great uh good morning people uh we are really excited to have uh Dr nan Aurora from uh Portland Oregon come all the way uh to us for to present on the art of decongestion uh so Nan is an associate professor of medicine at the OSU uh previously he was at Wash in Seattle and he was recruited to Oregon a couple of years ago uh where he co-launched the inpatient cardioral service so then where I guess he will talk to us about that uh his hobby is on diuretics of course uh in the cardioral space he's also uh an avid golfer uh but he's also on the my co-filtrate on the freely filtered podcast so many of you may have heard his voice before thank you Swap and uh thanks for the invitation it really is an honor to be here to to speak to everybody so I apologize about the maple leaves yesterday look pretty bad um so yeah the title of my talk is the art of decongestion as swap mentioned uh when I started at the University of Washington I had the privilege of helping launch and and run an inpatient cardioral service and so a lot of the talk today is going to be uh the things that we thought about and strategies we used in patients where we were consulted primarily for diuretic resistance um now at Oregon Health and Science University I uh co-un a outpatient clinic and the management is quite different and so in this talk we're primarily focused on inpatients with decompensated heart failure so before I get started uh see if I can this Yep i do have one disclosure i do consulting work for Novo Nordisk uh there's nothing in this talk that represents a conflict of interest because of that relationship so this was what AI told me is a is an image of somebody with heart failure and fluid overload i'm not sure why but but this is you know what it was um and you know I think fluid overload has really impacted humans since the dawn of humanity if you go back to the E virus this was from Egypt in 1550 BC there's actually mention of fluid retention and fluid overloaded states with actually proposed treatments at the time and the term um edema comes from from the Greek word to swell and actually the Greek hero Edipus is named uh because of swollen feet that were inflicted by his mother to to try to prevent a prophecy so the the terms go go way back and many writings of hypocrates actually mention uh edema and and various therapies but really this culminated in the word dropsy which you guys have probably seen in in you know older literature and this uh originated from the Greek word for water in the in the um uh Middle East in the excuse me the um period many years ago and really came to describe any situation where you had excess fluid in the and it preceded our knowledge of sophisticated and distinct disease states uh but you can see kind of what various therapies were at the time so on the top left you have purgatives you have leeches bloodletting uh herbal therapies escapius and mythology actually cut the head off of somebody who was fluid overloaded turned them upside down to drain the fluid put their head back on which probably wasn't based in trial data and then in uh 1877 Reginald Soothi created these soothie tubes which were these small metal canulas inserted into subcutaneous tissue to drain excess fluid and as you might imagine the big complication there were infections but they were really used up until the 1960s i think the way we see um treatment of fluid overloaded states and what we would recognize today really started in around you know 1920 or so and so this is a fascinating account if you haven't read it I I highly recommend it so this is an account by Alfred Vogle when he was a third-year medical student at the Winky Bach Clinic in 1919 and so he was responsible for taking care of a young patient with syphilis and syphilic heart disease so his physician he was working with at the time asked him to inject a cc of uh solicitative mercury into the patient and because he had uh provided incorrect orders to the pharmacy they weren't able to compound it so there's a delay in treatment and it's fascinating the concernation he had as a medical student feeling like he was going to fail a task that was given to him and it just so happened that there was a army surgeon who was returned from the war happened to be on wards that morning he had received in the mail a sample of Nvaserol which was a new uh uh mercurial synthetic agent and so uh Alfred Vogel injected that into his patient and and he writes on the day of the first Nasserol injection a tall column indicated that the patient's urine output had reached 1,200 cc's as compared to the usual 200 to 500 this evoked my curiosity but no further comment at the time following the second and third injections however when she avoided 1400 and 2,000 cc's I excitedly mentioned it at rounds my report produced a benevolent smile and rather lengthy but unconvincing discussion of the wavelike rhythm of biologic functions so essentially dismissed but when they saw this working in multiple patients including those with without syphilis mercurial diuretics uh became quite common uh because of the toxicity associated with it spurred interest in synthetic diuretics and so acettoolamomide gets FDA approved in 1953 and that was followed by uh thioides loop diuretics and mineralic corticoid antagonist in the 50s and and and mid60s so when we think about the biirectional pathways between the heart and the kidney um of course all our decongestive therapies are working via the the kidney uh this is kind of an elegant depiction by Clauddio Ronco back in 2008 uh but over that time I think we have to modify this a bit and so you know the the feeling used to be that all of this was driven by decreased cardiac output leading to reduced renal blood flow and that drove the the the kidney dysfunction and we know from escape trials and and other trials that that's not necessarily true although it remains important and I would argue that the pendulum has swung uh sometimes too far where it's not considered enough and I'll talk about that in a minute he also has this pathway with exogenous factors um I don't want to get into a debate about the nephrotoxic potential of contrast media but I think we can agree that things like ACE inhibitors diuretics aren't inherently nephrotoxic there's also a lot of interest in immune mediated damage specifically with endothelial activation a lot of research going on in this but as a clinician because there's nothing we can do about it uh when I see the patient in front of me I I you know can kind of ignore this this pathway for now so really what it comes down to is increased venus pressure which we know uh uh elevated central venus pressure has an inverse relationship with glomemeular filtration rate and then uh blockade of the ren and angotensin eldoststerone pathways but to show you slides uh later on that that's going to suggest that you know neuroumoral blockade while obviously vitally important for long-term outcomes is maybe not as important on the on the inpatient setting when somebody's acutely decongested so a lot of our focus goes to increased venus pressure and how do we effectively treat that so when I talk about you know the the cardiac index and cardiac output not being quite as important this is uh an older study from 1990 looking at patients with heart failure and and breaking them down into tur tiles of cardiac index so essentially what you can see is as cardiac index declines on that x-axis you have a linear decline in renal blood flow filtration fraction goes up promoting sodium reabsorption but GFR is relatively constant across a wide uh array of cardiac indices and that's really because of the auto regulatory capacity of the kidney really what it's doing is vasoc constricting your eerant arterial that whole system breaks down at some point in this case it was around a g cardiac index of 1.7 we think about this uh somewhere around a cardiac index of two there's a lot of interpatient variability this is not going to affect the majority of patients admitted to a hospital with with decompensated heart failure our argument is that most of the institutions I've worked at really all of them nefrology is a consult service we get consulted for cases of diuretic resistance or acute kidney injury i think this is going on more than than we think and we've caught many patients on the floor that don't have obvious signs of lowflow states uh and we'll measure a cardiac index and it's low anecdotally this is going to be your younger patients that are able to better compensate so something that's always running through our mind when we're getting those those consults the other variable that I don't think gets uh discussed quite enough is renal profusion pressure you can measure this relatively non-invasively with a map and a central venus pressure so I'm borrowing here from the hpatrenal literature um see if I have a pointer uh so on the bottom you can see with uh decline in renal blood flow you have a rise in norepinephrine levels so essentially uh uh your sympathetic nervous system gets activated and again this is heterrenal physiology but I think a lot of the same principles apply to patients with cardioral physiology where on the right you have the renal autoregulatory curve and what happens is when you have a state of sympathetic nervous system activation that you get this rightward shift in your renal autoregulatory curve and what happens is that blood flow becomes becomes even more critically dependent on blood pressure and so this is another thing that we think about because as you guys all know people want to jump to talk about diuretics and everything which is the more interesting part of this but without appropriate flow to the kidney you're not going to maximize potential of diuretics so these things are always running through our mind and we have strategies to impact these variables uh if if they need to be acted on but what it comes down to uh mostly is how do we utilize diuretics you know we just talked about that loops and mineralic corticoid all of these were FDA approved in in in the 1960s over the next 60 years we don't have other tools and I would argue we still don't really know the best way to utilize the tools that we have and so this is how we've thought about the data and then we uh created a a diuretic um algorithm which I'll show you towards the end here in terms of how we we kind of go through this process so uh not surprising to anybody this is I could show you many of these trials this happens to be the protect trial but the point here is that if you're discharging patients with residual ongoing congestion outcomes are worse and so in the solid line here these are patients who have been fully decongested uh this was based on um uh jugular venus pressure uh peripheral edema and orthopia in this study if you have even mild congestion your outcomes are worth both in terms of mortality and rehospization if you look at registry data it'll suggest that only about 15% of patients with heart failure are congested at the time of discharge that uh suffers a bit from different uh definitions of decongestion but uh either way it's a minority of patients even if you look at a you know trial data so this is the dose trial this was looking at bullis dosing versus continuous dosing of loop diuretics also low dose versus highdose if you look at the highdose arm and look at the proportion of patients that were free of congestion at 72 hours it was less than 20% uh so and this is in a trial setting let alone you know us taking care of patients uh in the hospital and so the question is you know why are we so bad at this and and I think there's a few reasons one is that serum creatinin is just a a bad biioarker in heart failure particularly with active decongestion i'm not going to talk about that today because I think that's been discussed um you know in many forums i think in a group of nefologists we've all accepted that you know small trivial changes in creatinin are not uh necessarily detrimental in fact a lot of studies have shown actually better prognosis in patients where they have a small rise in creatinin with decongestion but the other factors are traditional metrics may not be accurate that that you know we we usually use and then finally diuretic resistance is common and we don't have a lot of defined strategies of how to overcome diuretic resistance so when we talk about traditional metrics it's really looking at cumulative fluid balance with uh intake and output as well as you know changes in weight um and so this is an often quoted study by by Jeff Dani out of Yale who's obviously done a lot of work in this field so he looked at the correlation and agreement between diuretic induced fluid and weight loss in three large trials so the dose trial the escape trial and the pen cohort and on the right you have these bland Alman plots and and if people are familiar with these essentially what you're seeing is that because of the nature of this the correlation between those two outcomes were very poor it's not a great study in the sense that it's hard to interpret these and you can you you can't tell if the discrepancies based on one variable or the other here the author's conclusion that it was both but if you just think I think practically about what we see in the hospital I have a very hard time getting accurate uh intake and outtake data uh in my nonICU patients in particular and though we ask for daily standing weights many times bed weights are being done which show a lot of variability day-to-day even if they use different scales we see different variability and so it can be hard to trust that the data you're getting is accurate and to act upon that so one of the things that uh has uh gained a lot of traction recently is using a spot urine sodium uh timed approximately 2 hours after a diuretic dose particularly a loop diuretic dose to at least get uh determine a threshold dose of your diuretic and for whatever reason this has actually evoked a lot of uh strong opinions especially on social media about the utility of this i will tell you we use this a lot and there was smaller studies that actually showed that if you weren't rece uh achieving a a threshold dose of urine sodium your outcomes were worse and other studies also showed that what was important was achieving net negative sodium balance so if you achieve net negative sodium balance in the in a hospitalization you had better outcomes irregardless of your cumulative fluid balance or your weight changes during the course of that admission so that culminated in two relatively large trials this is the push AHF trial was uh over 300 patients that were randomized to either a naturesis guided diuretic therapy or standard of care when they were admitted for decompensated heart failure what they looked at was 24-hour urine collections and showed better natures in the group that was uh randomized to the natures guided diuretic therapy uh as with every diuretic trial we have there was no difference in all cause mortality or heart failure rehospization at 180 days so there's been no diuretic trial uh that has actually shown mortality benefit or long-term benefit um and the protocol that they used was was this so what they did was they use this urine sodium less than 70 to define a poor response and they would increase doses of loop diuretics to a maximum of 5 millig of bmetanide and if patients were still below threshold they would preferentially add hydrochloroioide followed by either acettoolamide or an SGLT2 inhibitor to achieve that that that urine sodium threshold the ANAT trial was the other trial looking at this this was over 400 patients uh similar methodology they used a urine sodium greater than 50 to define a threshold response to their diuretic therapy similar to push AHF they would maximize uh their loop diuretic in this case it was a 200 milligram dose of fioamide and then they would add athide if patients were were below threshold i think this is the outcome that really matters and they showed a reduction in length of stay uh with patients that were randomized to the uh natures guided protocol because really what you're doing with this is you're removing clinical inertia most of the times what we see is somebody gets a diuretic people wait 24 hours they see the next morning what was their cumulative fluid balance what was their weight and then they make changes based on that data what this is doing is allowing you to get data within 2 hours and adjust your diuretic therapy if you need to and so if a patient comes in in the morning it's often that we'll make multiple changes over the course of that first hospitalization day uh in order to achieve decongestion more quickly a lot of people would argue well you can just use urine output which is absolutely true if you have an accurate way to collect urine output and you trust that data we use 150 cc's an hour to define an an adequate response but many times we don't have that that data available it's easier just to get a urine sodium which is quick it's cheap it's easy to get it goes in the chart and then you can make changes and there's actually programs that will uh have created nursedriven protocols where it's an automatic uh escalation of therapy if patients aren't at goal uh this is not some magic biioarker that's going to tell you if a patient is uh fully decongested or not you still have to use your traditional tools whether that's physical exam right heart cathizations we use a lot of bedside ultrasound in our practice to to determine uia uh but I think this does uh help you in certain situations but the the main I think issue is that diuretic resistance is is quite common if you look at the literature it's going to suggest that it's about a 30% prevalence i think you know the problem is diuretic resistance lacks a uniform uh uh definition i tell my fellows it's like a duck you can know it when you see it you you know when patients aren't responding adequately to to loop diuretics and the one of the main causes is adaptation in the nephron and and this is a really nice review by David Ellison that's still relevant uh published in 2017 showing this increased expression of sodium chloride coransporters in the distal tubule which cause uh you know sodium reabsorption beyond uh where loop diuretics work and make them less effective that's been supported by animal models these are mouse models uh that are exposed to loop diuretics and you see this hypertrophy of the distal uh tubule and and and increased expression of NCC mRNA and so this has led to the gold standard of of thazide generally being used preferentially if people are failing loop diuretic therapy which I agree with but worth noting that that's not based on robust uh randomized trial data in fact you know probably the the best trial we have of this is the chlorotic trial this was published in 2023 it's a Spanish study they took uh 230 patients with decompensated heart failure like most diuretic trials this was upfront therapy meaning patients were randomized at the time of admission to um 5 days of either hydrochloroioide or placebo to be eligible for the trial they had to be on at least 80 milligs up to 240 milligs of oral fioamide that number is going to be important as we try to compare studies uh and so we'll go back to that on the right you can see uh hydroponicide in blue here and placebo in gray so you had better weight loss and better diuretic efficacy which was defined as change in weight per 40 milligrams of ferosomide over 96 hours if you got hydrochloroioide that came at the expense of more hypocalemia as you'd probably expect as well as increases in creatin but we already talked about you know that may or may not be uh relevant so that's the main data aside from the crust trial which obviously used matlazone as step pharmacologic therapy this is the main uh randomized data we have to support the use of thioides when I started doing this um I think one of the things that that struck me especially as I got interested in the uh use of um you know uh net negative sodium excretion to define success is why we didn't focus more on the proximal tubule we all know that in in normal circumstances we reabsorb let's say 65% of our sodium approximately that goes up to about 80 85% in patients with heart failure combination of you know increased filtration fraction which we saw uh but also increase in lymph flow which washes out interstitial proteins decreases colloid osmotic pressure in the interstitium basically creating this environment to promote sodium reabsorption proximally and even though acettoolmide was the first FDA approved synthetic diuretic it really lost favor part of this was there was randomized trials of acettoolamide versus uh mercurial diuretics and and no surprise to anyone accetolomide lost that battle because loop diuretics are or excuse me mercury is essentially a toxic loop diuretic which is obviously going to be more effective but there was uh obviously the ADB trial so there was a number of smaller studies from the same group in Belgium that culminated in the Adbbor trial in 2022 i know people are familiar with this but to remind everybody this was a multic-enter randomized trial so it was 27 sites in Belgium uh 519 patients with detoxed heart failure who had to be on oral maintenance therapy of at least 40 milligrams of fioamide for a month prior to enrollment but no more than 80 so that's going to again going to be important as we compare studies uh important exclusion criteria were an EGFR less than 20 or uh use of an SGLT2 inhibitor was uh conceptualized before we knew how um uh important SGLT2 inhibitors were and they were then randomized to either once a day accetolomide 500 milligrams introvenously or placebo with a primary endpoint of successful decongestion with uh secondary outpoints that secondary endpoints that looked at longer outcomes on the right you have acettoolomide in red here placebo in blue and so there was more cumulative diuresis as well as naturesis in the arm that got um acettoolamide so the difference in mean sodium excretion was 468 mill moles if you got acettoolamide versus 369 mill moles if you got placebo and so they also showed um better uh decongestion at 3 days so 42% versus 30% in placebo we'll talk about this congestion score on the next slide and more successful decongestion at the time of discharge so 16% more patients were successfully decongested at the time of of discharge they also showed about one day uh uh decreased length of stay if you got acetylolomide so the the bottom line of the study was was that was positive it got a lot of press i think increased awareness and utility of of acettoolomide uh in practice but one of the problems was uh the way they defined decongestion so this was a novel congestion score that they actually created which composed of peripheral edema plural fusions and ascites to be defined as being success successfully decongested you had to have no plural fusion no asites and no more than trace edema i think practically if I think about my patients I can't remember the last time I had somebody with ascites that I was able to diarase off their ascites within two or three days with with diuretics alone and so I have a little bit of a problem with how they define that and this was buried in the supplement actually um and so we were big fans of acettoolite even before this it was part of our diuretic protocol for years before this came out i'm not convinced that if I wasn't already a fan that this would have convinced me uh to change my practice but we'll we'll show uh some care comparisons in in a minute here the other proximal uh diuretic are SGLT2 inhibitors if you want to classify them as as diuretics these are of course the only medications that have also shown mortality and morbidity benefit in in patients and there is a physiologic basis for for considering these in terms of acute decongestion we already know that SJOT2 inhibitors are should be started on on every patient uh with heart failure it's safe uh to do during an acute inpatient hospitalization the question is can it help you with uh acute decongestion and so when you look at mouse models so for rats that were infused with angotensin 2 and they're looking at uh SGLT2 mRNA and so these are controls angotensin 2 increase expression of SGLT2 the rest of the study was just looking at the impact of low sartinum pagalflotin but the point here is that angotensin 2 is obviously a major player in in heart failure it increases sodium reabsorption uh indirectly through its impact on the sodium hydrogen antiporter but could it also be doing that through SGLT2 channels as well so a few studies have looked at this this is the meag HF trial uh this was a single center trial uh randomized patients with acute decomposant heart failure like every other study upfront therapy within 12 hours to either 25 milligs of impaglasin or placebo it was 60 patients all of them were receiving loop diuretics and their primary endpoint was simply what happened to your urine output over 5 days and on the right and is in blue placebo is in red there was a 25% increase in urine output uh greater improvement in BMP and improved diuretic efficiency which in this case was defined as milliliters of urine output per milligram of fioamide equivalent and so all looks good but then you look at studies that have actually looked at the composition of the urine in these patients so this is a substy of the emperor response trial which was looking at the efficacy of empagalosin and acute detoxed heart failure 79 patients randomized to 10 milligrams of impagloin versus placebo they similarly found a 25% increase in urine output but on the right here you're looking at what was actually in the urine in a pagoplasin versus placebo and they found that the primary driver of the increased urine output was glycoseria uh so really creating an osmotic diaresis more of an aquaresis not uh a a naturesis which if you believe the data that we showed before may not be achieving the goals that that you want them to achieve and so the pendulum really swung back and forth about how useful these actually are really until uh this study by by Cox and colleagues was published at the end of 2024 so this was a multic-enter uh trial of 240 patients randomized within 24 hours of admission with hypoalmic you know heart failure to 10 milligrams of dapagloin versus placebo they actually uh obtained 24-hour uh uh urine collections and in this case they did show that combined with fioomide there was increased 24-hour if you got dapical fluos in versus usual care uh similarly increase urine output but at this point it does seem you are getting a naturetic response that seems to uh wayne after a few days but can help you uh in your patients that are acutely uh uh congested and so it's not generally going to be the difference between a patient needing ultra filtration or not but given that we know how important these are anyway uh and safe to do so you know can help you a bit the problem we have is that all of these studies what they've looked at is they've taken a population of patients with heart failure randomized them to one diuretic versus two diuretics and then looked at looked at outcomes and I think we can all predict that two diuretics are better than one that's essentially what they've shown and that doesn't necessarily help us figure out how to utilize these drugs i think I don't know if anybody read the I love these books growing these their own adventure books this is essentially what's happened for people taking care of these patients is that they're kind of left to uh decide on their own how best to to use these these different tools that we have and there's no guideline to help us with what is the optimal diuretic strategy in folks and so you know there are a number of studies such as this one showing that if you have higher doses of loop diuretics these are ambulatory patients your outcomes are worse okay and and the the logical conclusion to this is this the sicker the patient they need higher doses of loop diuretics that's driving these outcomes as I've done more outpatient work in this field I've come to realize there's probably something uh to this where you really want to minimize your doses of loop diuretics in your outpatient we've been very successful with with GDMT particularly with things like uh secubitrol bellsartin and and SGLT2 inhibitors to minimize and even remove loop diuretics from patients because we know that loop diuretics also act on the macula densa to uh increase rein release right they're blocking that signaling in the maculadensa and every study has shown that increased levels of of renin and aldoststerone lead to worse outcomes or at least associated with bad outcomes in patients with heart failure i don't know if that's relevant in in patients and so what uh this study by by Menson colleagues showed was they looked at the dose trial and the caress trial and they looked at patients that had plasma renan activity and aldoststerone measured so on the left is your P uh within the trials they're looking at bolus dosing of diuretics continuous dosing low dose highdose pharmacologic therapy versus ultrailtration in all of these groups your plasma activity increased it was most for the ultra filtration arm higher for continuous infusion but basically went up in in all groups if you were getting uh loop diuretics there was really uh no significant change in eldoststerone but what's important is that those changes in in P and the folks that did have changes in eldoststerone it didn't lead to worse uh 60-day outcomes and so whether that's because you know renan and and aldoststerone don't matter in the acute setting versus these transient uh changes aren't aren't important I don't know but it was reassuring that you know using high dose of loop diuretics in patients who are uh clearly volume overload doesn't seem to be harmful on the inpatient side and we have very few uh diuretic comparison trials this happens to be one of them so looking at mitoone versus daploin in patients that were hospitalized with heart failure and diuretic resistance so this is one of the few trials that actually looked at diuretic resistance the way that was uh defined in these 61 patients was a decrease in weight by less than 1 kilo or cumulative fluid balance less than one liter over the preceding 24 hours despite at least 160 milligs of purosomide and so it is a population that we would consider you know failing loop diuretic therapy they were then randomized to 10 milligs of dapagloin or excuse me mlllesone and on the right here so what you're seeing is daploin in blue mlazone in in this gray color uh and there was no change in weight between the two groups no change in the the advore congestion score you know whatever we want to think about that uh there was more hypocalemia and a higher creatinin if you got uh mlloazone versus dapagophosin so it kind of seems like a win for dapagoploin uh but when you look at the actual data the the patients that were on mlazone needed significantly lower doses of loop diuretic to achieve the same response so still seems that that thioides are going to be you know more powerful than than SGLT2 inhibitors to achieve these results the other one this is a a really nice study this is the DEA heart failure trial uh small study it was it was 42 patients uh and these were amulatoratory uh patients that were randomized to one of three diuretic regimens and it was a crossover trial so each one got uh weekly treatments with either ivferosomide plus mlazone fioamide alone and fioamide plus acettoolamide fioamide was given at 250 milligram so it was a 40 milligram bololis followed by 50 milligs an hour for 4 hours uh and and then they looked at various results so I'm going to blow that up for you and on the left you have fioide versus ltoazone in each graph the middle is ferosomite alone and on the right is ferosomite plus cettoolomide and they looked at things like natures urine volume and weight difference interestingly only firosomide plus matlazone improved those parameters whereas the addition of acettoolomide in these patients ambulatory patients so may not be relevant to inatients was no better than than ferosomite alone the other way to potentially compare these is to look at those trials and say well what was the urine output in the intervention group versus placebo so in the advore trial acettoolomide increased urine output compared to placebo by about 12 1.5% in aagoplasin it was 25% in the chlorotic trial was about 27% or so and then if you look at well what was their baseline fioamide use it was 40 milligrams in advore versus 80 in chlorotic so not only did the thighs that give you more urine output compared to placebo these patients were more exposed to loop diuretics making them a more you know quote unquote diuretic resistant population i didn't include implement because the study was primarily denovo heart failure so a minority of patients were on loop diuretics prior to the trial what about total urine output over 48 hours in these studies so ADB was about 4 and a half lers at at 48 hours empag HF was um you know just under four liters and then caress was six liters when with step pharmacologic therapy with with loop diuretics and tolazone when you look at push ahf and anac 20% of those patients needed adjunctive therapy on top of loop diuretic uh to achieve you know that threshold response and this is primarily with with thioides and similarly they found six lers of urine output over 48 hours so it's possible that there's something about 6 L in 48 hours that that is you know maybe should be our target and same thing baseline ferosomide in in caress was 80 milligrams so double that of the ad for population so this this is how we ca synthesized this data and came up with a diuretic protocol so I'll be curious how how people do things here the top is really uh analogous to the crust trial so we had escalating doses of loop diuretic with the addition of of generally mutolazone in our institution as the thioide of choice the way we assessed success was we did use a lot of spot urine sodiums this was a compromise amongst a few different people that were involved in putting this together so we just gave a range of 50 to 80 uh and then we had parameters to increase or or potentially decrease therapy depending on changes we would tolerate you know up to a 50% rise in in creatinin if uh decongestion was appropriate but realistically we were involved in the vast majority of these cases if if creatins were going up significantly uh during therapy the bottom of this uh uh protocol had this you know flow for proposed adjunctive therapies it's very telling that we had to put this you know no evidence for lowdose dopamine uh because this was still used a fair amount um and so first line again was was thyide diuretics but then we had choices for second line therapy and and so it really depended on on the characteristics of the patient if you were hyponetriemic uh if you were hypercalemic uh particularly if you had low chloride and really that that's you know going to be high bicarbonate we would use acettoolomide sub analyses of the Advoir trial showed that acettoolomide was particularly effective if you had a serum bicarbonate greater than 27 and uh we used a lot of hypertonic saline in our practice as well if you had low potassium we would use preferentially a milleride actually because of the rapidity of action uh sporolactone can be used it just is slower uh and there was a a study by Schwatha Bonsol suggesting that to actually achieve natures you needed 100 to 200 milligrams a day which is very different from the you know guideline directed medical therapy doses that are used uh and then we had SGLT2 inhibitors here on the right uh suggesting 25 milligrams we had impleosen on on formulary so we would preferentially use that you know maybe we're going to need to move this up higher uh depending on you know as as more data comes out but that's how we would kind of you know think about utilizing these other agents and this was posted in our CCU for the practitioners there to to reference if they needed the the point though is that if you're going to do this uh con decongestion is important but it has to be paired with a plan for appropriate long-term medical therapy there's a reason these studies have not shown improvement in mortality and heart failure rehospization because you need that that medical therapy and and the way we do this is all of these patients particularly if they have acute kidney injury or chronic kidney disease they see us in our cardioenal clinic and we very rapidly uptight titrate uh we call it guideline directed medical therapy but it's actually just medical therapy because we do this regardless of your GFR we do this in dialysis patients in order to recover EF and so we have a very strong program and a protocol to very rapidly initiate and and and continue these medications because when you look at so in in red here is enhanced decongestion and what that means is studies looking at a loop diuretic plus an adjunctive uh agent versus GDMT in in green early in an admission you're going to make patients feel better right they come to the hospital because of that venus congestion leading to symptoms you're going to make them feel better pretty quickly but that plateaus after that you're not getting more benefit to an extent and you really need that other medical therapy to not only improve symptoms but improve functional status uh for these patients and I think that's one of the reasons that ADBR uh has that paradox that we've seen with many trials that they improved decongestion based on their definition but they didn't show improved outcomes and if you look at the use of GDMT in that in that group uh high uses of of beta blockers remember SGLT2 inhibitors were excluded from this or not included here uh only about 50% were on an ACE arbor arney which really only went up to you know about 58% at the time of discharge similarly you know a minority were using mineralic corticoid receptor antagonist that did increase a bit but without that long-term therapy you're really not going to you know do much for these patients long term and so in the last few minutes uh because uh hypertonic saling was discussed at at kidney week this year and actually generated a lot of comments we do use this a lot so I did want to spend just a few slides on this and so I'm going to focus on the original Italian studies which really are our main randomized trials here um so the initial one was in 2000 this was a single center uh trial of 60 patients refractory heart failure i'll show you that definition in a bit that were randomized again upfront therapy to either fioamide alone at pretty big doses 500 milligrams to a gram with or without hypertonic saline it was 150 cc's given twice a day at varying concentrations based on the serum sodium and what you're looking at here is the fioamide without hypertonic saline on the left fioamide with hypertonic saline on the right they showed improvement in weight loss about 500 cc's more urine output and better buun and creatinin if you got hypertonic saline this was followed up by the largest randomized trial we have but same single center it was in 2011 called the smack heart failure trial over,900 patients very similar methodology except now they randomize people who got hypertonic saline to a quote unquote moderate sodium diet at the time of discharge which is about 2.7 grams of sodium a day versus low sodium diet if you got ferosomalone that was about 1.8 uh grams of sodium a day this was the criteria so adult patients with uh low ejection fraction unresponsive to this you know cocktail of things for at least four weeks if uh you had a serum greater than 2.5 or bun greater than 60 you were excluded from the trial and very similar here but now you're looking at fioomide with hypertonic saline on the left fioide alone on the right similar findings reduction in weight by about 3 kg 500 more cc's diuresis better bun and creatinin if you got uh hypertonic saline they decreased length of stay by about 2 days and unbelievably showed these incredible Kaplan meer curves curves of mortality and hospital readmission over almost you know like a six-year follow-up uh which I I do not believe these results to be honest with you i don't think you can you know show this significant you know mortality benefit with that intervention alone there's only been one other trial looking at mortality uh with hypertonic saline administration it was a Chinese study also single center uh they looked at hypertonic saline combined with a very restrictive fluid intake of 500 cc's a day only other study to show any kind of mortality benefit but we're limited to these single center uh trials so again I don't believe this data but I will say that we've used a lot of hypertonic saline successfully for acute decongestion um but the problem is this so the the the reason I show the Italian studies is they collected 24-hour urine collection that looked at uh sodium excretion so I'm going to summarize all this for you in a couple slides but this is just to show that you did have more sodium excretion uh if you got hypertonic saline versus ferosomite alone both in that initial uh 2000 study as well as the smack heart failure study so I'm going to summarize those numbers here so in the initial study you had 198 versus 129 mill moles of sodium 119 versus 76 so the difference is 69 mill moles versus 43 millles that looks good until you remember that they're getting 150 cc's of hypertonic saline twice a day regardless of the composition of saline if I'm giving this twice a day these patients are coming out net sodium positive at the end of these 48 hours right and so if you believe all this sodium attrion data this this is paradoxical to how we would think about treating folks right uh so how can you explain you know some of the success that that other trials you know studies have at least suggested in this field and it made me realize you know maybe not just me many people have thought about this maybe it's not the sodium maybe it's the chloride that that is driving that benefit uh there's a a a lot of literature suggesting that uh hypoclemia is associated with bad long-term outcomes in patients with heart failure uh but because this is more of a diuretic talk I just want to focus on the diuretic resistance component So this is a study by uh Dr hamburg and colleagues out of Yale and what they looked at was what is your diuretic efficiency and this was uh defined as sodium excretion per doubling of loop diuretic dose uh across a range of of chloride and so basically they found this U-shaped curve where both hypercchlormia and hypocchlormia was associated with reduced diuretic efficiency hypoclemia being worse than hypercchlormia when they did a multivariable analysis chloride remained an independent uh predictor of of uh hypo respponsiveness to diuretics even when you control it for things like uh serum sodium serum bicarbonate and other factors and there is kind of physiologic basis for this so if you look at basic science uh data what you're looking at here is uh in vitro studies with o sites were injected with NCC NCC and wink 4 NCC and wink 4 plus wink one bottom line was there was no change in the glycosillated NCC but when you did aminoistochemmetry and you stained for uh NCC you know surface expression of NCC you saw that wink 4 suppressed NCC activity by about 85% wink one tended to prevent that inhibition but in my discussions with David Ellison on this it it seems that wink one is not a major factor within the kidney so it's really just wink 4 that you know seems to be controlling uh uh NCC expression and when you look at mice with wink 4 misssense mutations they display hypertrophy of the distal convoluted tubule which is very similar to what we saw in the animal models that were exposed to loop diuretics right and so the simplistic view here is that wink 4 seems to inhibit NCC activity and the reason this is relevant to chloride it appears that wink 4 is a chloride sensor so if you look at studies with knock-in mice that are have chloride insensitive mutant wing 4 so unresponsive to chloride these mice phenotypically essentially have Gordon syndrome so they're hypertensive they're hypercalemic and they have these hyperactive NCC channels and when you give potassium chloride it doesn't change the total number of NCC channels but change the number of phosphorolated NCC channels only in the the wild type mice not in the mice that had the the chloride insensitive mutant wing 4 and so it appears that wink 4 acts as a chloride sensor to to regulate NCC activity and if you move beyond you know the bench you know back to the bedside that same Hamburg study so this was a study of of I think 140 patients at the Yale transitional center and so they looked at patients with uh hypervalmia that were given loop diuretics and looked at the response in the patients that were hypocalemic versus h versus normal chlorimmic and what they found was that in the hypocclemic population there was no difference in the quantity of diuretic excreted so it's reaching its its sight of action there was no uh excuse me there was a decrease in diuretic efficiency which we saw previously and no difference in the fractional lithium suggesting that the issue is beyond the proximal tubule uh so it can't pinpoint where in the in the nefron this is taking place but at least is supporting uh the the prior hypothesis and when you look at a post talk analysis the salt HF trial so salt HF was was a study of hypertonic saline in ambulatory patients with with volume overload they looked at the response of uh hypotonic saline in patients that were hypocchloric and so similar to the prior study they showed that if you were hypocchloric this is this is fiosomide alone you you were hypo respponsive in terms of 3-hour urinary sodium excretion hypertonic saline appeared to attenuate that response in in patients that were hypocchloric and when they uh looked at the dichotomy of uh response to hypocchloria or not at a transition point of 96 millles per liter that seemed to be the the transition point where if you had a chloride above that you didn't see that differential response versus if you had a at a hyp below 96 you you did see that change so maybe that helps guide you know how to how to utilize some of these things obviously whether chloride is a target or just you know kind of an innocent bystander we don't know um Jeff Testani and others are doing studies on lysine chloride to see if it's a if it's a potential therapeutic target but we won't have that data I think for for a few years so uh in conclusion you know after doing this for a while I've come to the conclusion that it's probably the destination not the journey i don't think it really matters how you decongest patients as long as you're doing it so you know maybe that choose your own adventure was correct you know you can kind of use whatever tools you have you know maybe there's something to the six liters in 48 hours but again that's just supposition based on on what's been done in in other studies uh obviously decongestion has to be paired with long-term medical therapy to have sustained success you know I I had this period where I thought that maybe balanced diaresis was better than maximizing the diuretics first i still think there's some value to that if you want to avoid some of the electrolyte abnormalities that you would see but again if you're actively paying attention and repeating electrolytes again it probably doesn't matter how you're how you're approaching this you know it'd be nice to know if there was a synergistic effect of SOT2 inhibitors and acettoolamide i I think there probably is they're acting on different places but we don't have that data and it'd be nice to get prospective studies in patients with with diuretic resistance we don't have a lot of studies most of it was upfront therapy uh so I'm going to end there and uh I might have gone a little over but I'd be happy to to take questions awesome thank you um so if there are questions oh there are some in the chat that we hadn't got to uh so if there are questions please uh raise your hand and ask them let me stop sharing oh there are um Manish do you want to go first uh very very nice talk i'll spare you the visual i'm on my bike uh that was really excellent the question I have and it's something I uh noticed maybe 10 plus years ago and I'm wondering if it's improved which is baseline creatinine measures in these trials so many of them use serum creatinine and presentation which we know is going to be an intermix of AKI and EKD i would render studies that don't do a nephrological baseline i would almost say they're uninterpretable when you have those two populations mixed i'm just curious if the literature is improved is there something for maybe us to teach our cardiac colleagues about that yeah no you're absolutely right the the it is basically uninterpretable because of the the reason you're mentioning and the literature unfortunately hasn't improved in that and you're still looking at you know creatinins you know at presentation um and so you know we had a good relationship with our cardiologist but it took a while to convince them to you know I don't want to say ignore creatin but but you know really put much less weight on it you know the way we approached it was if it was cardioenal syndrome we weren't you know using creatinin for for that much um now there are patients again with lowflow states they're not getting appropriate blood flow where you're seeing this rising creatinin with with congestion you have to look for that the other thing obviously we're looking for is you know could something else be going on do they have tubular injury do they have interstial nefritis are there other factors involved but you're absolutely right it's it's a it's a poor biioarker in general and even more more poor in the trials because of how they were ascertained thank you uh Gray yeah kind of a similar question um so at your hospital with your your diuretic protocol are you using that is that kind of widespread on the floors in general medicine patients cardiology units or restricted to the units no so it's it's well so the idea was it it for to be widespread at the time that I left which was just you know last year the plan was to present this more to the general medicine wards as well so that they could utilize that uh if needed at at the time that I was there was mostly utilized on the cardiology floors that's you know most of the pretty much all the heart failure patients were admitted to cardiology services so this was used both on the the cardiology floors as well as the intensive care unit Um and initially when we started it it was essentially our service that was driving these things and then over time you know as the cardiologist we had a we had a very small team it was just two of us when we started and so we were doing the same things over and over so that kind of rubbed off on the cardiologist they started to see that mostly run by APS and then they would kind of use this independently and we would actually get called less unless they were failing uh all that therapy on on those protocols and sort of a follow-up to what Manishius answered so in practice so are using this on sort of widespread GFRs like across a range not just sort of yeah we are the the one exception is hypertonic saline um not necessarily a GFR cut off but if they have tubular injury or or other factors driving their their kidney injury then we tend to not use it and we pretty much were restricting that to patients with quote unquote pure uh cardioenal syndrome and in those patients sorry our last question you are using hypertonic saline for most of them not I wouldn't Not most uh the way we generally use it were if you were failing uh let's say loop diuretics thyide diuretics acettoolamide plus or minus an SGLT2 inhibitor uh then we would that that was our practice to generally reach so that's different than how they used it in the in the studies uh we were mostly using it uh to to as as a last resort to stave off ultrailtration i gota Okay thank you Mark i really enjoyed that talk thank you very much um I'm interested to know what's happened uh in terms of use of ultrailtration so so on the one hand it kind of seems that if you're if you're using the spot urine sodium and you're you're seeing that patient multiple times in the first day and you're escalating really quickly maybe you need less um so has that happened but at the same time you're also saying that the most important thing is to get these people decongested as quickly as possible like where in that protocol does everyone know when to fold their cards just put the person on yeah yeah so so you know um the the there's no easy answer to that you know there's no studies looking at you know well let's use all of these things before we resort to ultrailtration again like suffering from the other trials most of the ultrailtration trials were a patient hits the door and they get randomized to diuretics versus ultra filtration we would reserve it for hey you failed all of those things uh in the absence of other reasons for diialysis that's how we reserve it we have internal data from UDub showing that we reduce the rate of diialysis in these patients um again that's internal single center data but but utilizing and I don't know that it was the diuretic protocol I think it was the fact that we literally had two people that were seeing all these patients that practiced very similarly the communication was great with the cardiologists and so I think it was a variety of factors that led to that but we did use less dialysis because of this and and again that's where I think urine sodium potentially help you is that you can make multiple changes within a day and that's what we tell the cardiologist like "Hey get a urine sodium let's do all this within the next 8 hours and if they're failing we'll we'll dialize them." And and I think that also gave them reassurance that we're paying attention and that we're not quote unquote withholding dialysis but we're doing it appropriately and how much of that is like early I guess a culture of early engagement of nefologist so you're not you're Yeah because I I will tell you at my my current institution we don't have that because there's no inpatient service and generally we don't get called by cardiology until like hey this person needs diialysis and at that point it's it's almost too late right and so that is a problem so I think early engagement is is the number one uh factor here good lot of questions u maybe Brendan and then Yolanda said um yeah I I really enjoyed the the talk as well and and and one thing that kind of kept coming up but but you didn't fully explore is the the concept of free water clearance and decongestion uh because there there's no question that there's a link there i mean we've known forever that that hyponetriia is a very very bad prognostic marker uh we know that SGLT2 inhibitors are great at free water clearance and that might be part of it and even you know there's a hint that the the hypertonic saline that that that's correcting hyponetriia and actually increasing uh increasing your your urinary water excretion and so so should we be focusing a little bit more on that because I know that with the urine sodiums it is very sodium centric and of course you know while we think of water as being an intracellular you know mostly associated with intracellular volume we often forget that your blood volume is 40% intracellular and and that that that increasing pre-war clearance there's good rationale why it should help decongest you yeah and so it's it's there's a lot of strong opinions on this also and people kind of have two different camps on this and you know the people that believe that that we should be focusing more on on free water clearance versus not obviously you know Everest you know looked at Baptan etc and you know the the um the criticism of that was well it didn't change long-term outcomes but but none of these studies have shown long-term outcomes and so how much of a role I don't know that basically what we know from all these studies is that urine sodiums do are associated with with better prognosis whether that's you know because maybe you're not diluting your urine you know whatever that may be uh that that's the data we have we don't in our practice focus as much on on uh free water clearance you know maybe we should again that uh Chinese study when they gave hypotonic saline that's what they were focusing on because they've restricted patients to less than 500 cc's of of water a day um the time that we really focus on serum sodiums is if a patient is about to go in for a for a heart transplant and then we'll kind of you know uh uh bring their sodium up so that you know in preparation for surgery but otherwise that's been our practice not to focus as much whether right or wrong i don't know if that's the right thing to do yeah um I'm curious about your the outpatient clinic do you have this nice kind of step-wise algorithm for inpatient care and you know we often stabilize football as an outpatient but then they destabilize so do you have a similar sort of algorithm or how do how do you monitor like we have these cardiology clinics where patients call in and they get advice from the nurses i find that never works bring them in they give them crazy things do you have something that kind of keeps people stable prevents that readmission right so so our focus is on getting them on GDMT in the hospital seeing them very we have the resources to see them very quickly in our outpatient clinic and there's a whole team involved and I can show you our actually our our outpatient protocol uh you know maybe a little later I I brought it with me where we have a nurse or a pharmacist that calls every patient the day before we sees them and has already done all the prior offs you know tells us you know what what the patient can get and we institute that you know very quickly and rapidly titrate that up with every two week visits um and I think that is the main thing that that stabilize these folks and so you know with arnes in particular and SOT2 inhibitors we found that we can keep people decongested uh you know much better in the outpatient setting obviously we'll use diuretics as needed and and you know we're we don't have a protocol for that it's usually diuretic plus or minus the thazide we also have subq um fioamide we can use for patients if we if we really have to uh we also use um a lot of you know uh pulmonary artery monitors like cardoms or cordellas uh we have a lot of patients that live quite far away and we found that that can be very helpful in terms of keeping people out of the hospital and then do the patients have some kind of protocol they can adjust on their own or are they contacting you for changes so yeah so they you know we do give them kind of a weight you know saying hey if your weight went up by three pounds you know add an extra whether that's a loop di take your take your thide uh but but they contact us a lot and we have a very good nurse who fields all those calls and uh can address things and then you know reach out to us in in cases that they need to yeah yeah without that infrastructure we we wouldn't be able to do any of this okay that was a great talk thank you um couple questions so you mentioned you're doing a lot of point of peril just to establish decongestion how how how helpful do you find that and like specifically are there things that you Yeah so we we personally find it very helpful um you know so we I'll I'll generally and part of this is training our our fellows also we'll do it on every patient that we see upfront uh we do utilize you know this kind of VEX score which you might have heard of the Venus exh ultrasound score uh so we're looking at IVC's we're looking at uh hpatic veins renal veins and uh portal veins and then we we actually try to do that you know maybe not every day but but you know every other day maybe and and until we you know see improvement in that we did a small study where we at UDub where we correlated this with right heart cats and actually found it to to be pretty useful i I think what it comes down to is that we know that exam is great but people aren't necessarily that that good at it all the time and and it can be hard to see you know jugly venous pulsations and certain patients you know relying on things like edema and others you know may not be that effective and so for us it's just something that's maybe more objective uh and if I think you're trained at it it can be a useful tool if you're not trained at it it's it's a terrible tool because you don't know what you're interpreting um and so this has allowed us something to make maybe it's just making us feel more comfortable that we're effectively decongesting people thanks the other uh question is um you know obviously peripheral ultra filtration like the negative trials were done but like some could say you know the trials were not perfect in the sense they were kind of like set it and forget it ultra filtration yeah do you think the door is completely closed on no uh and I think our cardiologists would love it if they if they didn't have to contact us heard that from Yeah so yeah and so I I I hope that doesn't happen because I frankly think we do a better job uh at this than they do and I'd like to keep control over that i don't think the doors right exactly just you know it depends where the money is in this here 15 years ago yeah yeah they saw one thing they got one and we told them that was a bad idea just because you know they're not seeing the patients afterwards right i think we all know that that there's harm to dialysis right and and they're if they're not going to be seeing the patient in clinic or the like it I don't think they should have control over a technology that they're not then following patient i mean those trials are I mean serial trials are complete BS like the diuretic resistance tried 40 of froze might work plat one exactly yeah um yeah last question maybe yeah I mean I have about five but that was you raise your hand a milleride or other case bearing diuretics were seem to be very much an afterthought in your algorithm and cardiologists are always causing hypocalemia and giving a case supplement which strikes me as insane I wish it was we use we use it we we do use it more and it is kind of you know your second line in that I sort of look for oh I hope the potassium's below above 4.8 So I can add it now i don't wait till the potassium's low tell me what do you do if somebody's already on baseline spironolactone before they come in is that continued it's it's continued yeah and but not escalated to the di if we potentially need to we will um again I haven't found that much success in terms of hey I'm really struggling to diaris patient and then increasing the spinalactone is the thing that makes a big difference i think that's where we certainly continue it's way better in unstable patients right uh and of course I have about five questions about hypertonic saline because I suppose that's real um yeah it's an Italian trial and you still showed them italian trial the early trials had no rationale for why it should work and then oh they give you know few doses over a few days in the hospital and it improves mortality in six months like I don't believe any of those like what's that because I mean I like the rationale that it alters wink response to hypo to low plasma chloride but surely your plasma chloride only goes up transiently after your hypertonic saline i have the faintest idea how long it stays up before it goes back down and once it's back down wink's got to change and right any effects it's got to be very transient and all of this is also is it intracellular signaling is it you know the the serum chlor i mean there's so many questions about this um but you think that when you give it you see more diaresis and a more I I'm very confident we do because we we have used this I don't know last I checked maybe 50 some odd you know patients and we have avoided diialysis in in a number of those I think um I can't say for sure it's not it's not randomized it's not a trial this is all anecdotal but we have patients on everything else you saw on on the protocol that's the only intervention and people people with diaries uh I mean I really like that you add all those things because cardiologists consult need dialysis when they're on adoproside and maybe one other drug and like how about piling on with multiple diuretics and I think they know that hey if we're reaching at least in our practice we're reaching for hyperonics alien you know the the diialysis line is the next step right and and so and so I think the biggest thing is the study showed no harm in using it and so hey if this is a last gasp effort then and there's no harm in it and it's a cheap intervention you know might as well try it excellent so on that hypotonic ceiling note thanks everyone for joining in uh and uh for the fellows in the audience there will be another talk by Nan in the afternoon a chalk talk uh on diuretics in the outpatient setting but the staff nephologists are also welcome to join this afternoon thank you there's a throwaway in there about using GDMT in diialysis patients