the survival here is quite poor across all of the sides. Um Then as ECMO became available at these centers, uh there was a move towards the labour pair with preoperative ECMO. Um and really you can see largely no real change in survival with that, with that change in their approach. And then in boston they adopted a strategy of permissive hyper campania. So this was based off work and care that was given Colombia um in new york and again ventilation being a critical problem with one hyperplasia. They now said we will accept higher co two s. In fact permissive lee high CO two is higher than normal and therefore we won't need to do as much work with the ventilator to meet our goals. And there you can see they saw a significant improve all improvement. Excuse me and survival. And then in this last era, what we've seen is what we use at UCSF and which has evolved in in these centers as well as many others. Permissive hyper capital and lung protection. And what this means is that not just are they allowing for the coaches to be high but they are limiting the help the interrogatory pressures. So really limiting that barrow trauma that exists um And also aggressively weaning oxygen and allowing for a doctor level shunt so allowing that pulmonary hypertensive physiology to persist um and um weaning oxygen as oxygen itself, although it's a pulmonary basal dilator also causes inflammation and injury to the lung next slide. Um So this is some work that to be was referring to. This is a retrospective data that we collected from 2000 to 2012 and I think Conman mentioned that we have a pulmonary hypertension Center of Excellence. That's a accreditation awarded by the pulmonary Hypertension Association. Um and so we are very fortunate to be able to follow these kids both during their initial hospitalization, as well as beyond our multidisciplinary clinic. And what you can see here is this is a data from 140 newborns who had cereal echocardiogram. So we do routine echocardiograms on a weekly basis for the first about six weeks of life. Um and those who are excluded. So basically, you needed to have one echocardiogram to get into this study. And you only excluded if we weren't providing full care or if you had conflicts in general heart disease, which would um confound the interpretation of the excavator And what you can see here. We employed a scheme that we developed and published in 2010 Around that classifying pulmonary hypertension and on the blue survival curve, you see that 70% of the babies had resolution of their pulmonary hypertension. Um, 19% of this group died and 11% survived with pulmonary hypertension. And if you go to the next slide, you'll see that consistent with our weekly echoes. Uh, the median time to resolution of proponent hypertension and the group that resolved with 17 days with an intercultural range of seven and 21 days um consistent with the timing America program. On the next slide, you can see how that relates to outcomes which uh to be had reference. So we have death on the left column endeavor, prolonged respiratory support of 56 days, which is the proposed definition of moderate to severe bronco former dysplasia for uh babies born about 32 weeks such a station. And then on the Far left, you see the uh classifications at each week of life through six weeks from 1-6 weeks of age, or get between four and six there. Um and then on the next slide, you can see that the vast majority of the infants actually resolve their pulmonary hypertension. You would see mis classification system at 2-3 weeks of age. Again consistent with that medium. We showed you on the prior slide. And um this is a really interesting um Concept because in healthy term babies without respiratory disease, you actually see them resolve their uh normalize their pulmonary pressures by Echocardiogram 2-3 days of age. So here we see a delayed transition in this group of Children who all survive and have um low rates of this broncho pulmonary dysplasia. Um and um this suggests that this transition um is delayed. So this this is permanent vascular disease with a delayed transition and whether it's in some of the inflammatory markers that could be showed or other effects, um these are this is a delay and what we need to do in this case is to support these days needs to allow them the time to have that vision. So on the next slide you see here um that this is really influences our strategy. So our primary strategy of course is prevention. We have lung hyperplasia. We know that high pressure is high volumes, persistently. High levels of oxygen uh delivered will um injure the lung, cause growth arrest and result in lung dysplasia or potentially inability to recover. So it's gentle ventilation and promise about situation. And we use these routine weekly echoes to carefully monitor um the evolution of the rights of elevation and right sided pressures as well as assessing for right ventricular function. So people with pulmonary hypertension really die from a failure of their right ventricle. And so we're really really focused on maintaining allowing this right ventricle to continue to pump well even though it's pumping against an elevated um resistance. So time is really really key. Time is one of the therapies. Um And then we use interventions that are based on on this right ventricular function. So we um we use inhaled nitric oxide to help dilate the circulation. Um for those babies are evidence of systemic to super systemic pulmonary vascular resistance. We use um PG. E. To maintain the patent see. So we allow them to shunt through there away from their pulmonary circulation um and we see uh their force and lower oxygen saturation is as a result. And then we consider additional permanent Visa dilator therapy in the acute setting early setting. We actually use nowhere known, which is a hospital histories inhibitor and unload both the left and right ventricle. And then chronically we consider many of the other classes of drugs that you probably have heard of. Um And for chronic treatment we actually music cardiac catheterization to help assess how how uh aggressive we want to be in that therapy. So, to finish up on the next slide, this is just a cartoon of my uh picture. I need a long time ago to show you the evolution from this bilateral lung vascular hyperplasia with the numerous insults um And two along that has both one in vascular display shin. Um And so next I will introduce um the person who does our long term follow up for these Children. Dr lang New Lawn is an associate professor of surgery. She directs the life programme which uh follow up for the government of cornea Children um goes through that program and she's also the director of our surgical quality improvement program. Thanks roberta. Um So thank you everyone for the opportunity to present today, meant to be part of this amazing panel of experts. Um My name is Leon View and I'm a pediatric surgeon and as roberta mentioned, I'm the director of the life programme here at UCSF Benioff Children's Hospital in SAn Francisco. Um The life programme provides multidisciplinary approach. The long term care of Children with congenital diaphragmatic hernias. Next line, mm hmm. So today I plan to briefly discuss some of the key long term surgical and medical outcomes associated with C. D. H. And R. Program surveillance guidelines to help evaluate and manage these issues. There have been a few advances in how CDH is repaired to minimize some of the surgical complications. C. D. H. Is usually repaired through a laparotomy. Um Closing the defect primarily are using some synthetic mesh when the defect is large. Next slide. Yeah, adhesive bowel obstruction is a known long term complication of the operation to repair the diaphragmatic hernia. But it can be minimized by a minimally invasive approach. Um As illustrated in these photos, authorities coptic repair is usually recommended when the defect is small, only bowel is creating in the chest cavity which you can see in the upper left. Um There's colon, small intestine and stomach and spleen in the chess. Um And primary pair can be done um And the lower right um Photo is complete repair of the hernia using the patient's own diaphragm tissue next line. Mhm. In addition, what are the important long term surgical complications include risk of re herniation. When the defect is small and close using existing diaphragm muscle, The incidents of re herniation is low um As shown in this Kaplan meier curve. Um Primary repair is seen um Um as the full line and then patch repair is seen as the dotted line when the defect is large and when there's no diaphragm tissue and pat repair is required. The incidents of re herniation can be as high as 50% occurring usually within the first years of four years of life. This is the safest part of the growth curve in the child, leading to potential tension on the repair site. Um Because of the risk of re herniation, our program recommends um surveillance for re herniation using a two view, chest X ray. Every three months in the first year, every six months for two years afterwards. Then yearly until five years of age and then every two years after starting school. And MRI is obtained when the chest X ray findings are concerning for re herniation. Next line, About 10 years ago we started repairing the defect using the patient's own abdominal wall muscles called the internal bleak muscle flat. The inner muscle layer of the lateral abdominal wall is used to close the defect theoretically. Since this is the patient's native tissue, the muscle will grow with the patient as he or her. Um he or she grows decreasing the risk of re herniation. Since that time there's only been one recurrence um in our cohort at our institution. Therefore, this is this method of repair has become the standard technique to repair a large defect which cannot be closed primarily next time. No development delays have been identified as an important outcome in Children with CDH. This includes hearing loss, motor dysfunction in both cognitive and sensory and behavioral dysfunction such as autism or a A. D. H. D. Next line follow up data on patients enrolled in our fetal tracheal occlusion trial, as discussed by the previous panelists. Um A cohort patient with the most severe CDH showed a high incidence of neurodevelopmental comorbidities, Greater than 50% cognitive to delays, 40% your motor delays and almost 50% of patients with hearing loss. Next line, the hearing loss is most commonly sensory neural hearing loss in the high frequency range greater than 1000 hertz as demonstrated in the sample audio gram result recommended surveillance include at least three formal oughta grams before starting grade school and then of course referral to the OHMS service when hearing loss is identified next line. In addition, our life program works closely with the high risk infant follow up program here at UCSF which provides regularly scheduled neurodevelopmental exams by especially trained team of neonatologists, nurse practitioner and a child psychologist at six months 12 to 18 months, 2.5 years and 4.5 years. Um Subsequent referral to existing resources whether locally or at UCSF are made when problems are identified early to prevent chronic problems. Thanks slide. One of the key members of our life team is our dietician who provides full nutritional support for our patients in the program. Children and C. D. H. Can have poor growth due to increased caloric needs. Um leading to G. Two placement, oral feeding difficulties and issues and related to gas yourself, Jill reflux disease. Thanks slide Data has shown that the Z. scores for weight and height for age below -2 is common in the first six months of life. Um As seen on the graph um of the two graphs here. Um First graph on the left is the wait and see score and the graph on the right is the height. C. Score, Ketchup growth occurs after six months but failure to thrive as you can see, still exists in about 21% of patients at one year of age next line. Mhm. The nutritional implications continue into childhood and adolescence where 58% of Children of patients with C. D. H. have been demonstrated to have increased resting energy expenditure, leading to ongoing nutritional needs. Even though only a quarter of the patients required you to placement during infancy, about 16% of patients still needed G to um for supplemental feeds at seven years of age. Next line lastly, given the development of chronic lung disease and pulmonary hypertension as discussed by um dr Keller in the previous talk, Children CDH are higher risk of respiratory and infectious complications. Um Therefore in a statement published in 2000 and three, the American Academy of Pediatrics recommends and R. S. B. Vaccination for our patients for the first two years of life. Next line. In conclusion, multiple factors lead to chronic problems in Children with CDH. Therefore it's important to follow these patients in a multidisciplinary program with experts who can help identify and manage these issues at different stages of the patient's life. Key personnel includes a care coordinator, usually our nurse practitioner, a pediatric surgeon, dietitian, your developmental team, a social worker and a feeding therapists. In our program, we work in synergy with other specialties, including cardiology, dermatology and gastroenterology. Mhm. And and I think we're open to questions by um any of the attendees.
