Chapters Transcript Video Therapies for BPD-Associated Pulmonary Hypertension – What Do We Know Now? Back to Symposium Dr. Kevin Engelhardt presented on therapy options for BPD-associated pulmonary hypertension. So we have kept a lot of exciting talks for the second half. So we talked about mainly about our lungs and um brain and now we'll talk about partly heart and vascular. So the next two are very exciting talks. So with that, I'm going to invite Doctor Kevin Engelhart who is both a cardiologist and pick you trained. He is an integral member of our family hypertension team. We run with him every week. And um so with that, I am going to welcome Doctor Engelhardt and he will talk about therapies for BPD associated for hypertension. What do we know? Now? Please welcome Doctor Engel. Good afternoon. Thank you guys. I hope that uh it is interesting post lunch. So I was asked to talk about our therapy options in pulmonary hypertension when it occurs in bronchopulmonary dysplasia. I don't have any uh conflicts of interest to discuss. So, uh one of the challenges with pulmonary hypertension in general is that there's sort of multiple definitions and so which definition you use Walter, you know, which patients are included in the group you're, you're interested in. And um and from there, these are from the 2015 A H A and A TS pediatric Pulmonary hypertension guidelines. These are probably the most common definitions you'll end up using. So again, it's a mean P A pressure of over 25 millimeters and a Children greater than three months of age and then pulmonary arterial hypertension same but with a wedge pressure, that's below 15 and index, pulmonary vascular resistance of greater than three woods units um in idiopathic or isolated Pah, um it's gonna be a ph with no underlying associated lesion. Um and then pulmonary hyperten and vascular disease is also another way you can look at that. And that's a broad category including ph but subjects with an elevated transpulmonary gradient. So that would be most of your congenital heart disease populations where you have an abnormal either single matric pathway or a high L A pressure that's known. But you also have pulmonary hypertension um at the knees world symposium that uh threshold got looped down to 20 millimeters of mercury. So it depends on which definition you want to use. Um And then here's our kind of classification from the World Health Organization. Again, this is adult focused and this is one of the challenges we face in pediatric pulmonary hypertension is that the vast majority of these diagnoses don't occur in pediatrics um or they're kind of just thrown in. So, um you know, pulmonary hypertension and DPD really has kind of elements of multiple groups. And so one would be, you know, you have congenital or acquired heart disease leading to postcapillary, pulmonary hypertension. So, again, the vast majority of these patients will have a ductus arteriosus um as well as an A SD or PFO. Um they have obviously developmental lung disorder. And then, um there's usually a component of uh persistent pulmonary hypertension, the newborn as well. Uh Second classification just to add to the confusion is the pediatric Ph or pulmonary hypertension vascular uh vascular disease subtypes from the Panama um classification scheme. And so those subtypes are just a different way of breaking it down here. Bronchopulmonary dysplasia is sort of its own category. So as you're looking through a literary, you can be categorized one of either ways which makes it a little confusing as to what you're really looking at when you're talking about one group or another, right? So recommendations from that uh A TS guidelines is that we should be screening for PH in patients with established BPD. Um And that's uh level uh level level is one, a grade B recommendation. Um We should be evaluating and treating lung disease including assessments for hypoxemia, structural airway disease, the need for respiratory support before we initiate our therapies. Um and then um we should evaluate for long term um therapy following recommendations for Children. Ph. And you know, they include cardiac catheterization here. I would say our group is a little less likely to catheterize in this population. There's a high incidence of morbidity, even mortality. And um the um you know, under 10 kg, especially under 5 kg um catheterization for diagnostic um understanding that it's actually one of our highest risk groups. And so we really worry about the injury to, you know, vascular structures as well as just the risk of mortality with those. So a lot of these, we, we tend to put off that c until a little later in their care. Um They feel it's reasonable to uh use supplemental oxygen um therapy and keeping those SATS between about 92 and 95% just to prevent. Um And as you guys probably recognize those kind of profound response to hypoxemia that these infants can have. Um And then if ph targeted therapy can be useful in these. Um although an optimal treatment is, is not uh really known and then it says, you know, premo with no can be effective in this population as well. And I think we know that we've all seen that effect with ion O. Although, you know, it's the kind of set up that you won't really be able to have a trial proving the efficacy of ion O in this population is it's really already been established and trying to set up a um randomizer control trial, looking at the efficacy of IO in this population would be ethically difficult, I think. Um And then serial electro cardiograms are recommended. So the epidemiology you're gonna look at you can see pulmonary hypertension and prematurity, it's fairly common. Um And you can see there, you know, the ranges are pretty big depending on what, what series you're looking at anywhere from about 15 to 45%. Um If you're looking at under 30 weeks, um about 2 to 20% of those patients who develop pulmonary hypertension and then 25 to 40% overall of our premature infants with BPD will end up developing pulmonary hypertension. So just a few different ways of looking at it and those are gonna be increased if you're extreme prematurity, if you have uh increased PPD disease burden. So a higher grade of BPD or um you know, kind of overlap with all of our risk factors for a poor neon outcome as well. Um And so this is, you know, one large, probably the largest, look at this question of the incidence of BPD or ph and BPD. This is putting together three cohort studies. Um one from Seoul, one from Alabama and then another from Colorado and Iowa. And again, you can see the numbers there. It's actually a pretty large overall group and see if you don't have BPD. The incidence is quite low and these were all premature infants if you have mild BPD. Um You can see the incidence is still quite low on the order of 2 to 9%. Um But as you start coming up in the incidence of BPD, um is as a Ph with the grade gets higher and higher. So you're looking at, you know, moderate anywhere from 9 to 40% and then from 8 to 30% depending on the series here. Then overall again, about, you know, 15 to 25% of the patients, um all patients regardless of grade would have uh pulmonary risk factors for chronic pulmonary hypertension infancy. Um They kinda again overlap with the risk factors for outcome in this population. So you're looking at um you know, oligohydramnios, premature rupture, growth restriction, advanced maternal age and maternal hypertension. You know, these aren't surprising risk factors when you look at them on the surface and the neonatal risk factors. Again, all risk factors for a poor outcome in ICU um and then coming on down to BPD itself is, is a, you know, independent risk factor for developing pulmonary hypertension and all infants who develop pulmonary hypertension. Um when you look at the disease burden, um it's gonna be an increased morbidity. These patients are going to be exposed to mechanical ventilation for significantly longer periods of time than infants. That would be um you know, same age but not develop pulmonary tension. They're gonna need increased oxygen exposure. And you know, while we may be under thresholds that, you know, worsen the incidence rop or other things, I think we all can appreciate the prolonged uh uh exposure to high levels of oxygen lead to increased multiorgan failure, decreased lung function over time. And so I think we, you know, we would ideally avoid it, but we know that these patients won't survive. If we allow them to have those spells. There's increased mortality. Again, poor survival in the, even in the post surfactant or new VPD era. These patients you're looking at, um, if you have PH NDP D beyond the age of three months, it's about a 40% mortality depending on the series. And if you have ph and DPD beyond one year of age, that's a 47% mortality within two years. So there's still a significant mortality burden. I feel like we probably do better here. I don't have our own numbers, but it doesn't feel like we have this many patients um who, who are ending up, uh you know, with mortality there in terms of lifelong disease, these patients, you know, working in the pu we certainly see them. Um you know, on the other side there and, you know, they, they're frequently readmitted, they have altered exercise capacities, altered lung function and lung capacity. And they have an abnormal response to hypoxia that persists throughout their life. So, the ideology of this, what, what we uh at least understand to be going on is that there's abnormal or dysmorphic lung growth and that leads to smaller arteries and an altered distribution of that vascular um tree. Um and that leads to a reduced alveolar capillary surface area and impaired angiogenesis related to that early injury and insults. Um and then you have abnormal uh alveolar development, abnormal or increased vasoconstrictor response to hypoxia. And I think that's a big one contributing to those spells that we see. And then these abnormal abnormalities persist later into life, but the patients better able to handle them with growth, um kind of putting it all together. And again, this is from Moreni and uh nice review and perinatology of this. And what we're looking at here is that you have, you know, a prenatal injury, whatever that may be and some genetic or epigenetic factors. And again, we don't completely understand the genetics, but there's probably some component of a genetic risk to develop pulmonary hypertension with the combination of BPD as opposed to um you know, known genetic causes of idiopathic hypertension. Then there's some kind of post anal injury. You have hypoxia, you're mechanically ventilated, you get infected, you have acute or chronic hypoxia, your hens, right? You have a PD A that increases your qut to q acid increase flow to those smaller vessels. And that leads to um you know, decreased growth or abnormal angiogenesis alteration, abnormal function in the lungs and an abnormal structure. Then you get smooth muscle proliferation and alter altered extracellular matrix. And overall this will lead to a decreased alveolar capillary area for gas exchange. So, well, let's do this will worsen the effects of an existing left to right shunt lesion. So, patients who would otherwise have, you know, tolerated left to right shunt lesion quite well, not developed pulmonary hypertension over time, they will muscular eye more quickly. They'll need oxygen therapy for a prolonged period of time. With all the negative effects of that, there'll be an altered um redistribution of blood flow in response to um infection in the sense that when you have that pneumonia and you have regions of uh shuns because you, you know, had basal constriction around the area of insult, that's gonna be even more profound in these patients. Um And then later on exercise intolerance and eventually form their hypertension that's persistent or intractable. Uh Another way to look at this pathogenesis. And again, this is from an adult review in nature, but I think it still kind of gives you a nice picture of what's going on is that, you know, you have some risk factor and in this, you would just add in that it's gonna be BPD, not these, you know, adult risk factors. There's some genetic predisposition, we know some of the associated genes and there's nice gene panels out there for pulmonary hypertension but kind of 50 most common. But there's gonna be a lot of polymorphisms or genetic susceptibility that we don't quite understand yet. Then you kind of get early muscular organization which gradually leads to um you know, increased risk of thrombosis or muscular organization that increases the point of your obliteration of the uh of the vessels, small vessels, this again, the pathogenesis of pulmonary arterial hypertension. And you're gonna see that your um you know, hemodynamics are altered by echocardiography. You know, here you're gonna see, you know, atrial enlargement and decreased function. These patients eventually develop a picture of right heart dysfunction. So they're gonna get dis fatigued, um decreased exercise capacity and heart failure, which is very difficult to diagnose in the neonatal population as they, they aren't challenged in many ways other than in feeding. Um So how do these patients present um in the Niki, what you're really looking for is an oxygen, oxygen or ventilatory need beyond what you'd expect. So I think anytime you have that, that neonate, that's not doing what you'd expect them to. Um and you suspect BPD to, you know, mild, moderate or severe, especially with the severe group, you know, getting that echocardiogram and taking a look if they're difficult to progress or lean off the ventilator would be another cue to say like, hey, let's take a look and see if ph is a contributing factor. Um you know, at least in the PPHN net uh recommendations. Any patient who is ventilated beyond seven days, they recommend an echo screen. Um Yeah, it's pretty early. Um but it, it is out there um and then sensitive hy hypoxemia. So, you know, is this a patient who has these hypoxemic spells? It's always a little difficult to understand. Was that spell related to BPD or PH or both. And I don't think you always have to get it all completely sorted out how much contribution of one versus the other. But I think I understand that if they're having spells that they may have some ph and eventually you're watching for right heart failure. And this is really what we're trying to avoid by joining is, you know, is that patients developing, you know, that omega tachycardia edema fluid overloaded and difficult to feed, you know, you're already probably pretty far along the way and it's gonna be much more difficult to rescue that patient. Um So the screening, there's really two forms of screening that we have. So one is echocardiography. And so, you know, and that's a recommended uh again by uh A TS and um and the uh AC C and again, that's a, you know, a, a good strong recommendation to go ahead and screen. Um and the echo evaluation. So you're trying to understand, you know, what is the estimation of that? Right ventricular systolic pressure you're trying to evaluate for right ventricular function, you're looking for shunts. And um you know, there are limitations. So all echoes you know, occur under the loading conditions that are happening. And also part of that is the ventilation. So if that patient has an ugly X ray that morning and is agitated, that echo is going to look very different than a patient with a well expanded X ray who's not too agitated and sometimes it's difficult to understand as the consulting team, you know, what's really going on with this patient. Have the conditions changed for that day for that patient or is the has the pulmonary hypertension worsened? Because again, the right ventricular systolic pressure estimated will be higher if you have adalacis collapse or over distention. Um and they'll be higher if that patient is agitated at the time of the study. Um And then you have image quality and interpretation. So these are, you know, performed by echo text or read by echo readers. So all this is, you know, dependent on, on human interaction with the study. And then your other biomarkers are naturally tic peptides. This is got like got the largest body of, you know, evidence looking at this. Um It's currently recommended by the Pulmonary hypertension pediatric Network, but not recommended by the A H A and A CS statements. And so your two markers that you can look at are uh NT pro BNP and BNP. And these, you know, don't come, you know, don't tell the whole story either. So you're gonna be affected by fluid status. So if you are fluid overloaded, your BNP will be elevated as will your N GB NP and your renal function. So, if you have abnormal renal function or abnormal clearance, it'll be um you know, falsely elevated as well. Um It's just a little more on, you know, your B MP. So there's uh BNP is secreted by your cardiac myocyte. Um It is, its secretion is induced by wall stress as well as a response to the perricone and endocrine signaling. What it does is it causes some diuresis basal dilation, inhibition of ren and aldosterone. So, when that atrium is feeling stressed and there's increased while stress and there stretch, then you know, the body's appropriate response to that is to remove fluid and not, not hold on to fluid. The N TB NP has a longer half life and in multiple settings from, you know, adult heart failure to pediatric heart failure and a number of others, the N TB NP tends to perform just a little better as a diagnostic test. Um but it sort of depends on what your center has, right? Like if you have BNP, like I wouldn't avoid using it. It's just like if you're, you know, advised in the lab and which one they would choose. NTPNP is probably a better study to, to purchase. Um And you know, background utility, I mean, this has been used in, in uh neonatal populations that are close to the BBPD population but has never really been shown to be effective in that BPD population. And so it has been shown to identify a hemodynamically significant PD A in the NICU. And so I think that's a good screen. Um It's been shown to be a pretty effective congenital heart disease screen in the er, for neon aids who present to the er with any kind of respiratory distress screening, that respiratory distress from congenital heart disease. And it's been pretty effective in pulmonary hypertension risk stratification for Children. Um But again, the use in um in PB PD is a little less clear and this is probably the best uh systemic review of its use. So um this is a very nicely designed, you know, uh systemic review. They looked at nine studies, the overlap between those studies didn't, it wasn't enough that they could do a quantitative analysis, but they were able to do a qualitative analysis. Um And their conclusion was really that, you know, based on some, you know, what they called low quality evidence suggests that BN TB NPN or the BNP are adequate for triaging patients. And so, you know that what that came with was um you know, a sensitivity and specificity um that you can see there just about uh what was that about 0.9 on both. So, actually quite good. Um And then here is your um receiver operating curves from that same analysis and just highlight it in orange as both the BNP and the N TB NP. And so I think it can be useful. It just has to be taken in the context of if my patient's BNP is elevated, it doesn't necessarily mean that they have pulmonary hypertension. It could be that their fluid overloaded needs some diuresis. Now, after that diuresis if it's still elevated, then that, that may indicate that they, they do in fact have some pulmonary hypertension. And again, the physiology that's going on there is that RV is seeing after load and there's some atrial stretch that is leading to the release of the MTV and P. And so getting into echo, um you know, to estimate RV, afterload, you've got your shunt gradient, I'd say that's probably the most reliable measure. Then you've got your um TriCor regurgitation jet that's pretty reliable. It is dependent on the angle at which you look the parasternal short axis round, this is probably less reliable but more available. Um And that's really gonna be reader and angle dependent. And so that's where I think sometimes it's difficult for us to say how significant a patient's PH is. Um And then, you know, another one we see it's easy to the end diastolic P I jet. We don't always get it, but it's a nice measure in cath versus um versus P I jet, it's been shown to be quite comparable, not in, in the units necessarily, but in, in larger patients. Um And so I think it is a good measure when it's available. You do, of course, have to have a pulmonary insufficiency jet to, to get and they probably, or at least reliable for most available measure. Is that a SD or PFO um direction. And so I think we get a lot of calls about that but, you know, the physiology is really, you have RV, afterload leads to some kind of fiber lengthening and, or thickening and then diastolic dysfunction. And remember it's just the A SD or PFO is just going to go in whatever direction is the lower of the two diastolic pressure. So, if your LVEDP is higher than your RVDP, then it'll go left to right. If your RVDP is higher than it'll go right to left. And so it's a very indirect measure of RV afterward. Um And all these, you know, it's, it's again, reader, depression um for function. Um And then, um there's no real reliable measure for RV function and pediatric use to date. There's a lot of papers that come out, it's definitely generated careers looking at like T index RV, fractional, um shortening index, but none of them have really panned out in pediatric, let alone the neonatal population. The only one that's pretty good is TSI, that's the best available that we have and that there's a lot of limitations because what you're really doing is you're just looking at the movement of the free wall of the right ventricle. Um And so if you again are volume loaded, that free wall will move more than it would if you were not volume loaded and may falsely increase the function of RV. So whenever you see RV function in our reports, it's always going to be a subjective qualitative report. So your overall reliability of echocardiography, despite all these limitations is still quite good as long as it's performed by, you know, cardiologists. And so, um, you know, when you look at a pulmonary hypertension diagnosis, um and this was a look at, um, gosh, this is about uh 500 echoes by three different cardiologists and in a group of 40 patients, and you can see that, you know, overall there's a pretty good fly Kappa at 0.8 near 0.8. Um And then, you know, that is broken down by period as well from the reading periods that kind of, they broke it into 33 regions of time. And so kind of taking that away. Um Again, I think you have high inter and intra rater agreement um as far as echocardiography, but again, it depends on the team you're using, right? So not just anybody can jump in and you probably really want echo readers, you know, so, you know, your cardiology team really specifically reading and that's, you know, we have that advantage here at a big center that, you know, it's not just the on service cardiologist who's giving you your report that somebody who's reading echoes, you know, at least a few times a week for their career. Um And then advanced imaging. So when do you do advanced imaging? It's always a good question. Um So the disease isn't following your expected course. I think this is probably the most important reason is that you have this patient with BPD, they're on a single agent for pulmonary hypertension and they're just not doing what you would expect them to. Um, if you develop pulmonary Eden with your vasodilators, that makes me wonder if you have some kind of postcapillary disease process going on. So, is that pulmonary know occlusive disease? Is that pulmonary vein disease? That really is a clue to me that says, you know, that vasodilator is not helping the patient. Because again, all our pulmonary vasodilators are directed to pulmonary arterial hypertension. You can always have postcapillary disease that won't benefit will be harmed by, by treating with pulmonary vasal diaries. Um and then making sure that, you know, your ventilation, your m emulation, your reflex are all as optimized as they can be. I know we're limited in what we can do. But I think again, having those, you know, multidisciplinary team rounds with Pulmonology as well as ENT is really helpful because, you know, we can then sort of come into most of our consults as a phd, knowing that those things have already been looked at and then as optimized as they can be um until we get the perfect reflux treatment that will probably just have to make it non painful. Um And then, you know, I think for me, the next best step is often AC T scan, you can pick up a lot here. So, you know, one of the big things you're wondering about is, does this patient have pulmonary vein stenosis? There is a pretty big overlap in pulmonary vein stenosis and PH and BPD. So you're looking at, you know, somewhere depending on the series of up to 10, maybe even 15% of those patients have been published. Um There's probably some selection bias in those publications because I don't feel like we see that much here. Um And then other things you can kind of pick up indirectly is developmental lung disease. So, do you have alveolar capillary dysplasia surfaced? Um, uh abnormalities, lym enasa pig. Again, all these disease processes, they have sort of unique findings on CT scan, but it's, it's not perfectly diagnostic, but at least it can take you in that direction, especially in a patient who's not doing what you wanna do. Um, and some of these, you know, you're gonna worsen their course. If you really add pulmonary your stomach, it's important to know that as well. And some of these, it's just important to know because you'd wanna be redirected care. If you have alve allergic capillary dysplasia, you don't wanna drag that along for months and months with those families. And I think, you know, unfortunately we've all had those, you know, both in the, in the cardiac unit. We certainly had them where you find out later and it's, it's really pretty awful. Um, and then cardiac cath. And so I think, you know, when you go to Cath, I think when you wanna understand the hemodynamics, if you're worried about pulmonary vein stenosis, and you wanna know that cardiac output and diastolic dysfunction. So, for me, that's, that's a patient who's on single agent, not getting better and, and, and even showing some early signs of right heart dysfunction, that's when I'd say, OK, it's probably worth the risk of that vascular injury to really understand what's going on, get that imaging and expand our diagnosis at that same day. That would also be a patient where I'd start looking for. Do does this patient have a genetic cause of um you know, idiopathic pulmonary retension or, or a genetic cause of primary pulmonary hy pretension, sorry, not idiopathic, that's contributing, right? Like, so you may be sending genetics at that point too. Um Even those CT scans, you really want to probably do a high resolution and you'd also, if you have a question of pur stenosis, you're gonna want that to be a cardiac study because otherwise you may not pick that up. Um And so then, you know, looking at that kind of screening path all along this is again from the phpn uh net network. So again, pulmonary hypertension pediatrics network, um and we pretty much follow this in our practice. So again, you know, is it mild or moderate uh to severe BPD, you know, for the moderate to severe, you definitely wanna get that echocardiogram going earlier if it's mild or none, you know, if they're just having more oxygen requirement than expected, take a look, they don't have ph, then, you know, you don't have to worry about it. Just continue managing their BPD or at least I don't have to worry about it. You guys still do, um, if you have mild to moderate, you know, and this is where it gets really hard, you know. Are you half systemic, two thirds systemic? What does that really mean? Like was the patient just a little angry and now they're two thirds or was it real? Um But you really kinda want just optimize that patient outside uh their ph management. Again, we here would probably be taking, you know, adding in a single agent somewhere around here for, you know, really any of this for our group. Um You could make an argument that maybe you should reserve it for the higher pressures. But um we tend to be a little earlier in our in uh therapy. So this would probably be a deviation for our group is that patients that are persistently more than half to two thirds of stomach. But we don't have another good reason. We would probably get them started on therapy rather than wait too much longer. Um And then I think this other idea of just continuing to repeat your echocardiograms. And again, as a group, we will tend to wait a little bit longer on our catheterization, especially because we, we feel like we understand often what's going on with the patient and we can't offer much in the way of intervention. And so I think, you know, modern cats really want to have an interventional plan going in if you want to be able to modify their disease. Um And so are therapies. So your treatment pathways, you've really got three pathways you can treat right. You got prostacyclin, the IO pathway and then the endo one pathway. And so the FDA approval for these, you had epoprostenol back in 1995 followed by Bosin. Then um Sildenafil came along not until 2005. And Bosin was actually improved for pediatrics in 2017. And it's really these three that we're using to treat. So you have your phospho Ditra as five inhibitors um that's gonna be treating that ino pathway. So, again, the most obvious is you just give ino, right? So in phd INO is down regulated. It's a long, they had long standing use to direct immediate effects. Um it improves your VQ matching. So even if that patient doesn't have pulmonary hypertension, their SATS will still probably go up and their oxygen will still go down for at least a period of time. You do have to monitor for me hemoglobinemia and then there's a significant cost associated with it. Um And then, you know, and uh you know, further down that pathway, again, your um nitric oxide production is decreased that um for the phosphor iray in five inhibition, you're gonna maintain high levels of psychic GMP, which potentials that affect dos io. And so in the end, you're going to get basic dilation, anti proliferation an effect. And so that's again your Tadalafil so that Sildenafil and others, um you know, one new option in this pathway, which we don't really have two available is rio squat, that's a soluble Guana cycle stimulator. So that's down here. And so what you're doing is it has what's called a dual mode of action, right? So you directly based the dilate you increase the to ino but our, our experience is pretty limited and, and for our PH group, we really haven't used this a whole lot yet, but it could be um an interesting medication down the road. You do have to completely come off with the Sildenafil to go on to that. So you do, it's a little bit of a challenge there. Um And again, the PD A five inhibitors, what we have available you get Sildenafil is probably the most experienced. Um You have multiple small trials in both PB in BPD. You have pediatric trials. This both starts in one in two trials for congenital heart disease and pulmonary hypertension as well as idiopathic. Um you got some pediatric persist or persistent pulmonary hypertension, the newborn trials. Um and then it's also been used for ino withdrawal following um congenital heart disease operation when they just want to avoid that withdrawal. It's your first line therapy. It's a class one recommendation and a level B of evidence. Tadalafil is a great option if you're bigger but not, not really a great option in the eu um but it is one day dosing once you get beyond about three years. Um And this is really the medication we have the most evidence for. So this was, you know, a meta analysis of, you know, so dental use in bronchopulmonary dysplasia, there are five studies that fulfill criteria. Again, you can see I entered the, the numbers of patients and it's small a pool, you know, study of only about 100 and one patients total in the experience. Um and their conclusion with, you know, soils associated with improvement in their P A pressures and respiratory scores, there was no clear evidence of effect on mortality, but they probably didn't have enough patients who to really look at mortality as well. Um Then you come into your end theil receptor agonists or antagonists. So, again, that's down the end thelin pathway. So this pathway is basically endo one is basically constrictive um causes new muscle proliferation and fibrosis. Um and effects are mediated by endo A and B down here. And so you can inhibit this pathway with bosin massac um or a selective like Amberin. They all have similar efic efficacy. Bosin has probably got the most experience as well as approval, although it does cause transaminitis. And at least there's some known fluid overload. Um not clear if it is. Well, it is clear that the transaminitis doesn't occur as much with the masses set nor the uh Amberson. Um But the fluid overload is probably still yet to be determined. And so that's always a worry of mine as we add, this is that it's something you usually want to avoid in, in a primary lung process. Um And so our evidence, it's all observation series. So we don't have any good trials of this. There's, there's probably a need uh for that. And then, um there's some BPD patients like one or two BPD patients included in each of these sort of available series. So it's not even really enough to make any determination of whether that was effective in this specific population. It was more just a large cohort of neonates in the NICU who received these medications. Um It does appear to be safe and it is used and our group uses this kind of our typical second agent and then prostacyclin, I mean, it's a big commitment, but it is really effective. So again, prostacyclin pathway, Rachon acid turns in the prostaglandins creates PGD one. And then you got your prostacyclin derivatives that you know through this um Ay Colin sorry, at least the increased cyclic A MP. And then that is uh Vasil and anti and inhibits smooth muscle growth. It's anti-inflammatory and it causes some platelet inhibition. So they're all very favorable effects for patient with pulmonary hypertension, sort of everything you'd want to be happening, right. Um, two available medications is op prostin its flow and very difficult medication to use. We don't have it on formulary here, uh, any longer, which is good. It's got a very short half life. It's the only medication to increase survival. Adult ph, you'll hear this from some of the adult folks that are on service, but that's a bit of a misnomer, right? Because once it was approved, as compared to a placebo that you could no longer ethically prove the efficacy of tr prostin or a module which came along later. So all the studies since have been comparison trials between trap prostin and epoprostenol and Trap prostin has never been shown to be superior, but it has been shown to be similar in effect. It's also a lot safer because it has a longer half life of 30 minutes. It's got more stable formulation and thought to be equivalent to prostin. Um There's gonna be slow advances with both because the systemic side effects um can be pretty significant. Primarily hyper hypotension is when we worry about the most clinically. Although there is G I distress flushing and agitation are also very common with both things. Um You can see how this would be a life threatening emergency if you lose a line. That's one reason in pediatrics. Um At least my preference is to avoid the, the flu and other options you got CeleXA, it's oral. Um, in adult studies, it seems to be similar. It's actually maybe a pretty good drug and may, you know, at some points plant for most of adult pulmonary hypertension, we just don't know enough about it yet. Um, but it's normal medication which is excellent. And then I Laros again, we don't have a lot of literature to support it, but we do use it. Um, it is approved for adult Basal Dilator testing in the Cath lab. It's got a very short half life. So you're gonna need repeated interval dosing in about 23 at the, the max if you want to reach steady state, um there's some technical considerations so your RT S have to know how to use it. Um And then um it is tri so you gotta be careful about your bedside staffing and exposure as well and uh difficult in the current physical setup of the NICU. Um And then you know your evidence for it is we have some observational series and C DH as well as PH with congenital heart disease. It seems to be effective, but there's just no literature really looking at BBD specifically. Um And they're kind of summing it all up. So again, if I know, but on the annual pathway, we have observational data, there's no current studies plan or pending. Um it is approved for PPHN and N Unites. Um So then fl again, it's approved in adults, it's probably our go to single agent medication for this disease process and should cover the vast majority of patients with BPD and pulmonary hypertension. Um Citra is kind of interesting. So there is a phase one PK study. So this is if you go back to that pathway, all you're trying to do is just provide that um sort of up, you know, upstream um reagent to kind of create the effects uh down the, the pros uh the PD five pathway that said, like, I've certainly seen a lot of really disappointing trials that, that look into supplements and their effect. You know, like I, we got really excited about sepsis and, and vitamin C and the adult and pediatric IC world and that, that turned out to be a real big disappointment. So, um you know, we'll see if it plays out as well as we hope. Um but then again, um no current studies, it is approved in Children, which is nice. Um And I think it does have a role as a second agent, but again, a lot to it because you're, you're adding, you know, monthly monitoring for the transaminases um as well as the risk of fluid overload. Um you know, trade pro again for our patients that are really, you know, stuck in it. I think it can be life saving, but you're pretty far along the way and if you got BPD with this, you probably wanna look for other other things going on as to why they're there. And then I pro I think it's an excellent rescue and I think we should have it available. Um And I think some of the strategy of BPD, which is sort of hard, maybe rather than adding or layering on medications may be a single agent strategy with just good rescue. Um, but that's a lot easier to say as a consultant than the one at the bedside doing the rescuing because it's not fun. I know. Um So put it all together, you know, you want to be screening, you wanna be aware, you know, understand that this diagnosis does require some echo expertise, um evaluate and mitigate those uh associate these processes that this multidisciplinary teams big. There. You get a single agent disease is the way I think of this disease unless you know you're outside of bounds and she's looking more, you wanna allow for that somatic growth. If you just wanna keep this patient adequately controlled and rescued until they're bigger because this disease process should get better as they get bigger as you guys do a good job keeping them. Um And if they're not following their expected course, without clear reason, you wanna expand that differential, look at hemodynamics and then don't forget about looking for the AIDS. It's fairly common. Sorry. Thank you guys. Published December 8, 2023 Created by Featured Providers Kevin Engelhardt, MD Cardiac ICU View full profile
