Dr. Nicolas Bamat, assistant professor of Pediatrics in the Division of Neonatology & Center for Clinical Effectiveness at Children’s Hospital of Philadelphia, was the keynote speaker, exploring the evolution of pharmacologic management of BPD, and explaining how to apply the evidence for medication use to support local care guidelines and practices. Specific examples of Dr. Bamat’s research regarding use of diuretics was discussed.
With this, I want to introduce Nick. Um So he's a, an assistant professor of pediatrics with Division of Neonatology and Center for Clinical Effectiveness at, at Children's Hospital of Philadelphia. And he did his medical training at University of Pennsylvania and then subsequently did fellowships in neonatal perinatal medicine and all as well as hospital outcomes and epidemiology at shop. Um As um Doctor Van will tell you he um has a career development award at the NIH and he's also received multiple Young Investigator awards and teaching awards for um his local group and has numerous peer review publications and also is uh frequently um mentoring students and trainees and I most recently have worked with him through the BB collaborative Pharmacology working group. So, um with that, I would like to introduce Nick and um please make him welcome. Right? Um Thank you, Doctor Griffiths for that generous introduction. And um thanks to everybody here for um a warm welcome to Phoenix. I have uh I've really enjoyed my, my time here and I'm really looking forward to learning from all of you over the course of the day today. So, as pay mentioned, I am grateful to an ACH D for career development funding. Uh And I do not have any commercial conflicts to disclose these are our lecture objectives. Give you a moment to look those over. So this is our road map for the next 40 minutes or so, um which also doubles as really just following what my academic journey has been as an early career investigator. Um So we're gonna start with uh a broad look at medication use in uh establish your BPD and then focus on the clinical research evidence supporting their use. We'll then our turn our attention to why the pharmacological management of established BPD is so challenging and dive into furosemide really as a case example of this third point. So those of you who were at ground grounds will not have to suffer through my life story again. Um But I do want to provide a little bit of context for how I got to this topic. OK. Um So I arrived at Pen Meed in 2006 with an existing interest in research based on some really wonderful experiences as an undergrad at Williams College. And in med school, I found myself drawn to respiratory physiology into chop, which serves as the department of pediatrics for Pen um through some really great dumb luck. Um I was assigned to Dave Munson who's one of our GP D docs and also a NICU medical director in a med school mentorship program. And he introduced me to the NICU atop and also to harsh Kilani uh who was a very accomplished clinical researcher, um an expert in neonatal lung disease in the past advocate of evidence based practice. Um Rush is married to Barbara Schmidt. Some of you may or may not know that they're like this evidence-based, you know, anthology Power couple. And they've recently retired from chop and they um were absolutely wonderful mentors to an entire generation of currently very active investigators in ch hers should also help establish the chronic lung disease program at chop before he retired. Uh And as a fellow, my interest in respiratory physiology and lung disease led me to gravitate towards this program. Um This really is both my clinical and research home and I'm really grateful for that. I get to do research that is informed by my clinical care and vice versa. But one of the things that made me very uncomfortable when I joined the CHOP COV program was to see the very long list of medications that many of our infants were on. Oftentimes admitted on. And around this time, harsh was beginning to retire and I began to explore medication use and seve VPD under the mentorship of Scott Horsch, um who has generously shared his time and vast experience in clinical research and epidemiology. As my primary mentor ever since our first project together had two objectives. First, we wanted just to describe just how many different medications infants with severe BPD are exposed to. And second, we wanted to support research prioritization by identifying the most common medication exposures. We use the FIZZ database to identify infants developing severe BPD in United States children's hospitals over a decade. And we identified their daily medication exposures after after BPD diagnosis at 36 weeks, post menstrual age. For our first objective, we found that infants with severe BPD were exposed to a median of 30 different medications during their hospitalization. 30 it's a lot to put that in perspective. A 2014 study of community based nu managed by the pediatrics, uh Medical group reported a median medication exposure of four and a 2012 study of pediatric IC US admitted to his participating hospitals identified a median of 20 different medication exposures. So even comparatively the patients that we care for the patients that you care for in your BPD program use a particularly high number of medications. Further, we found that the extent of medication exposure is varied significantly by center. So this graph shows an estimate of the number of medications an infant with severe BPD would be exposed to at various centers after adjusting for differences in case mix. And you notice that there's a greater than twofold difference between the hospitals at the extremes. So why are infants exposed to so many medications? I would argue that it's mostly a combination of three things. The first is they're very high disease severity. The second is the prolonged length of stay. And lastly, and perhaps most importantly, is the very difficult to resist urge that we feel to do something right. We wanna help. And oftentimes that comes in the form of prescribing something for a second objective, we found that the loop diuretic furosemide was the most commonly used medication. And actually by quite a bit, uh it was present in one third of all patient days across the cohort far more than any other medication. And this is how we came to study Furosemide. I had no specific interest in furosemide prior to this. Um But it's where the data pulled us. So we decided to focus, there are frequently used medications targeting respiratory health with Corzide budesonide, caffeine albuterol. We'll hear about some of these later today. Ok. So what is the research evidence supporting the use of these medications? Pardon the slide? It didn't stretch out appropriately when we went to the um landscape mode? Ok. Um So the following slides summarize the highest levels of evidence that I encountered when diving into the furosemide that have chain. I asked um in infants with established severe BBD less than one year of age. Ok. I was trying to capture the patient population that we cared for in the CLD program. How does furosemide compare to control with respect to physiologic or clinical outcomes? Reflecting pulmonary health or function? The evidence is limited to four small crossover or single arm trials. The next few slides summarize these studies in some detail on the slide, but in the interest of time and your sustained attention, we will stick to the take home points. All right. So the first study found a transient improvement in airway conductance and compliance in 10 infants receiving a single dose of furosemide, but that went away within two hours of the dose. The second study also found a transient improvement this time in a clinical respiratory distress score and in arterial co2 levels in 10 infants, but the improvement was gone within six hours. In contrast, there was no improvement in oxygenation as measured by the A a gradient. 1986 trial of 16 infants exposed to furosemide for 6 to 10 days rather than a single dose found an improvement in pulmonary resistance and compliance a week out from sustained therapy. But these improvements in pulmonary mechanics didn't translate to sustained improvements in gas exchange with an initial three point improvement in transcutaneous co2 at one hour, no longer detectable at one week. And lastly, a 1990 trial of 11 infants exposed to furosemide for eight days found improvements in dynamic compliance and total pulmonary resistance but failed to show a statistically significant improvement in oxygenation. So in summary, the existing evidence suggests that furosemide provides short term and possibly longer term improvements of pulmonary mechanics. However, it remains unclear whether this translates to improvements in pulmonary gas exchange and there really are no data at all on clinically important outcomes. Further, these data are really, really old. The the the most recent is 33 years old and that makes it awfully hard to generalize to modern neonatal practice. So this is the evidence supporting the most commonly used medication in a vulnerable high risk infant population. And I find that unsettling a year after the study that drew our attention of furosemide, we went back to the P database and we asked, OK, how do children's hospitals vary in the extent to which um they use loop diuretics in infants developing severe BPD. And how do low versus high use centers compare to each other with respect to mortality and age of discharge? The ones that use more loop diuretics do better. So not surprisingly, we found statistically significant variation in use but with a fairly dramatic range between hospitals at the extremes. And when we dichotomies the hospitals into either low or high use centers, we found that the adjusted mortality and the post menstrual agent discharge were remarkably similar. Really, the only difference that we noticed was that high use centers were far more likely to still have those babies on a loop diuretic discharge. So personally, I would not interpret this as damning evidence against smide use, but it certainly suggests that we need to study this more rigorously. Ok. What about some of the other respiratory medications? Unfortunately, they make the furosemide literature look robust. By comparison when I last searched, I did not identify any clinical trial evidence for chlorothiazide or Budesonide or caffeine in established severe DVD for Albuterol. We do have a little bit of data. A little bit at least so harsh Karla. Well, before he became my mentor in his early days at the hospital for sick Children in Toronto, studied IV albuterol and six ventilator dependent infants in a single armed trial um measuring outcomes before and after the albuterol exposure. So all but one infant showed an improvement in respiratory um system resistance while all infants showed improvement in respiratory system compliance. Um but he noted that they did not see any consistent changes in gas exchange. Similar story improvement of pulmonary mechanics don't necessarily translate to improvements in gas exchange. So this is a more recent study uh by Ed Shepard and colleagues at nationwide children's. Um they performed infant pulmonary function tests on 100 and 10 infants with severe BPD. The objective of this study um was to demonstrate that infant pfts could reveal distinct severe BPD phenotypes not to evaluate the effectiveness of albuterol. So, they tested overall responsiveness in infants that they had classified as either having restrictive obstructive or mixed phenotypes on the basis of that PFT testing. And they found that the infants with an obstructive phenotype were significantly more likely to show albuterol responsiveness than those with a restricted phenotype. And the response was um measured as a 10% increase in fev 0.5 So these data do not provide evidence of albuterol effectiveness and clinically important outcomes. But this is great data. I would argue that the best data that we have to date suggesting that we can subclass infants on the basis of on the basis of observable characteristics in the phenotypes. And notice that there's a difference in how they respond. OK. So for me, this is kind of like a template of what we're gonna need to do. 5, 10 years from now when we have um greater capacity to do it as a collaborative Natalie Napolitano is a respiratory therapist and clinical researcher in our CLD program. She recently led a three period crossover trial in 22 infants with BPD on the vent. Uh The comparisons were normal saline placebo, 1.25 mg or 2.5 mg of albuterol. And all of these were aerosolized every four hours for 24 hours with a six hour washout period between, there were no certain differences noted for the primary outcome of um of the absolute difference in expiratory flow with 75% of exhalation. And really the only statistically significant difference is what was a very modest reduction um in the peak inspiratory pressure required to meet the set T volumes in the 2.5 mg group compared to placebo and also a modest increase in heart rate in the same group. So in summary, the existing evidence suggests that albuterol may provide short term improvements in pulmonary mechanics. Um, and raises questions about appropriate dosing while suggesting that we need to be thoughtful about which patients we expose because the benefit may very well depend on the phenotype. So clearly, we need medication trials in established BPD. Um, but first, we need to pause and ask ourselves if we even know how to appropriately use a lot of these medications in established BPD, we even know how to dose it. Um How much medication should we give? Uh how often should we give it? Um I love Doctor Griffith's slide about the six um rights of medication use, right? Like if we were to dig in there and answer all of those questions for each man and these patients, we would make a lot of progress that's gonna be decades of work. So it may seem like simple prerequisite knowledge like, oh, of course, we know the dose. No, we don't. Um And in reality, neonatal pharmacology is really, really challenging and we're gonna explore a little bit of why. All right. So there are several reasons. Yeah, I'm good. Here. There are several reasons why um neonatal pharmacology is really difficult. OK. One is that the financial incentives for developing drugs and conducting rigorous early phase studies from which these dosage regimens are classically derived is really, really low in our patient population, right? If you are heading up a large pharmaceutical company and you are trying to make money, you are not looking at our babies, right. You're looking at cardiovascular meds at those. In addition to that, there's more ethical and regulatory scrutiny which is appropriate but adds challenges. Ok, high quality pharmacology studies have historically relied on sampling blood volumes that are not possible in our babies, right. We can't come in like give me 15 mls of blood and now give me another 15 MLS of blood. Um we cannot do that. And lastly, the pharmacology and physiology of preterm neonates is distinct. So we're gonna step back and consider pharmacology a little bit more broadly. This is a quote from Paracelsus. I hope I'm saying his name right. I'm not sure. Um But this is the father of toxicology who reminds us that all things are poison and nothing is without poison. Only a dose makes a thing, not a person. So the goal in dosing is to identify the amount of drug that is neither too little or too much, but rather just right. OK. To target that sweet spot known as the therapeutic index where there is enough drug for it to be effective but not so much drug that is toxic. What the body does with an administered drug. A K pharmacokinetics and the effect that the drug has on the body. A K pharmacodynamics. The KPD jointly determine whether a medication dosing strategy is just right, but I don't wanna put you all to sleep with too much clinical pharmacology. OK. But we're gonna simply recall that pharmacokinetics can be complex. Um because various processes influence the amount of drug that reaches the therapeutic target over time. All right. So when you don't give a drug intravenously, the drug has to be absorbed most commonly through the gastrointestinal tract is then distributed through different body compartments. Metabolism, primarily hepatic function breaks down drugs often inactivating them or facilitating their clearance by making it more polar soluble and aqueous fluids. And finally, medications are ex excreted often through renal elimination. All of these processes play an important role in determining whether the amount of drug you prescribe is just right. A key challenge in neonatal pharmacology is that the processes that determine just right are dramatically influenced by disease and they are dramatically influenced by development and neonatology is the management of life-threatening disease during a time of dynamic development. One of the things that makes neonatal clinical pharmacology so hard is that we are aiming at a rapidly moving target. And I would argue that infants with severe BPD are actually a perfect reminder of just how far that target travels in the hands of neonatologists. Both of these infants are routinely cared for by neonatal providers and the same nicu referencing, the same neonatal formularies, but just as Children are not small adults. And the point of emphasis here is that four month old infants with severe BPD are not big premature infants with RD. Si think every single person in this room would agree that we need to manage their vent, their ventilation very distinctly. Um And we also need to manage their medications very distinctly, but we often don't. So we're going to dive deep with furosemide as a case example of some of the challenges that I've tried to describe in the last few slides. So when our research revealed that Furosemide was the most commonly used medication. So UBBD, I started to ask questions, right? So I was approaching my colleagues and say, hey, why do you start Furosemide? Uh why do you start fur? What are you, what are you hoping it's gonna do? What do you think? Um Most common answer was it wasn't me. I didn't do it right. I think somebody else put them on it and I just left them on because I didn't want to rock the boat, right. Um Otherwise, this conceptual model captured the predominant responses, all right, the expectation or the hope. Let's call it a hope. Um Was that furosemide would increase diuresis resulting in a decrease in extracellular water and pulmonary edema, which would improve pulmonary mechanics benefit in gas exchange and ultimately resulting in some sort of clinical benefit. There's a hope. OK. Along with this hope is the knowledge that there is a cascade of known or suspected adverse effects, right. So, diuresis leads to the urinary loss of electrolytes by design, this includes calcium, this can lead to nephrocalcinosis and metabolic bone disease because we're losing electrolytes, we then need to monitor these electrolytes in the blood. Um This requires phlebotomy which leads to pain, which Doctor Griffith just mentioned, right, and contributes to anemia through blood loss. It's electrolyte supplementation often gets started. This has its own set of adverse effects, right. Raise your hand. If you're taking care of a baby throws up every time you can KCL, right? Um And there are various possible extrarenal harms with concerns for ot toity being the most prominent, right? So we have hope over here that we cling to and causes all of this cascade harm. So we really need to get to the bottom of this. OK. Um I'm gonna say up front that my, my bias, my worry is that at a population level, furosemide causes more harm than good. OK. But I do think that in the right patients using the right way there probably are some that benefit. OK. Um And so I'm not out to show that yes, you know, furosemide is helpful or that yes, it's harmful. OK. But I think either way we use this medication all the time and we need to understand its effect on clinically important benefits and harms in a rigorous wedding. All right. But we can't get here, right? We can't do a big randomized trial. Um providing us some sort of estimate of benefits and harms without first asking these questions about how we should optimally use it. All right. So we're gonna roll it all the way back to what I've learned about fos bromide is an ion channel blocker. It inhibits the sodium potassium fluoride co transporter, which is highly expressed in the ascending limb of the LPO HLE in the kidney, but is in fact expressed throughout the body. It's everywhere, brain, the basket through the lungs. This explains some of the plausibility of extra renal harms. Duos is routinely administered in both IV and in formulations, one interesting feature is that duos undergoes both gastric and intestinal absorption and it has a relatively small volume of distribution because it binds really strongly the album. And so because of that, it largely remains within the intravascular space. So because stick with me here, this one's a little bit complicated, right? So because of this strong albumin binding furosemide has very low glom filtration. OK. Kind of just skips on by OK into the aer arterial. And then down here where we here in the peritubular capillaries and in the peritubular capillaries at the level of the proximal convoluted tubule, it gets stripped off of albumin by organic acid transporters which have really high affinity uh for furosemide. And then they're actively secreted, actively secreted into the renal lumen. And this is how furosemide um is eliminated from the body and also how it reaches its therapeutic targets within the lumen within the urine side of the tubules. And this target is the sodium potassium or a co transporter as we've mentioned in the Luminal side of the loca handling. So in addition of this ion channel blocks the reabsorption of these electrolytes, ultimately leading to diuresis. This action also disrupts the normal electrochemical gradient that drives the reabsorption of cations like magnesium and calcium, which is why we get into these issues uh with urinary calcium loss. So two specific concerns about furosemide arose as we just started to read a little bit of the literature. We honestly did not have to dig very deep. The first was whether we were using an appropriate dosage regimen. Um I want to note that in clinical practice, prolonged courses of furosemide are common. So in one of the studies that I described earlier, um we found that over half of the infants that were exposed to furosemide received at least one course that was longer than one week in duration and that a quarter were exposed to furosemide for over a month. So with repeat dosing, the goal is to use doses and dose frequencies that result in steady state drug concentrations that avoid toxicity. Ok. But also remain above the minimum effective dose. So we don't want our antibiotics to be fighting bacterial infections part time. We don't want antiepileptic drugs to intermittently be preventing seizures. Um And I would argue that for furosemide, we probably wanna remain above the threshold diuretic effect, but we wanna be below drug concentrations where they affect just plateaus and all you're getting is increased toxicities for more drug. So, in adults, and I will say that a lot of what we've learned about furosemide is based on adults with congestive heart failure. It's another population that gets a lot of furosemide and where there is a far more robust literature. So in adults, it's been noted that when furosemide concentrations fall below the threshold for diuretic effect, the kidneys actually hold on to more sodium and water than they would have a baseline. Um This is a process termed rebound reabsorption. And this compensatory process can essentially negate the preceding diuresis. Um So how do we dose furosemide in preterm infants? And what has influenced this? So, an interesting anecdote is that Lasix is derived from last six hours in adults, right? But early pharmacology studies found that this was not the case in preterm infants. So, in the 19 eighties, there was a series of very small studies that noted that the elimination of half life of furosemide was much, much longer in preterm infants with half lives often in excess of 24 hours. So this led to guidance like this one warning of the danger of furosemide accumulation to potentially ototoxic levels and recommending that immature infants should receive uh one make per keg of IV furosemide no more often than once every 24 hours. OK. This is a common practice for us. I was talking to Doctor Griffiths uh and R yesterday and we're saying this is sometimes a practice here as well. Um And this is very reasonable. OK. First do no harm. And a six month old with established BPD is not a newly born preterm infant. OK. So data from this group may not generalize to this group. So it is believed that furosemide's elimination, half life is very prolonged in younger preterm infants because the tubular secretion responsible for furosemide clearance that we emphasized here. OK. This depends on the activity of these organic acid transporters that have very, very low expression in younger preterm Memphis. So this is a study from 1988 that found that beyond 32 weeks, post menstrual age duos clearance increases exponentially. OK. Uh And this is likely due to an increase in the expression of these organic acid transporters as part of normal developmental maturation, right. So the infants that we care for in our program, they're like 36 to 60 weeks. Post menstrual age, they're way out here, way out here and they likely clear furosemide much, much faster than younger Bres. But this isn't well known or understood and providers do not adjust furosemide dosing as pre commitments mature. So this is a study that we published this last year. We collaborated with the pediatrics group to look at changes in fos dosing as a function of post menstrual age. There are no meaningful changes. Ok. So one make per cake per day is the most common dosage regimen followed by one make per cake every 12 hours. And this is true, irrespective of post menstrual age. So while one make per cake per day may be just right. In some younger preterm infants, it may lead to long subtherapeutic windows and rebound reabsorption of sodium and water in older preterm infants such as our infants with established BPD. The second concern we noted early on relates to its duration of use. So as we've noted prolonged furosemide exposures are common, but the kidney is really really good at its job. OK. I'd say that over these last five years, my biggest revelation is that I have not been respecting the kidneys nearly as much as I should have been. Um the kidneys are really, really good at their job and their job is not to make urine, that is the waste product. Their job is to keep you alive through homeostasis, right? And in the face of chronic furosemide exposure, the kidneys will adapt to curb or counteract diuresis and to maintain homeostasis. And one of the ways that they are thought to do this is by up regulating receptors in the distal convoluted tubule. OK? To suck back the sodium in the water as blocked up stream, right? So we think we're clever and we're like a, we're gonna block reabsorption of sodium here and the kidney goes, no, you don't. We're just gonna suck it back up or. All right. So if Yosemite benefit is mediated by diuresis and diuresis diminishes sharply within a few days. The benefit, the harm balance may become less favorable during chronic exposures. All right. And this would be particularly true if these extra renal arms are not mitigated by some sort of tolerance or if the kidney isn't able to equally compensate for um other renal effects such as urinary calcium wasted. So, imagine that after a couple of days you're not getting strong diuretic effect, you're still wasting plenty of calcium. I don't know if that's true, but possibility. Ok. So my career development award tries to tackle some of these uncertainties. Um So that with time, we can get down here to where we all wanna get, we call these the fab studies. And we have two studies that are currently enrolling infants. The first is fat decay with a goal of characterizing fos pharmacokinetics specifically in established DPD. This is a prospective observational PK study with blood and urine sampling. We're measuring uh furosemide levels in the blood and in the urine. And we are enrolling infants with grade two or three BBD between post menstrual age of 36 and 60 weeks that are already on furosemide for clinical indication. So we're not approaching families saying, hey, we're gonna put your baby on furosemide. We're saying the clinical team has decided to do that. We're gonna take advantage of this, try to understand furosemide concentrations over time after the dose. So earlier, I shared that a key challenge in uno pharmacology is blood sampling limitations and most of you know that there's been some recent drama OK, related to fraud in the blood micro sampling space. Um but the technology is actually real, OK. It's just that they made a lot of lies about it. Um It's not new. So dry blood spots are a very crude form of micro sampling and the technology is evolving. So for fat PK, we are using the same technology that this group at Stanford describes as a nose that works. It's called volumetric absorptive micro sampling. And we use these very fancy and very expensive Q tips um to collect a precise volume of blood and facilitate quantitation of small molecules such as furosemide with as little as 10 microliters of blood that is a third of a drop of blood. Um So these very small blood volumes allow a rich sampling strategy which historically is not possible in the Unites uh where we do collect five separate samples via heel stick during a single dose. In our one uh we developed and validated micro sampling essays at chop and work led by Athena Zappa and Ganesh. They pictured here and unlike their, no, we did submit our claims to peer review. Um So, so I wanna share some very preliminary results from FPK with you today. Um We are continuing to enroll infants, but we are almost done with this study. Um And the PK models being developed by my colleague Kevin downes may change somewhat. But our current best estimate is that the elimination, half life of furosemide in infants with established BVD may be as short as two hours, which is far more similar to adults than it is younger pres. And this may be leading to long periods below the threshold direct effect between doses, facilitating rebound absorption. Our second active study is called fatal and the goals are to determine the presence and timing of diuretic tolerance. In other words, we're asking does the diuretic effect of fos might drop off over time as we talked about in that prior slide. This is a prospective observational cohort study with longitudinal urine measures. Uh In sampling, the study population is, this is the same as that PK here. The key difference is that we enroll patients and then they become a valuable if and when the team chooses to prescribe furosemide, and then we jump in and try to measure before furosemide is started and then the three days after furosemide, um whether or not the diuresis changes over time, enrollment continues but slowly in part because um having happened about Furosemide and my colleagues and they've changed their practices. Um But we've recently completed a study that basically asks an analogous question with retrospective data that's available in our clinical data warehouse. Um This is a figure from the paper that I just resubmitted after favorable peer review comments. Um And this figure depicts fluid balance on the Y axis as a function of time on the X axis in the three days before and after initiation of repeated dose furosemide for at least three days in 83 infants with established seve VPD. So as you can see, uh fluid balance is fairly stable in the three days leading up to exposure, we were surprised to see that it crept up a little bit and this is probably a selection effect because its kids are holding on to fluid that we're starting the diuretic on. Uh And then in that first day, although there's a lot of variability, the central tendency is that there is a big significant drop of fluid balance. But by the third day, you're basically back in baseline. All right. So what's next? Um Our hope is that these studies will allow us to develop an informed furosemide dosage regimen in infants with severe BPD that we can then compare the current standard of use on short term benefits and arms in a small single center trial. But ultimately to reach out to uh other centers, hopefully be pretty collaborative to do a large multi center trial to give us evidence based guidance. Um I do want to emphasize something because I gave part of this talk at grand rounds at chop and some of my colleagues got the message of, oh I can just dose for a bit more frequently now. OK. Uh And so I wanna caution against that. OK. Um Now, I think it's fair that likely um more frequent dosing will not lead to accumulation um of drug over time, but it may make it more effective and you could have more renal harms as a result of that. Ok. So um please don't let that be the, the take home message and run off your units and dose it more frequently. We're not quite there yet, ok? Um We're also gonna continue to follow some unexpected findings. Um Some of you spoke to me yesterday know that this is something I'm starting to get really excited about. But um one thing that we found in the preliminary PK models is that the PK profile of furosemide is quite distinct when it's given in the stomach versus beyond the stomach. And at least the chop, um, we use post pyloric feeds fairly frequently as a lump protective strategy and there are centers all over the country that do, right. The broader implication here is that differences in sight of G I administration may lead to meaningful differences in PK profiles and effectiveness of drugs unless dosing is tailored to consider, consider site administration, I don't know of any centers that are making thoughtful adjustments and their dosing on the basis of whether or not meds are gastric versus in post war. Um So we're looking at this possibility for FOS and NDP D but this is broadly relevant to a variety of different drugs uh all over the country. All right. So I'm gonna conclude with a story. Um So this last year P A si bumped into a former colleague who introduced me, a former trainee who introduced me to um his new colleagues and the typical pas small talk gravitated towards research interests. And I shared that my focus was for my pharmacology and BBD and the young pediatrician. I right. Exclaimed, oh my God, you study the most boring thing ever. Um And my first thought was, well, that's not very kind. Um, but my second thought was she's not wrong, right. She's not wrong. Here is my from college and BPD. Come on. So if somebody told me as a medical student that I was gonna be studying this, I would have laughed or run or something like that. But I feel good about how I got here. Right. Um, I started from a place of being worried about the number of medications that our babies were exposed to. Um, the data we generated, pulled us towards duos and a little bit of reading made us realize that we need to go back and think hard about pharmacology. Right? I very hesitantly moved into pharmacology space. I was like, oh, no, I'm not being clinical trial person. Um, but I've loved it. It's been fun. Um, and it's been a process of, of continuous learning. All right. And I would say that studying medications that we've been using for 40 years is not the most exciting thing that you can possibly do. But you know, if we believe in our oath to first do no harm, we owe it to our patients to go back and check some of these assumptions that we have had for decades. Um Pediatric pharmacology has some new tools like many fields. We have some new tools that allow us to go back and do the work that we should have done three or four decades ago. Um But it needs a lot more people, it needs a lot more resources and I am hopeful that the BPD collaborative can be a big player in filling some of these old knowledge gaps um in medication used for BBD. So, all right, with that. Um I'll say my thank you. I have a large mentorship team, uh a chop and beyond. And then I have a small research team that um that keeps me sane. I want to say thank you to them. And obviously, um all of our families who agree to participate in these studies, despite everything else that they have going on in their lives, it's uh um it's amazing that with all the stresses that they have, they take on additional stressors and patients and studies the, the babies and studies.
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