Respiratory and Cardiovascular Care for Neonates with Fetal Kidney Failure

Uh, it's an honor for me to present Doctor Stanzel today. Uh, she is a neonatologist at Mayo Clinic at Children's Center, and she serves as the medical director of the neonatal fetal Treatment Center. She is the leader of the Children's Hospital Neonatal Consortium at the fetal therapy focus group and is actively involved in. The North American Feal Therapy Network. She's extremely passionate about fetal therapy and moving the field forward with an eye for outcomes. Today her talk will focus on pulmonary and cardiovascular care of neonates with congenital anomalies of the kidney and urinary tract. Please welcome with me Doctor Stencil. Thank you. All right. Well, thank you for inviting me once again. I'm uh Doctor Ellen Bendel Stencil. Um, I am a neonatologist at the Mayo Clinic and for the past 10+ years, have really focused my, uh, both clinical and research interests in, uh, patients that have had fetal interventions. So, I'm gonna skip past this in the interest of time, but I have nothing to disclose. Um, so, Um, basically, up until relatively recently, bilateral renalgenesis or other forms of fetal kidney, uh, failure with anhydramnios were considered lethal. Um, the lack of amniotic fluid led to profound pulmonary hypertension and pulmonary hypoplasia, and oftentimes these patients would die of pulmonary death before we ever got to even address the renal, uh, or kidney failure issues. But this dogma is really now being challenged. A lot of this came after uh this case report was published, which was about, uh, in 2014, uh, Washington State congress, congresswoman, uh, had a fetus with uh bilateral regenesis, and she underwent amnio infusions at Johns Hopkins University. And she went on to deliver at 28 weeks gestation, a baby that weighed 1230 g and uh required CPAP support but did not need to be intubated nor did it receive surfactant therapy. Um, and that infant then went on to peritoneal dialysis as a bridge to transplant. Um, so in the years that followed this case report, amnio infusions to mitigate pulmonary hyperplasia have become more and more, uh, uh, have been offered more and more to families, and as neonatologists, um, we have been beginning, we have seen more and more of these patients on our units. Um, but what we continue to struggle with is that this is still unstudied and optimal care to transition patients from fetal kidney failure to transplant is far from standardized. And while there are cases of successful neonatal dialysis to transplant, it's really limited to a few case reports and anecdotal information. So this is really well illustrated by this 2019 article that Stephanie Rule and colleagues from Cincinnati published where they looked at a 14-year experience with this patient population, and of 8 infants that received amnio infusion, only 2 neonates survived beyond 30 days, and both of those infants died on dialysis while awaiting transplant. So it's clear that we still have much to learn. Um, full disclosure, in the following slides, I'm gonna describe a combination of lessons learned through clinical experience and augmented by theoretical recommendations, but really there's no randomized controlled clinical trials to validate this approach. So I'm gonna start with a case presentation. This was our most recent uh infant that we cared for who had multicystic dysplastic kidneys with anhydramnios. We had a 28 year old gravida 2 para 0111 woman who had unremarkable prenatal labs. She had a normal microarray for the fetus and mother and the brother also had unilateral renal agenesis, which is a very common finding, uh, because there's a strong genetic link, as we all know, to, uh, kidney abnormalities. Prenatal diagnosis showed multicystic dysplastic kidneys with anhydramnios, and the family underwent extensive prenatal consultation but decided to proceed with amnio infusion therapy. Um, so the mother underwent serial amnio infusion. She had premature rupture of membranes after her ninth procedure, and then there was fetal bradycardia that prompted delivery. The infant delivered at 33 5/7 week and had a weight of 1530 g, which is the 2nd percentile. And just to note that's extremely, extremely common history, uh, in these infants to deliver early. Uh, and to deliver a growth restricted. This child had apars of 3 and 7 and initially had a heart rate above 100 but continued to be apneic without cry and therefore received TPs positive pressure ventilation with settings of just 20/5. By 3 minutes of life, we intubated for ongoing apnea and hypoxemia, and then, uh, saturations gradually increased to 90%. And 60% oxygen by 7 minutes of life. We placed umbilical lines and a chest x-ray was obtained. And you can see that the cord blood gasses suggest that there was in utero stress with the metabolic acidosis present. The infant's first gas showed a combined metabolic and respiratory acidosis. Our first chest x-ray was concerning for IDS and we gave some surfactant in the delivery room. And then we initially were on pressure-targeted ventilation of 25/5, but there was very poor compliance noted on our ventilator graphics. Our oxygen needs were still above 50% and therefore this child transitioned to an oscillator. The mean arterial blood pressure was low and a normal saline bolus was given. Um, so I'm gonna just, I'm gonna, um, go through the respiratory followed by the cardiovascular course, but based on the day of admission, uh, chest x-ray, uh, showed bilateral small pneumothorases that were not under tension, so we thought we could safely, uh, uh, monitor those without, uh, intervening with chest tubes. We were on the oscillator of a mean repressor of 8 amplitude. To 24 and hertz of 15, and we gradually were able to wean this infant to room air over the first uh uh day of life. By day lift number 2, there were still pneumothorases on X-ray, but they were smaller. We have been able to wean our oscillator to mean a pressure of 7, amplitude of 18, and still at a hertz of 15, and the child was in room air, and by day of life 3, we were able to extubate to CPAP. From a cardiovascular standpoint, we had more difficulty. There were significant issues with hypotension. Child was on dopamine and stress hydrocortisone and then we added epinephrine at 0.02 mics per kilo per minute for persistent hypotension. We had an early echocardiogram that showed normal intracardiac anatomy, but there was severe pulmonary hypertension and large right ventricular chamber size. The function was good though, but we had estimated RV systolic pressures of 50 and uh mild to moderate tricuspid regurgitation, and there was a small PDA present as well as a PFO. By day of life #2, however, we were able to wean the epinephrine off and start weaning our dopamine, and by day 3 we were off dopamine and began weaning our hydrocortisone. So, um, when we, uh, talk about these infants, I think it's important to acknowledge that optimal management actually begins in the delivery room. And, um, the way I manage these children in the delivery room is similar to, uh, a, um, Child with um uh diaphragmatic hernia, the most experienced person is at the head of the bed. So at our center, the neonatologist is at the head of the bed, um, because we know that there are many uh very uh important things that need to be considered when we resuscitate these in. Anhydramnio leads to poor compliance and stiff lungs. Whether you're doing serial amnio infusions or not, that's the reality. These kids come out with very stiff lungs. They have either relative or outright pulmonary hypoplasia and therefore you need to use very thoughtful, gen gentle ventilation right from the get-go. You need to consider using pressure-limited uh ventilation early in the course while you're assessing compliance because these kids are at risk for pneumothorax and so you need to be prepared. Have a trans illuminator, needle evacuation kit, a chest tube setup all present right there prior to delivery. These kids also have associated pulmonary hypertension, so nitric oxide therapy may be indicated, and we always have that present in the delivery room. In terms of monitoring, in order to optimally care for these kids, you really need to have the best, uh, bedside monitoring, uh, available, and, uh, it's somewhat limited, but pre and post ductal stat monitoring, uh, should be started in the delivery room as that will help you determine the degree of pulmonary hypertension until you can get to an echo echocardiogram. Transcutaneous CO2 monitoring, what we call a TCOM, is particularly helpful. Uh, if you're on high frequency modes of ventilation, you can follow minute to minute changes much more closely. An arterial bloodline is necessary both for monitoring and for blood pressure, sorry, for blood gas monitoring and for blood pressure determination. And of course, point of care monitoring of blood gasses at the bedside is very helpful because oftentimes, there's a lot of um uh titrating of the ventilator settings to get to the sweet spot. So just starting with conventional ventilator strategies. Uh, once again, early prevention strategies are the mainstay because of the given pulmonary hyperplasia. So since these kids are often delivered early, surfactant is often an appropriate intervention as well if there's any concerns for RDS. From, from in terms of your initial ventilator settings, um, as I alluded to before, I like to start with pressure limited because I can then titrate or get an assessment of what my compliance is like and I use my flow volume loops to assess compliance. If I'm able to meet my my title volume goal of 3 to 4 mLs per kilo and keep my pressures below 25, I then In addition to more of a volume, uh, guarantee mode of ventilation. Still using a low volume but high rate strategy. So oftentimes you'd start with a rate of 60, tidal volumes of 3 to 4, peak of 4 to 6 and a low eye time. If, however, you've got pressures above 25, to get to your tidal volume, you really need to consider high frequency modes of ventilation where you can use very tiny tidal volumes. The oscillator is, uh, what we used in the particular case that I presented at the beginning of this talk. You know, typically we use high frequency, higher frequencies like 15 Hz because that is associated with smaller tier volumes. I'll be honest, um, do not be afraid of lower frequencies. That's still Physiologic. I happen to oscillate all my babies around the frequency of 10 Hz because that's what I've done for years. Uh, but oftentimes, uh, if you read the party line, you should start at 15. Basically, whatever's working for you is good. But you do need to know that it does affect your CO2 removal, so the lower frequency will facilitate CO2 removal better. Um, lowest mean air pressure is what you want for adequate inflation. You want to start low at 6 to 8 and then just gradually increase based on your chest x-ray and what your oxygenation is doing. But you, uh, uh, really have to remember that high mean air pressure will impede cardiac output, and it also increases your risk for pneumothorax development. So you have to pay close attention and that's why I always start low and ramp up gradually. From an amplitude standpoint, rule of thumb is to start at double the mean arrow pressure. That's oftentimes gonna be too low, but what you don't want to do is to overshoot. So we usually double the mean arrow pressure and then gradually go up on the amplitude based on the, uh, very scientific term, the Wiggle. All the neonatologists in the crowd will know what I mean by that. But basically you, you titrate up based on the wiggle that you're seeing and the CO2 values on um your blood gasses. Typically, on an oscillator, the IVE ratio, you're gonna keep it 1:1, and we rarely change that. Um, uh, high-frequency jet ventilation is another modality that actually tends to be my favorite mode of ventilation for these kids. We start at a rate of 360, a lower rate than the traditional 420 due to air leak concerns, um, as this will give you a slightly, um, a smaller tier volume. Changes though in our rate are rarely made in your in your hour to hour management of blood gasses, so typically you pick a rate and stay with that uh until it's not working for you. You can further consider decreasing the rate to 300 based on ventilation and chest X-ray concerns for um hyperinflation. An initial PIP of 20 to 24 is appropriate and then adjusted based on wiggle and your CO2 values. Um, but you have to remember your PIP is very attenuated. So higher values do not necessarily, they don't actually equate with the PIP that you see on a conventional ventilator. And you're, what you also need to keep in mind is your PIP is gonna be your chief determinant uh for um CO2 removal. So your delta P, the difference between your PIP and your P is truly your primary determinant of your uh PACO2, not your rate, not your frequency. Typically start a peak of 5 to avoid hyperinflation and the pneumothorasis that we've uh spoken about. Pep is truly your main determinant of, of, of mean airway pressure. So your goal is the lowest mean airway pressure for adequate oxygenation and once again, you'll be following your chest x-rays to adjust your peep for optimal inflation. But what's most important about peep is peep is really your uh control for your mean air pressure, and, and your mean airway pressure is determined by your peep and it's a measured variable. So when I'm talking to residents, I always ask them when, when they are presenting ventilator settings to me, I always request that they give me the uh mean airway pressure, which they have to read actually off the ventilator. Um, and that is most important for me to know for several reasons. One is that high mean air pressures are gonna affect your cardiac output adversely. Um, but it really gives me the best indicator of how my lungs are doing over time and gives me the, uh, most indication of when I'm ready for a trial of extubation. Eye time is generally fixed at 20 milliseconds to minimize air trapping, but if you are going up on your PIP, so for example, if you're going to 36 to 40, it's a pretty high settings and you're not getting any change in ventilation, then you need to consider lengthening your eye time. That'll give you a slightly higher area, more area under the curve, uh, so, uh, slightly bigger tidal volumes, but you still have in this high frequency. plenty of time to exhale. Uh, so typically, um, uh, uh, you would consider changing your eye time at that point. Side breaths are optional. If you have concerns for atelectasis, um, go ahead and add some side breaths, usually a low rate, 3 to 7, and a PIP of just 20. These are not intended though to facilitate gas exchange except for how they affect your atelectasis. Looking at hemodynamic strategies, an early echocardiogram is really helpful in, in determining how to uh support both your cardiovascular and your respiratory support. I prefer a functional echocardiogram if there's no prenatal concerns for congenital heart disease. And what I mean by that is that oftentimes when we get an echo on the NICU it can take a long time. They're finding the coronary uh vessels take off and getting me lots of Information, but in reality, when I have a very sick baby, all I really wanna know is how is the heart functioning and what's, what is, what's my ductal level shunt, and give me a an estimated RV pressure so that I can adjust my support accordingly. So basically, you do need an echo to assess cardiac function. Left ventricular dysfunction is commonly associated with pulmonary hyperplasia or hypertension, and you also want to determine the severity of your pulmonary hypertension. Um, The goal is to adapt your ventilator settings very similar to other pulmonary hyperplasia disorders. So at our unit, we shoot for an FIO2 to keep our preductile sats above 85 and we target our PCO2s of 50 to 70, so we do allow permissive hypercapnia. Hypotension is often problematic in these infants. Minnone, dopa, Norepi epi. These are all, uh, reasonable, uh, blood pressure support medications. Um, the goal is to target your mean blood pressure to drive your shunt left to right. So in the case that I presented when Where I was told the right ventricular systolic pressure was 50. I'm gonna shoot for mean blood pressure of about 55 to try and drive the shunt from left to right. But really, our ultimate goal is to maintain optimal cerebral perfusion because we're in this for a good neurologic outcome at the end of the day. Hydrocortisone is often indicated for concerns for adrenal insufficiency. Bilateral renalgenesis is notorious for giving us problems with profound hypotension, and although we don't truly understand why, there is a speculation that there's a relative adrenaline insufficiency due to abnormalities of the renal angiotensin pathway. Special considerations of nitric oxide therapy. Um, a therapeutic trial is reasonable if saturations and echo support this diagnosis. It is very common for us to use nitric oxide in these patients, uh, but we, whenever we use nitric oxide, uh, in particularly preterm infants, our son does a therapeutic trial. Uh, if we see no response, then we, uh, wean it away. Sedation needs to be treated seriously like any other pulmonary hypertensive patients. Dexamethaamidine, morphine, there are many other sedative drugs that different centers use. Um, the most important thing is to consider the blood, blood pressure effects of all these drugs and choose wisely. ECMO, very controversial whether or not it's appropriate to go to ECMMO in these children. They are often too small, they're growth restricted, they're preterm. Oftentimes, the decision is made for you just on technical limitations. However, there are cases where it may be uh uh Reasonable to consider ECMO, uh, if you consider that this child is likely to be a pulmonary survivor. The cases where I've seen that, uh, potentially offered to families is when you have adequate ventilation. So if you can adequately vent, ventilate an infant, but you're really struggling with oxygenation, secondary to pulmonary hypertension, ECMMO might be a reasonable way to improve oxygenation until the pulmonary hypertension resolves because usually the pulmonary hypertension is a transient phenomenon. Uh, the added benefit is that does facilitate scuff or hemodialysis. You can take care of your, uh, renal issues straight through the ECMO machine. So in summary, uh, pulmonary hyperplasia and hypertension are the primary drivers of respiratory outcome. Uh, amnio infusions may mitigate pulmonary hyperplasia, but as, as, as, uh, many of us believe, it doesn't really affect the long-term kidney dysfunction, so we still have to deal with how we're gonna get to transplantation. Cardiovascular course is often associated with hypotension. Really your ultimate goal is to preserve cerebral perfusion until your hemodynamic, uh, status has improved. You really need to respect the physiology of pulmonary hyperplasia and pulmonary hypertension. Adjust your support accordingly and really from the delivery room going forward, you have to keep this in mind with all your management. But I think most importantly, you need to participate and encourage research into this field and then share the knowledge. There's no question that we need more information, um, and I think later on, we talked a little bit about the RAF trial, um, which is looking at some neonatal outcomes, but, uh, really, we have a long way to go in terms of our really understanding optimal neonatal management for these infants. That's the end. Happy to take any questions. Thank you, Doctor Stanza for this amazing comprehensive summary. Um, I, I don't see any questions yet posted by the audience, but I have, I can have a few questions based on what you presented came in my mind. In your mind, what is the biggest challenge that we still have to overcome in neonatal management of these babies? Yeah, I think what, what I'm, because this, I, I think it's, for me, mostly the technical difficulties of getting these kids to a point where we can start dealing with the renal dysfunction. You know, we have done very well from a pulmonary standpoint, particularly with amnio infusions, uh, getting these children supported from a respiratory standpoint. But they're tiny and even if I can pull them through the respiratory management, I still oftentimes have these children who are less than 1800 g. Um, at our center, we don't set a minimum size for peritoneal dialysis. That being said, we tell parents upfront that below 1800 g, it's extraordinarily challenging, and we give them the, we give them multiple options to uh redirect care uh in these tiny babies because technically, doing uh peritoneal dialysis on these very tiny babies is challenging. Um, and hemodialysis, uh, although we're doing better, once again on preterm tiny babies, it's, it's truly a challenge. Thank you. Dr. Riddle posted a question, wonderful talk. Agreed that hypotension was a very limiting problem, especially when considering need for forms of hemodialysis. I think also on the same topic that there is a lot of challenges for mainly BRA, for example, at our center we have high potential is a major challenge in this population. What do you think other challenges could be? Yeah, I think there's no question that especially with the renal agenesis patients, the functional renal agenesis patients, we struggle, but we do much better with bilateral renal agenesis, it is, uh, it has been a real challenge. Um, my particular center, uh, really believes that this is, uh, predominantly an adrenal issue. And we start with, uh, early hydrocortisone and relatively high dose hydrocortisone. And then we are We are very quick to move to epinephrine support, um, uh, in our, in our institution. What I would really love to see is, uh, more research into this, uh, because I think we're, most of us are doing what we're most comfortable with and what seems to work in our particular centers, but realistically, I think that, that there is no universal agreement on how best to support these children. Thank you, Doctor Stan and there is another question from Doctor Daddy. Uh, how to manage hyrogenic infection and serial am fusion and bilateral renal agenesis. That means I can answer this question since mainly it is a prenatal. When we do amnio infusion, if we have infection, it is similar to, um I think he meant prenatally true or. Yeah, he meant prenatally and serial infusion. In patients who have serial n infusion, if there is evidence of infection, we treat them then any pregnancy, then we're indicate this is an indication for delivery if we have confirmed diagnosis of infection prenatally after Mni infusion. Doctor, uh, Bendall Stencil, I have a question as well. Um, you know, regarding patients who are, um, potential candidates for peritoneal dialysis, um, let's say that there's an additional complication of, um, some additional intraabdominal surgery that's needed like an ostomy of some kind. Um, how does, how does your, um, institution handle that? Uh, it is a challenge. Um, and I think, uh, we get our pediatric surgeons involved prenatally, so oftentimes the family has already met them before we, um, get there. Um, and I'll be honest, before we do anything with the abdomen, um, we have surgery involved because we are gonna have, we only have so much real estate. And we're gonna probably need a G tube eventually. We're gonna need peritoneal dialysis. Uh, oftentimes, not oftentimes, but there can be stomas present, there can be vasicostomies present, and we have these tiny abdomens. So, I don't know that we have a, I can give you a, how do we, it's a case by case basis. Where we have all of the players involved. Um, this truly is a multidisciplinary approach, and, uh, you know, I, I, we keep using that word, what does that mean? But it means on a very regular basis, we need to get all the players in the room to talk about how to optimally manage this child. I don't know if that really answered your question, but the best I can do. No, I think that each case is unique, and I think you have to respect that and then do your best with, with what you're given. Yeah, and, uh, you know, these, these are similar challenges that, uh, that we have our, at our center and uh hoping to spark a discussion from the other panelists in the group as well regarding um their approach to this. So, um, does, you know, Doctor Lim or Doctor Goldstein, do you, do you have any further comments on, on that? Um, yeah, hi, thank you so much, Doctor Taba. Um, you know, we used to not, uh, do that, uh, if a patient was going to have, especially, you know, prenatally, if we knew that, um, they had a bowel obstruction and we're gonna need a colostomy, um, we used to say that was a contraindication, and then actually the, there are data published now from, um, the, uh, International uh Pediatric Peritoneal Dialysis Registry. That demonstrate that this, um, had been done at other centers with, um, some reasonable success. And so now we've had a couple of kids, uh, we changed our practice based on the data, um, so even Uh, uh, even not having a randomized controlled trial, um, that's exactly what, uh, Doctor Bendel Stenzel said. We need to share our experiences because we thought this was absolutely a contraindication, and we now have a child being worked up for kidney transplant who still has an ostomy and is on peritoneal dialysis. I have a question for Doctor Binel Stencil. You know, discussing the controversy surrounding ECMO, uh, do you have, or have you seen patients that you see prenatally, you do the amnio infusions, and then the baby's born and potentially may not be a candidate for ECMO? Are you struggling with the push from family to continue on, um, even though maybe you feel like they may not be a good candidate for ECMO? Yeah, um, so, um, I think this isn't always, always an issue. Um, we've all dealt with families that are, um, despite being very well educated or unrealistic on what we have to offer. Um, and I would say that we are pretty strict about, we On offer ECMO if we feel that we can have some opportunity, so some opportunity for a good outcome. Um, and so we don't actually talk about ECMO with families prenatally because the majority of our patients will never qualify for it. So when we, we, when we offer ECMO to families, we have already discussed Beforehand, uh, as a group that we think we have a reasonable chance of being successful with it. Um, I, I hope that answers it. We, we aren't trying to be paternalistic. I'm not, uh, I don't want to insinuate that, but just because I can do something doesn't mean I should. In other words, I could keep an infant alive on ECMO for an awful long time. Time, but if there's no chance of getting to the next stage, uh, of what it takes to survive, then we aren't being good stewards of health care resources and we aren't being fair to the families. So I think we have to, uh, be reasonable about what is our chance of, of getting to a good outcome with every patient. That being said, you know, we talk about, um, uh, you know, seeing is believing, but believing is seeing as well. So, there are chance, there are times when you just have to believe in a, in a patient, um, to ever see a good outcome, and I, I think you, it's a real balancing act, uh, when we try and talk to these families. And I think that reiterates the importance of, um, all the interdisciplinary teams being on the same page, you know, prenatally, and then once that baby is born, those first few days when these patients are really sick, it's so critical and stressful for all the teens involved. So, um, that's a really good point that, you know, getting on the same page prenatally.