Hi, I'm Dr. Corey Charton. I am an assistant professor of pediatrics in the Division of Critical Care Medicine and Pulmonary Medicine at Baylor College of Medicine in Texas Children's Hospital. I am currently part of the Pulmonary Hypertension Faculty, and I'm the associate director of our Right Ventricular Failure Program. I am going to be talking about pediatric pulmonary hypertension management, and this should be an update. I do not have any disclosures. And so first I'm just going to talk about an overview. So initially we're going to talk about pulmonary hypertension, the definition of it, and the vascular phenotypes. We're going to talk about classifications. We're going to go through pathobiology. We're going to talk about the role of early endothelial dysfunction associated with pulmonary vascular disease, therapeutic implications, the outcomes that we know, and then therapeutic and management options that exist for patients that have pulmonary hypertension. So first to start off, it's really important that you know that pulmonary hypertension has hemodynamic, structural, and functional implications and manifestations. And so typically when we think of the hemodynamic properties of pulmonary hypertension, we think about increased pulmonary vascular pressures, as well as pulmonary vascular resistance being elevated. And so the gold standard at diagnosing pulmonary hypertension, and what we call pre-capillary pulmonary hypertension, or PAH, has a pulmonary artery pressure of greater than 20 millimeters of mercury at rest. This used to be 25, but after the new criteria that came out, it is now over 20, with a pulmonary capillary wedge pressure less than 15, and a PVR greater than three Woods units. Structurally, it's associated with vascular remodeling, and this is both at the endothelial and the muscle cell layers. And then when we talk about functional disease, pulmonary hypertension functionally causes increased vascular constriction, and it also causes impaired relaxation. It's important to know that there are some populations that we talk about and that we clinically help and do consultations for, and these are patients where there are relevant pulmonary vascular changes. They may be present, and they may actually not meet this criteria when a cardiac catheterization is done, but they still could have a reactive pulmonary vasculature and could require pulmonary hypertension therapy. And the best example for this is patients that are part of the single ventricle population. So next, it's really important to talk about some of the physics involved in pulmonary hypertension, like Ohm's law. So Ohm's law, when we talk about it, is really the resistance equals the change in pressure over flow. And so when we talk about the resistance pattern, and when we talk about PVR, typically we talk about the mean pulmonary artery pressure minus the left atria, which usually, because we're only doing a right heart catheterization, is given to us as a pulmonary capillary wedge pressure over the cardiac index. And so that PVR value, the normal value, is typically between one and three Woods units indexed. And so you'll see some people use Woods units, and some people use Woods units indexed. And the reason is that you're dividing it by BSA, and that's really more helpful in patients that are pediatric size and age. And then the next important formula is Poiseuille's law and Poiseuille's relationship. And really what that is, is looking at the numerator, which is viscosity, and the denominator, which really has resistance as part of it. And because the resistance is taken to the fourth power, it really shows and exemplifies that any small decrease in the radius related to vascular remodeling can have a significant impact on the calculated resistance that you have. And so when we talk about increased right ventricular afterload, which is what pulmonary hypertension really is, what you have is increased PVR, which leads to decreased compliance. And you can end up with significant right heart dysfunction, right heart failure, and then death. And so this is a really nice picture to talk about the role of the right heart and how as pulmonary arterial hypertension gets worse over time, your cardiac output declines. And so when you look at this schematic picture, it really shows that there are three different categories. There's this pre-symptomatic or compensated phase, there's a symptomatic decompensating phase, and then a declining and decompensated phase. And as the pathology of the patient progresses, the pulmonary pressure increases, and the pulmonary artery pressure rises at the same time in order to maintain cardiac output. And as long as that right ventricle is able to compensate for the resistance, the pressure continues to increase as pulmonary vascular resistance increases. And the increased RV workload causes RV hypertrophy and a decline in efficiency. The right heart failure develops over time, and the pulmonary artery pressure drops as the patient decompensates. And then finally, failure to maintain cardiac output can ultimately lead to right heart dysfunction and at some point, death. And so getting into the pathobiology of pulmonary vascular disease, a lot is really known about endothelial injury, which is where most of our medications are specifically focused at. And so some of the other things that we talk about that are also important are inflammation, talking about altered metabolism, patients that have coagulation disorders, or increased either clotting and or bleeding, it's really helpful, as well as genetic predispositions. And then also potassium channel disorders have been linked to patients having worsening pulmonary vascular disease over time. And so it's important to talk about the historical data that exists before available treatments were even readily available, especially to our pediatric population. And so before targets were available, the estimated median survival for adults that were diagnosed with pulmonary hypertension was 2.8 years, and the mean five-year survival was less than 40%. And so as most of you know, pediatric data is pretty limited. But what we do know is most pediatric patients prior to 1995, the average time from diagnosis to death in those patients was about 10 months. And so luckily, outcomes have significantly improved. And as these comprehensive care centers with pulmonary hypertension specialists exist, and there are referral centers that can take care of these really complicated patients, I think that we have seen vast improvement in some of the outcomes that exist. So next is to talk about the pH treatment pathways. And so all of the pathways and all of the medications that we have that exist are really based on targeting the endothelial level. And so the three different pathways that you've probably heard of are the endothelium pathway, the nitric oxide pathway, and the prostacyclin pathway. And so the endothelium pathway really works well at inhibiting the remodeling effects that exist in the vasculature. Endothelium receptor antagonists typically work on ETA and ETB. And then when we drop down to the nitric oxide pathway, nitric oxide pathway is the one that really can be supplemented in three different ways. So providing inhaled nitric oxide by stimulating the enzyme to augment the cyclic GMP, or by prohibiting phosphodiesterase, which breaks down cyclic GMP. And then the prostacyclin pathway causes vasodilation. It causes inhibition of smooth muscle proliferation. And we have a couple of different medications that can be used to augment that. So when we talk about general pH management, it's really important to have these five goals are kind of what we think about when we're trying to manage these patients. So you want to prevent and treat active pulmonary vasoconstriction. You want to support the right ventricle in any ways that you can, typically by dropping the right ventricular afterload, and by potentially helping support either with inotropic medications or vasopressors. We'll talk all about that in the coming slides. Treat the underlying condition. So if this patient has known pulmonary vascular disease, but is actively infected with a new pneumonia, that in turn is probably going to cause your right ventricular afterload to be increased, and that treating the pneumonia itself and the underlying problem would probably help you. Preventing regression of structural disease, and then surgical and or interventional therapies that could help both the pulmonary vascular disease as well as the RB if it's failing. So it's really important to know the stimuli that increases pulmonary vascular resistance. So the things that we always talk about, which we'll go over in the picture of an algorithm in a second, is pain and agitation. So the alpha-1 receptor can cause stimulation and active vasoconstriction. We know that alveolar hypoxia can worsen pulmonary vascular disease. Intermittent acidosis, so hypercarbia, the inability to ventilate appropriately. Over or under distention of the lungs. So we always talk about that PVR curve that everyone has seen. And so either having lots of areas of atelectasis or being over distended with an extra amount of PEEP. All of those things, if you're not at FRC, could make you have worsening pulmonary vascular resistance. And then obviously in newborn babies that have persistent PH or PPHN, those patients will have a higher pulmonary vascular resistance that requires a little bit more help, sometimes with medication, to drop that pulmonary vascular resistance. And so this is the algorithm and the pathway that I was alluding to. So if you start at the top, you have the inciting events. So those are hypoxia, so alveolar hypoxia, agitation, acidosis. And if you go down, that in turn causes increased pulmonary artery pressure. It can increase your pulmonary vascular resistance, which in turn causes elevated right ventricular afterload, which leads to RV failure. RV failure can then increase your right ventricular end diastolic pressure, your right ventricular end diastolic volume, which could lead to interventricular septal shift, which can cause systemic hypotension. Systemic hypotension, in turn, could lead to a metabolic acidosis, which are back up at the top, which could then increase your pulmonary artery pressure, increase your pulmonary vascular resistance, causing right ventricular failure, which increases your RVEDP and RVEDV. That could lead to septal shift. That could decrease your left ventricular end diastolic volume, which decreases cardiac output, which then causes metabolic acidosis also, and increases your pulmonary artery pressure and your PBR. So we're going back in this circular physiology, which causes the right ventricular failure, which increases your RVEDP and RVEDV. That could lead to ischemic changes of the right ventricle or even the left ventricle, depending on how this patient is doing, which can lead to arrhythmias, and those arrhythmias could then lead to a cardiac arrest. And so one of the other respiratory parts of this circular physiology is that increased pulmonary artery pressure and PBR due to hypoxia, agitation, acidosis, can lead to RV failure. RV failure then causes decreased pulmonary blood flow, which could then lead to decreased perfusion. So you might be ventilating in areas that are not being perfused well. So that causes VQ mismatch, which leads to hypoxia, respiratory acidosis. And that could lead you back to increased pulmonary artery pressure, increased PBR, and RV failure. So when we talk about acute pulmonary hypertensive crises, it's very important to use this nomenclature appropriately. So it's important to know that for you to have a crisis itself, you typically need some kind of inciting event. You get an acute rise in your pulmonary artery pressure, acute rise in pulmonary vascular resistance, and that has to lead to acute RV failure. So if that doesn't exist, there may be little babies with BPD spells or acute hypoxia, but those might not be actual hypertensive crises. And so it's important to just utilize the nomenclature appropriately. We kind of harp this on our fellows and trainees because it's really important because sometimes the treatment may be a little bit different. And so when we talk about pulmonary hypertensive crises, these are obviously events that can be lethal at any moment. So any of that circular physiology could lead to arrhythmia, could lead to decreased perfusion, decreased cardiac output, metabolic acidosis, and this circular kind of spiral downward that typically can lead to death, especially if patients are not able to be taken out of that or have a shunt that allows them to maintain cardiac output. And so what this looks at is really the incidence of crises following congenital heart disease repair and knowing that it's really decreased significantly since the 1980s when really up to 50% of patients that went through cardiovascular surgeries experienced a crisis. And so today the rate is like much lower than that. It's now down to close to 4% in left to right shunts. And mortality has also decreased from between 33% and 50%. It's now closer to 20%, which is still pretty significant, which is why these kids are still very sick and really need cardiovascular physiologists to manage these patients appropriately. But understanding the pathophysiology of pH, really understanding pulmonary hypertensive crises and how to treat them is really very, very important. And so as we continue on, let's talk about the recognition of these pulmonary hypertensive crises. And so as we discussed, there are things that you can look for. Increased pulmonary artery pressures. So these are really for patients who have an active pulmonary artery line that's in place. In our institution, it's very rare that this exists. In the pediatric world, we're not doing as much swangan catheter placement as we used to or PA catheters post-intervention. But every once in a while, a really difficult patient may come out of either the OR or the cath lab with a PA line, which could be very helpful because it's active time. As you augment and apply management, you can then use those numbers. You can use potentially an increase in right atrial pressure if you have an RA line. You could also use your CVP as potentially the surrogate to the right atrial pressure and you can augment therapies based on that. You can look for a decrease in systemic saturation and you can also look for a decrease in blood pressure. Typically in patients that are starting to have worsening RV dysfunction, what we will typically see is obviously patients that are hypotensive and they become tachycardic because they're trying to increase their cardiac output. And so when we talk about treatment for a pulmonary hypertensive crisis, there's a bunch of things that you can do. And so hyperventilation, so if the patient is not ventilating appropriately, trying to get them to normalize their pH by making them even a little bit alkalotic so you can kind of relax that pulmonary vasculature. The fraction of inspired oxygen, so oxygen is your best pulmonary vasodilator, it's the easiest one to obtain. So if they're not on 100% of 502, you acutely should change that. Making sure that this patient is sedated, that if they have a breathing tube, that their muscle relax. So this way they are not actively coughing against their breathing tube or causing any type of vagal maneuvers or just having more and more agitation as that noxious stimuli of a breathing tube is in. If the patient is a little bit acidotic, this is probably the one time it's okay to use sodium bicarbonate doses to really try to relax that pulmonary vasculature as well. You can also use inhaled nitric oxide. And then most centers now have some type of nebulized prostacyclin. At our institution, we use inhaled iloprost, which is a medicine that can be given scheduled, but it also can be used for these crises events as frequently as really every 20 minutes as needed. And so next, we're going to talk about management and management that's utilized to support the right ventricle. So we know that we can decrease the right ventricular afterload. We can do that by increasing the inotropic state of the right ventricle. What these two studies using and utilizing nitric oxide and neonates that have hypoxemic respiratory failure, what they showed are the results of the second study led to really the FDA approving inhaled nitric oxide for this patient population. So in both studies, there was a significant decrease in both death or the need for ECMO compared to placebo. And about 30% to 40% of neonates really didn't respond adequately, and they still required ECMO. So nitric oxide is really, we know it's a very selective vasodilator. And so it is great to use in an acute setting, especially if there happens to be, if there's lung disease that's involved as well, because it's only going to go to areas that are actively involved in ventilation. And it's going to only go to be able to diffuse across the membrane, the alveolar membrane to allow for vasodilation, which makes it that selective vasodilator. Next, we're going to talk about INO and the prevention of pulmonary hypertension after cardiac surgery. So this was a study that really, it was a single center study that really looked and was a randomized control trial of 124 children that had congenital heart surgery. After surgery, these children were randomized to either a low dose inhaled nitric oxide for seven days, or they got placebo. The children who got nitric oxide had lower PVRs over time when you compare them to kids that had placebo. And then nitric oxide was also associated with a lower risk of pulmonary hypertension crises. This is kind of the best data that we have right now. So when we talk about conclusion, INO after congenital heart surgery has really lessened the risk of pulmonary hypertension crises. It's also shortened postoperative course with no ill effects, which is why this is kind of the first, you know, this is the medication that people are using in almost all of their ICUs post-cardiac surgery, especially if there's concern going into the procedure or during the procedure that this patient may have elevated pulmonary vascular resistance. And then when we talk about acute effects of inhaled prostacyclin therapy in babies that have PPHN, it can be a useful second pathway. And so we use this somewhat often in patients that are diagnosed with PPHN. If they're already on INO, they're already intubated, they're already ventilated well and oxygenating as well as possible, we can use inhaled prostacyclin to try to decrease or, you know, get that persistent pulmonary hypertension to kind of decrease in a shorter period of time so that we can potentially avoid ECMO or, you know, cardiac arrest in those types of patients as well. And so there, INO and aerosolized iloprost were equally effective in selectively lowering pulmonary vascular disease, and that was found recently as well. This is probably one of my favorite topics to talk about. So RV inotropy and what medications should be used slash what combination of therapy should be utilized to help support the right ventricle when it's dysfunctional and the patient is critically ill in the ICU. And so this was a study that was sent out, it was actually just a survey that was sent to international experts that do pulmonary vascular disease. So it is important to kind of know that going in that, you know, if you ask a hundred people what their choices are, you know, depending on whether they treat adults or pediatrics or a combination of both, I think would change your opinions. At our institution, we are more interested in using low-dose epinephrine to help with contractility benefits and interventricular interdependence. And then we also use vasopressin really to help increase systemic vascular resistance to help shift over the interventricular septum to potentially allow for improvement in cardiac output and filling of the left heart. But if you look here, there are patients that are, some people that use dopamine, others that use milrinone, there are ones that use dopamine as well as norepinephrine and phenylephrine. We are a center that is, you know, for patients that have isolated RV dysfunction with typically hyperdynamic LV function, just because the LV cavity is so small, we do not use milrinone. I think milrinone, what we typically see is that it causes systemic vascular afterload effects. So you decrease systemic vascular resistance, which then shifts the septum even closer to the LV, which is already bowing at times. That's one of the concerns. One of the other concerns that we have is that milrinone, because it acts as a, it's a great pulmonary vasodilator, but it's also a systemic vasodilator. So if you have a patient who's got RV dysfunction, but also has lung disease to an extent, it's going to vasodilate areas that are, that it's going to vasodilate all of the pulmonary vasculature. And then if you have areas that are not actively involved in gas exchange, you may VQ the wrong way. So you might not be ventilating, but be perfusing areas. And so you may actually end up being more hypoxic, which could cause problems. So there's limited data that exists that PDE5 inhibitors or solid NFO can actually improve RV contractility. The theory is that because there's a crosstalk between phosphodiesterase type three and phosphodiesterase type five, so PDE5 inhibitors and PDE3 inhibitors, that by inhibiting PDE5 and increasing cyclic GMP, it would cause a corresponding decrease in PDE3, which would in turn increase cyclic AMP and contractility. In this study, they showed that the PDE5 inhibition effect may not entirely be a direct effect, but in part, maybe due to the fact that the indirect effect that causes cyclic AMP to increase as well. So ventricular interaction, I think is a really important topic, especially from the critical care side. And so typically in kids that have really high right ventricular afterload, their right heart is dilated, it is hypertrophied. Typically that interventricular septum that we talk about, instead of being a crescent shape right ventricle, you end up with kind of a concentric looking right ventricle with a bowing septum that bows, and that bowing part typically can bow into the left ventricle. And with increasing bowing of the left ventricle, you end up with decreased cardiac output. And so, we know that there is significant left ventricular contribution to RV systolic function, which is why when we talk about what are the medications that we could do to potentially help this, that's why low dose epinephrine, less than 0.05, utilizing the beta effect in the beta receptor, I think is the reason that those fibers that cross from the left ventricle to the right ventricle can help with contractility. And so when we talk about hemodynamic effects of the different agents that we use in pulmonary hypertension, this is a good study as well to look at. So this really looked at phenylephrine, it looked at vasopressin, and it looked at epinephrine. And the results that they found were looking at the ratio of pulmonary to systemic vascular resistance, and that it was decreased in three of the five phenylephrine patients, three of the five epinephrine patients, but it actually decreased in all five out of five of vasopressin patients. And so all three groups had an increase in aortic pressure, which is kind of expected, but only the vasopressin group was the one that consistently resulted in decrease of the ratio of systemic pulmonary artery to aortic pressure. And we think that the reason that this occurs is a couple of things. So one, you're increasing the systemic vascular resistance, which in turn then causes septal shift. That's kind of the way that we think that it potentially could help. And then the other thing, when we talk about phenylephrine and we talk about norepinephrine, because that's always brought up as an option, we typically don't use those or utilize those unless necessary at our center, really because we're trying to avoid having any alpha effect at all, because we know that there are alpha receptors in the pulmonary vasculature as well. All right, so we're gonna switch to talk about some of the medications now and the medications that we have to use to treat pulmonary hypertension. And so it's really important. Most medications that we are going to look at, everyone kind of knows sildenafil. This is the one that most people are comfortable using. This is typically ones that you'll see at almost every institution that you work at. And so it's important to know where the dosing comes from. And that's really what the STARTS 1 and STARTS 2 trial were. And so what it looked at is it looked at 235 children with pulmonary hypertension of all ages. And what they did was they randomized all these children to low, medium and high doses of sildenafil or placebo. And so they looked at a bunch of things. So peak oxygen consumption, functional class and hemodynamics that were improved with medium and high doses versus placebo. And those all kind of make sense. They ended up doing a STARTS 2 extension really to look at patients on placebo that were randomized to low, medium or high doses of sildenafil. And what we found, which is why we're gonna talk about the doses that we have is that increased mortality was observed with the higher doses. And that in turn has caused us to have an FDA black box warning. So if you work with colleagues from anywhere outside of the United States, they're still, we have a lot of people that are still utilizing higher doses of sildenafil, which typically above that kind of threshold dose, what we're seeing is patients don't necessarily have a whole lot more benefit, but they definitely have higher mortality that's associated, which is why we kind of have a cutoff. And so Pediatric Pulmonary Hypertension Network, so the PPHNet came out with recommendations really for the pediatric patients with pH, and this is what it is. So they say that it's really not a great idea to abruptly stop sildenafil, which I think most of us can understand that if you're getting a medication every eight hours and you miss that dose, what you can have is actually an acute vasoconstrictive event that could actually lead you to have a crisis. And so it's important for patients that take this as an outpatient also, that if anything were to happen with their medications, that they make sure that they get their doses appropriately and timed appropriately, because they could actually have negative effects associated with it. The doses typically, what we use is, full dose would be one milligram per kilogram. If they are less than a year old, we usually do four times a day. But if they are over a year old, then we typically do three times a day. If, depending on how that dose translates, other institutions will do 10 milligrams, three times a day for certain weights, and then 20 milligrams, three times a day for anyone that's over 20 kilos. The max dose that we typically use is 20 milligrams, three times a day. And so it's important that even if you come in, most people know the dosing of one per kilo. But if you're over that, if you're over 20 kilos, we still stick with that max dose of 20 milligrams, three times daily. And so when we talk about medications, it's really important to also know what the side effects are. And so this was a study that was done on 66 pediatric patients that have pulmonary hypertension that were either on monotherapy with sildenafil or had dual therapy with an ERA and or a prostacyclin. And it looked at really the side effects of medications. And so we know that if you think about how sildenafil works, because it's a systemic medication, it systemically causes vasodilation throughout. It works primarily in the pulmonary vasculature, but it will, when you're initiating it, it can cause systemic vasodilation. And so if you think of things that will happen if you have systemic vasodilation, typically you're decreasing perfusion to the gut. So that could cause GI symptoms like nausea, vomiting. If you are causing some degree of vasodilation or even vasoplegia in the patient, you can end up decreasing overall cardiac output at the times of the initiation of therapy. So you can end up with headaches, bone pain, leg pain, jaw pain, sometimes even neurologic events, which was what was listed here. So if you decrease your cardiac output enough and you're not sending blood up to the brain, then that could be the neurologic events that these patients were experiencing. Let's switch gears to the ERA. So the endothelial receptor antagonists, the main medications that we have are Bosentin, Ambrosentin, and Masetentin. We don't typically, I think we have one or two patients that we follow on Masetentin. Most of them are on Bosentin or Ambrosentin. Bosentin comes in a pill form as well as a suspension. Typically the dose that we will utilize is close to two per kilo per dose, twice daily. The issue with this medication is that it can cause liver toxicity. So it's important that liver function tests are obtained on these patients monthly and get CBCs on these patients every three months is usually what we will recommend. These medications are also, can be teratogenic. So you have a patient whose mother is of childbearing years or the patient themselves are in childbearing years, then these patients and families need to be enrolled in what's called the REMS program. And the REMS program is specific to prescribers. So you have to be part of this program. You have to sign a consent saying that you understand that you should not get pregnant while you're on these medications because you could lead to embryologic and teratogenic effects. Ambrosentin, similar with the teratogenic parts, but it comes in a pill. There is also actually a suspension that exists for that as well. Not, you don't need to get ASD-ALT monthly because it's not, does not cause as much liver toxicity. And so it's a little bit easier of a medication to take because it's once daily instead of twice daily. And now we're gonna switch gears to prostanoids or prostacyclin therapies, if you've heard the name before. And so there's a bunch of different types of prostacyclins that exist. We have a couple of different ones at our institution here. Epiprostanol or Flolan, if you've heard that name before, is typically a continuous IV medication that's given that has a really short half-life. It's between three and five minutes. Typically patients that have associated RV dysfunction and we are putting them on triple therapy, this would be the third therapy. And we typically will start them on epiprostanol before transitioning them to triprostanol. And the reason for this is that if they really do have dysfunction, the effects of this medication could make them extremely ill. And so that's typically why we would start with the epiprostanol. Triprostanol comes in many different forms now. It comes as a subcutaneous infusion, a continuous IV infusion. It comes as an inhaled option and it's called Tybaso. And typically patients that are started on this medication either have significant pulmonary vascular disease, but they don't have associated RV dysfunction at the time. And we think that they're a safer patient to go ahead and start on this medicine, which when you compare it to epiprostanol, who has a three to five minute half-life, triprostanol has a four to six hour half-life. Sorry about that. And then iloprost is an inhaled prostacyclin, which is typically utilized for patients that have precapillary or PAH. It is an inhaled medicine. It can be given via a face mask. It can be given through a CPAP circuit, BiPAP circuit or most commonly through a breathing tube while the patients are mechanically ventilated. And so this medication typically has a half-life anywhere around 30 minutes. When we schedule it, we typically schedule it inhaled Q3 hours. The dose of iloprost ranges from 0.25 mics per kilo inhaled Q3 up to one mic per kilo inhaled Q3. And we typically max out at a dose of 20 micrograms for this type of medication. This is something that we utilize here at my hospital pretty often. It's a nice medication as an inhaled option. It is very frequent though. So it's not a medication that we typically send patients home on. And so the next slide is looking at long-term IV epiprostanol survival in patients that have idiopathic pulmonary arterial hypertension. So I think this is an important one when we talk about survival rates in these patients. And so this study is really the only study that we have that has long-term survival data for prostanoids in children that have PAH. And what it did was it looked at 178 patients. The survival rates were higher in the younger kids that were started and found early. The factors that were associated with survival or poor survival in patients included really a history of right-sided heart failure, persistence of New York Heart Association functional class three or four at the three-month check-in and absence of a fall in total PBR of more than 30% relative to baseline. And so those all kind of make sense. So typically when we start patients on triple therapy that have idiopathic disease, what we're trying to do is kind of stop the progression of disease that's occurring. And so that kind of makes sense when you look at all of the things that were associated with poor survival or the patients who are either so far into their disease process that these medications may not necessarily help them. And these patients are probably also the patients that don't really have a great reactivity component to their pulmonary vasculature. And if you look at this paper, this was a paper that looked at long-term data for children that were treated with prostacyclines. And this was a retrospective study of 77 patients, 47 that had idiopathic pH and 24 that actually had congenital heart disease and associated pulmonary vascular disease. And in these kids, there was an improvement in the pulmonary to systemic vascular resistance ratio on both therapies at one to two years that was not sustained. And then the five-year transplant-free survival was 70%. Next, it's important to talk about surgical and interventional therapies that are potentially available for patients that have RV dysfunction and worsening pulmonary vascular disease. And so creation of potential right-to-left communication. So everyone has probably heard about atrial septostomy or creation for patients that have right ventricles that are not doing well or worsening kind of pulmonary vascular disease. Typically, the patient you think of is the one who comes in with a syncopal event, gets started on triple therapy and goes in for a kind of serial cardiac catheterizations looking at their pulmonary hypertension and how it's improving. And those are patients that if they don't have significant RV dysfunction, it may be reasonable to have an atrial septostomy placed. And so the reason for this is to, it doesn't necessarily decompress the right ventricular pressure because an ASD is a volume-based shunt and not a pressure-based shunt. But what it does do is that if the right ventricle fails for any reason, so if there's an acute afterload in the right ventricle, what happens is the right ventricle typically is trying to squeeze against a high pressure, it dilates, you end up with acute RV failure, that RVEDP and RVEDV rise, which increases your tricuspid regurge and increases the amount of volume and pressure of the right atria. And so if an ASD is present, it will then allow right to left shunting across that atrial septum that preserves cardiac output. It sends blood to the left atria, to the left ventricle, and then in turn preserves left ventricular output. One of the negative parts of having an ASD that's present, you might have more cyanosis that's present or mixing of blood across the atrial septum. The 24-hour mortality, at least based on some of the data we have, is 7%. The one-month mortality is 14%. So it's not perfect. There is some degree of mortality and morbidity that's associated with procedure, because typically these kids are just very sick in general. Syncope and right heart failure did improve in 88% of the patients that they looked at, which makes sense, right? So if you have acute right heart failure symptoms and you're out playing soccer, instead of having that syncopal event that maybe brought you to the hospital, you have acute right heart failure and exactly the physiology we talked about, you preserve cardiac output. It's blue cardiac output, but it's cardiac output that avoids you from having a syncopal event. The POT shunt is a really important one to talk about. This is the creation of a left pulmonary artery to descending aorta communication. And that could either happen via a stenting of a PDA in a small child with a PDA that's still present. It could be a surgical creation of a shunt that happens, which is typically done at kind of isolated centers. We are a center at Texas Children's that does offer this. We've recently started to do that. And the main group that's doing these procedures are out of St. Louis. And then Columbia is also known for their unidirectional valve closure, or sorry, the unidirectional valve POT shunt, which is a newer thing that's being offered currently for patients that have some degree of bidirectional flow or would have bidirectional flow through a PDA or PDA-like physiology. If you put a valve in that only opens up when the right heart is super systemic or the RV pressure is super systemic, it allows for offload of the pressure so that the right heart doesn't fail, but it doesn't cause additional QP when the patient is not super systemic. And so that's a really nice option. The issue with that is that it's typically only offered to a little bit older children just because of sizing, at least that exists currently. And then ECMO is one of the other things that we talk about, extracorporeal membrane oxygenation from a VA standpoint. So typically with RV failure, you need VA ECMO and not VV ECMO, because what you want to do is offload the pressure of the right heart and not volume load the right heart, which is what VV ECMO does. Typically when we talk about VA ECMO, it should be a bridge to something, right? So ECMO helps you support yourself to be able to diagnose the patient, to be able to, you could place them on VA ECMO as a bridge to up titration of therapy. That's something that we offer at our hospital. So if you have a newly diagnosed pH patient who comes in and is an extremist, sometimes we will put them on VA ECMO as a bridge to triple therapy, to blast them with pulmonary hypertension therapies that we have to kind of decrease their PVR as much as possible, with plans to come off of ECMO as soon as possible as well. You could also do ECMO as a bridge to intervention if possible. We recently had a patient who was placed on ECMO as a bridge to pulmonary vein stenosis intervention. And so they went on ECMO, we stabilized the child, and then we were able to actually intervene, open up some of the pulmonary veins, and then we're able to take him off and he has survived. So utilizing ECMO as a bridge to something. There are some patients that have severe pH that are already evaluated and are listed for lung transplantation. And so here at this institution, we will discuss patients to put them on VA ECMO as a bridge to transplant for lung transplantation in patients who are already evaluated and listed for transplant. And then the study that talks about the palliative pot shunt is listed here. And so this one looked at 24 patients. These patients were all on triple therapy, drug refractory pH. 19 of them were surgical. So that surgical approach to the pot shunt or the LPA to descending aorta shunt that's placed. Five of these patients were transcatheter-based. So in the cath lab, they evaluated these patients whose LPA or one of the pulmonary arteries was pretty close in proximity to the aorta. And they, in the cath lab, transcatheter-wise, put this shunt in place. The median follow-up for that was 2.1 years. For these patients, the WHO functional class dramatically improved in the 21 survivors that we're gonna talk about. And you can imagine that if you have an offload to that RV and it's no longer failing, the heart failure symptoms that existed seem to be better. There was no syncope, no overt RV failure that existed. One of the really important tests that we do to kind of look at patients over time is something called a six-minute walk distance. And it's something that you can compare from clinic visit to clinic visit to see if your therapies are working. And the mean six-minute walk distance improved for these patients pretty dramatically. BNP, or B-type natriurtic peptide, or N-terminal proBNP, depending on which level that you guys use in your center, they normalized in all the patients because, as you can imagine, because BNP is typically elevated in right ventricular strain, that if you offload that pressure to the right heart, the RV failure goes away, the strain goes away over time, and so the BNP would be lower because the right heart is not as dysfunctional or strained. A lot of these patients weaned off of IV epiprostenal or triprostenal, and there were some severe postoperative complications in six of the 24 patients. Three early deaths were related to low cardiac output syndrome. One patient ended up requiring a lung transplant six years after their surgical POTS shunt. And so what came out of this study or what came out of kind of looking at these patients was that the shunt really does allow for prolonged survival and really long-lasting improvement in functional capacities of these patients who, without this procedure, would have died. Okay, I think that's gonna be the end of my talk. This here, if you have any questions, please feel free to ask them. This here is an app that's present for Apple, so iOS app, it's called Pediatric Pulmonary Repetition for Medical Providers. It has a lot of information and some of the information we talked about today. It's a free app, so you're welcome to use it. This was created by myself and one of my colleagues, Dr. Coleman at Texas Children's. And so we hope that this would be a benefit to you. Like I said, if you have any questions, please feel free to ask them.

pediatric pulmonary hypertension

Dr. Corey Charton

PH management

hemodynamics

vasoconstriction

sildenafil

atrial septostomy

ECMO