19. Metabolic Acidosis w/ NephMadness

[BELL RINGING] I think lactic acidosis is one that should always be considered basically every patient, because you can be surprised. I've seen totally stable, seemingly stable patients develop pretty profound lactic acidosis, especially when they have cancer. Those cancer cells can start shifting over to anaerobic like colitis and create big amounts of lactic called the warburg phenomenon. So that's something that happens even in the absence of sepsis and the schemium. [MUSIC PLAYING] [MUSIC PLAYING] Welcome to Critical Care Time, the podcast for everyone who cares for the critically ill. I'm your co-host, Dr. Cyrus Askin. Here with my co-host, as always, Dr. Nick Mark. Thanks, Cyrus. It's great to be back for another installment of Critical Care Time. What do we have on the agenda for today? Well, Nick, we have a very special episode for our listeners today. For those of you who are kidney-efficient nodos and/or curbsiders fans, you may have heard of Neff Madness. It is a free online CME and MOC granting evidence-based non-commercial learning initiative that leverages the tools of social media to teach about the latest and greatest breakthroughs in the field of nephrology. It's a riff, of course, on March Madness. For those of you that are basketball fans, whereby the fine folks over at AJKD put together a bracket of the hottest topics in nephrology for the year, discuss them all in various forums and ultimately crown a victor for the year. Nice. And then we are fortunate to get to help out this year. We're going to discuss a topic that we think is a serious contender for this year's trophy, metabolic acidosis. We'll get into the weeds. Fortunately, we're joined by a couple of nephrologists, Dr. Timothy Yao and Jeffrey Cote, who will keep us honest and keep the ship sailing in the right direction, hopefully. Dr. Yao is an associate professor of medicine at the Washington University in St. Louis. He's a clinical nephrologist and an educator for the medical school as the co-director of their clinical skills curriculum. He's been part of AJKD and neph madness since 2016. Tim, you want to take a minute and introduce yourself, say hello and share some of your favorite trivia about the world of nephrology. Sure thing. Thanks for having me on. Always a pleasure. Big fan of the podcast and really pleased that you guys are going to be able to be able to talk about something near and dear to my heart. Full disclosure, I'm not like a magician or expert in metabolic acidosis, but it is one of those things that I think every nephrologist kind of intrinsically loves. So you asked for a favorite little bit of trivia. If it's OK with you, I'm going to deviate and not talk about a piece of medical trivia, but something that I just came across a few days ago when I was teaching med students, actually, which was super interesting. So as part of our breaks in between classes, sometimes we put up random trivia things for them to think about before we kind of move on to the next topic. And one of my co lectures put up a map of the entire world. And basically, the only areas that were highlighted were the province of Alberta in Canada and the Arctic Circle. And he said, what does this map represent? And I was like, I have no clue at all like what this map could represent. And amazingly, one of my first-year medical students raised her hand and said, does it show the areas of the world that have no rats? And that was the answer. Did you know that the province of Alberta has no rats? I had no idea. Oh, no. I did it. The scourge of humanity. That is no vitigus. Wow. I didn't know there was a place that was free from it. Crazy. Exactly. Yeah. I'm also learning something every day. I'm not sure that I needed to know that, but it's a great little factoid. In the pros consulist for Alberta, there's one more thing in the pros column, I guess. Yeah. That's right. Well, awesome. Thanks, Tim, for sharing that and for joining us. Next up, I'd like to introduce Dr. Jeff Cot, who is a current critical care medicine fellow at Stony Brook Medicine on Long Island New York. He completed his nephrology fellowship at Mount Sinai Hospital in Manhattan, and is on the executive committee for Neff Madness. Jeff, thanks for joining us on critical care time. I'd also love to give you a chance to say hello to our incredible listeners. And maybe ask you a little bit of a different question and get a feel for why you chose to do nephrology critical care, which I think we acknowledge as an emerging, but still sort of an uncommon combination of the fields. Yeah, no, thank you for having me on. I'm excited to be here. I think it's a perfect marriage of specialties. I've always been a big physiology person, kidney physiology, I think is probably some of the most interesting and complex things in a body. And acid-based, falling status, electrolyte disorders, Q-kinne injury, which is the crux of inpatient nephrology, also have a very big overlap with critical care. So if you're like me, you need a little bit of acuity, maybe a little bit of procedural on top of amazing physiology. It is an extra year of training. But you really get to handle everything about the patient. And maybe even do a little bit of inpatient outpatient, you can make your job as variable too. Very cool. Yeah, I always tell people that if you like medicine, you'll love ICU because it's like medicine turned up to 11, and I can see the same is probably true with nephrology. A lot of the interesting physiology, pathophysiology, it's like the final common pathway for all of it is critical care. Well, anyway, thank you, Jeff, and Tim, for joining us. They're telling us a little about your journey, sharing your trivia. Why don't we jump into it and have a great discussion about metabolic acidosis? All right, so before we get into the deep dive on metabolic acidosis that I know our listeners are dying to get into, I was hoping that one of y'all could spend a little bit of time, or perhaps both of you, discussing your overall approach to acid-based arrangements in the ICU. Yeah, so I think the first thing that you should always think about when approaching acid-based status is what is the pH? Can either we obtain from an arterial venous blood gastroenterinoe, or know something we're going to talk about a little bit earlier? There may be a little bit of an adjustment that is necessary for venous blood gas. But normal pH, somewhere between 7, 3, 5 and 7, 4, 5. But in effect, if there's an acid-based disturbance, let's just call 7 for the middle point. Anything less than 7.4 is going to be acidosis. Anything more than 7.4 means acidosis. I think the biggest misconception that I've seen really among young learners is they start with the bicarbonate. Low-bicarbonate means acidosis. But we know it could also mean compensation for respiratory acidosis. And I think in fellowship really a lot of times when I got called for these kinds of low-bicarbonate consults, it was in people with acidosis. And cirrhosis is obviously a incredibly complex physiology. But what we really found was you asked them for ABG, and it winds up being at respiratory acidosis. It winds up being the primary-- really big process for a lot of people with cirrhosis. Though there are obviously many reasons that they can have acidosis. But you really need the pH to kind of go ahead and say, is this pH an acidotic, or are they alkalotic? And to that point, I'm kind of speaking about cirrhosis, which probably talk about history. Like everything, history isn't perfect. It's not physical and not perfect. But they can certainly kind of point you in the right direction. Does the individual have any medical morbid? These things like diabetes or alcohol use disorder. And he's psychiatric disease where we're thinking maybe we should kind of worry about some kind of toxic ingestion and a history of things like diarrhea. What are their medications? Always a big one, especially given some of the big progress we've seen with SGLT2 inhibitors in the cardiovascular and kidney population. Big cause of u by CMKAA. Maybe they have neurologic disorders. They're on things that are essentially carbonic adhydrous inhibitors. Like a topopurimator, I see it as holomide. So medications obviously are important to go through as well. Then we can kind of go to our physical exam. Maybe they've got signs of euremia, semesterosis, big cause of acidosis. Maybe you decide to pull out your ophthalmoscope. We're all doing obviously very thorough physical exams. So you have evidence of optopropathy, which can point you in direction of toxic alcohol. So there's a lot of information you can get from history and physical. Again, it's not going to be perfect, but it can at least kind of start bringing you down the right direction. At that point, we can finally go further into our labs, looking at our bicarbonate and our PCO2, which is going to come from the blood gas. And the bicarbonate will come from your chemistry panel, though there is also one on the blood gas, which again, will cover a little bit later. In general, if the pH is low and the bicarbonate is low, your primary disturbance is going to be in metabolic acidosis. If the pH is low and the PCO2 is high, then we're going to look at a respiratory acidosis. It's a culprit. You want to start categorizing your acidosis at that point, using things like your anion gap, so your sodium, minus your chloride, minus your bicarbonate. And at that point, we start to-- we're not there yet, but we can start to think about treatment of the back of our minds. Once we have the primary disorder, at that point, we think about compensation. And I think to address compensation, it's either going to be your bicarbonate is going to be altered, or your CO2 is going to be altered. And the way that our body really handles acid bases going back to biochemistry, on one side of our equation, we've got water and CO2. And on the other side of our equation, you have acid, proton, and bicarbonate. So as either the acid or CO2 increases, whichever one is increasing, the equation, if you remember, just can get shifted into the opposite way. So that's essentially how our body will compensate for some kind of acidosis. So in terms of metabolic acidosis, we can use our winters formula, which I'm sure we all have memorized. It's 1.5 times your serum bicarbonate, plus 8 plus minus 2. And that's going to give us our expected PCO2. If it's higher than expected, then there's also a respiratory acidosis. If it's within that range, then we've got a normal compensation. And if it's lower, then we're looking at respiratory opalosis. For a conversation with a respiratory disorder, it takes a little bit more memorization than the formula, I guess. But there's that 1, 2, 4, 5 rule, which is really just for every change in 10 of CO2 problem in the acute phase, or respiratory acidosis is going to go up by 1 for alkylosis. It will go up by, it'll excuse me, decreased by 2. And for respiratory acidosis for chronic, on that for a couple days, you'll start to see the CO2 rise by 4, excuse me, by carbonate rise by 4, and in alkylosis it'll rise by 5. And finally, just because we always like to keep things as complicated as possible, you can actually have another acid-based disturbance. So this is where we talk about our delta delta, which essentially, I think of this as the change in the anion gap from normal over the change in the biprobernate. And if you're somebody like me who really just needs a pneumonic to remember everything, it's essentially a over b, n-n-gap over bicarbonate. The theory is that in a pure anion gap metabolic acidosis, if the anion gap increases, bicarbonate should decrease by approximately the same amount. So if the change in bicarbonate is out of portion to the change in anion gap, you expect there to actually be a non-anion gap metabolic acidosis on top of your anion gap metabolic acidosis. So on the flip side, if there is change in bicarbonate is less than they change in anion gap, there actually may be a concomitant metabolic acidosis, alkylosis pressing. So in general, the rules are, if it's the delta delta is between 0.4 and 1, that would be indicative of a mix anion gap and non-anion gap picture. If it's 1 to 2, it's pure anion gap, and if it's greater than 2, well, there's also going to be anion gap and metabolic acidosis. So that's a brief overview of how we approach acid base. And it sounds difficult going through all these calculations. But once you kind of get in the habit of doing it repeatedly, it becomes pretty simple. Excellent. Yeah, that's a wonderful overview. So we have a one-pager on this, and we're going to make it infographic to go with this episode that summarizes that. But that's a beautiful summary of kind of acid base in the critically ill, or in the not critically ill for that matter. I think just to double click on a couple of key points there, the emphasizing that the pH is your starting point, and then you can break into sort of four quadrants. It can be an acidosis or an alkylosis, and then you can subdivide those into metabolic and respiratory. Then you can subdivide your metabolic acidosis still further into anion gap and non-anion gap. And that's where the Delta Delta comes in. I think that's a great walkthrough from one number on the blood gas all the way through the complete analysis. Do you want to elaborate just a little bit more on the difference between anion gap and non-anion gap metabolic acidosis? Yeah, sure. I want to emphasize just one or two real quick things that Jeff said recently, which is, we start with the pH, and we think about pH as number 7.4, but you have to remember what that is. That's the negative log of a hydrogen ion. In a lot of ways, we're measuring the amount of protons in the body. So it's not that different than us measuring a sodium of 140 or a potassium of 3.5. A pH of 7.4 is a proton concentration of 40 nanomoles per liter. And so I think just keep that in mind when we talk about pH, we're literally measuring amount of proton. Although the units are much smaller, we're talking nanomoles versus milli moles. And I know, like, you know, talking about compensation is, I find that I lose a lot of learners when I start busting out equations and numbers and so forth. And personally, I can't remember anything other than winters formula, but I think just remembering the basics of if you're dealing with a respiratory problem, then your kidney should be trying to move things back towards normal. If you're dealing with a metabolic problem, your lung should be trying to move things back towards normal. So I just think as long as I look at the PCO2 and the bicarb and say that, okay, well, it should be a little bit low because we're trying to correct back to normal. That then I usually feel pretty comfortable about that. Your question about the anion gap. Let's jump to that. So the main difference between an anion gap metabolic astosis and an anion gap astosis is that in an anion gap metabolic astrosis, there's this additional anion that is responsible for the extra proton, whereas in an anion gap metabolic astrosis, there's just loss of bicarbonate. So if you imagine something like diarrhea, where you're just losing bicarbonate in the stool, or in an RTA where you're losing bicarbonate in the urine. In the ICU setting, which is what we're mostly talking about, most of our metabolic astrosis actually is an anion gap one. And those have their own differentials, whereas non anion gap metabolic astrosis are usually able to be determined and treated pretty easily by simply by giving bicarbonate either in pill or IV form. So the simplest way I think about an anion gap metabolic astrosis is to just like take an example. So we're going to talk about lactic astrosis a fair bit in the ICU. So let's use that one. So if you infused lactic acid into a patient or more practically in an ICU setting, if you are generating lactic acid due to some kind of ischemia or whatever it may be, what's occurring is the hydrogen ion that that lactic acid produces is being buffered by a bicarbonate, but then you're left with an unmeasured anion. In this case, it's the lactate. And so that is what is actually raising the gap. So any disorder where you have that unmeasured anion, so DKA or methanol or ethylene glycol, they all have some kind of retained anion will lead to that elevation in the anion gap. I think that's a great point. And I just want to emphasize one thing there, which is that sometimes people get confused by the idea of lactic acid, which is this thing produced as a product of metabolism, versus lactate, the conjugate base of that acid, which is sometimes given to people like in the form of, let's say, lactated ringers. And so people have some misconceptions that maybe we can, maybe we can mith bust a little bit here before we move on. Yeah, so great question there. And so I think a few kind of common misconcertions you mentioned, lactated ringers does not have lactic acid and it has lactic the conjugate base. And I think the other thing is that lactic acid is not a pathologic consequence, right? Abnormal production of it and the inability to clear it is not good, but we are generating lactic acid all the time when our bodies shift over to aerobic glycolysis. Like if you go on a big run and you stress your muscles out, you're going to generate lactic acid and your liver normally a healthy function in the world will be able to clear that out of your system quickly. Great. Awesome. So just a sort of double tap on that, you know, a lot of times the I see we're giving, we're giving fluids on, I probably, you know, we're giving fluids, we're taking fluids away, you know, doing all sorts of things with fluid management. But one oftentimes we're giving lactated ringers and we really shouldn't in general be too worried about that and causing a pathologic elevation in serum lactate. And then the other thing I think you mentioned, Tim is just that recognize, you know, pretty much anyone that does any sort of intense exercise is going to generate lactate as they're shifting from aerobic to anaerobic respiration and that that lactate gets cleared and in and of itself is not a bad thing. Is that accurate, Tim? Absolutely. Yep. Exactly. As a throwback to one of our earlier episodes, you know, I like to view a high lactate as a check engine light, you should, you should think about what's going on, but it's not necessarily something pathological and certainly lactate itself is not bad for you. It's cardio protective in fact. So don't be afraid of lactate, but nowhere it's coming from and why. Absolutely. Yes. So let's, let's move on a little bit now and say, you know, I think this is a great discussion so far. We've done some clarifying, I think a little bit of myth busting. Now one thing I wanted to get to is sort of this idea of discriminating between a hagma and an agma and using that anion gap and and actually just even getting super, super fundamental in asking, what is a normal anion gap and are there circumstances under which that anion gap might change? Yeah. So the concept of an anion gap is that all the cations in your body must equal the number of anions in your body, right? If you take the common cations in your body, sodium being the biggest one and the anions in your body chloride and bicarbonate being the main ones and you, you know, do the math and take sodium minus chloride minus bicarbonate, it quote unquote normal gap is usually around 10 to 12, but you said there are circumstances by which that normal value could change and I say the most common one is in patients who have low serum albumin and so as you drop your albumin for everyone that you drop the anion gap also decreases by factor of 2.5. So if we consider normal albumin to be about four, if someone had a serum albumin of three, we would then say this patient's normal anion gap instead of being 10 to 12 would now be closer to 7.5 to 9.5. I would say hypo albuminemia is the most common reason you have to kind of factor in for your gap adjustment, but there are some other unusual causes, other electrolyte abnormalities like hypercalcemia, hypermagnesemia and there are even some drugs that contain bromide which interfere with the chloride measurement which can lead to this pseudo decrease in the anion. gap. But I would say for the most part, practical purposes, the main time I'm adjusting a normal anti-gap from 10 to 12 is just in the setting of a low albumin. Okay, great. Tim, thanks for clarifying that. And then while we're on the topic of anion gap, there's this idea also of a negative anion gap, right? I think that's like seen sometimes in my aloma or other other conditions. Can you comment on that as well? Yeah, so that's similar to kind of like the pseudo-hypo-natremia phenomenon and basically what's occurring in situations like that is where you have high levels of these paraproteins, which are leading to kind of like a false falsely high concentration of those proteins in your plasma so that when it's diluted, you have a lower or potentially even a negative anion gap. So important to keep in mind in patients when you know they have either a multiple myeloma or a high-free light chain burden. Perfect. Okay, cool. So that actually is, I like how you kind of compare that to the pseudo-hypo-natremia. So that's actually like a function even of how the lab assay is run and then results in that "negative anion gap," which should then, if we aren't already tracking, should kind of tip us off to maybe the presence of these paraproteins that could be a tipping point in that patient's disease process. Now, another again, still talking anion gap. So another thing that always comes up is what you're calculating that anion gap in the setting of hyperglycemia, what should we be doing with that sodium? Should we be correcting the sodium and then calculating the gap or using the measured gap? How do we, or sorry, or using the measured sodium? How do we approach that? Great question. And this comes up really frequently in the setting of DKA, because these patients oftentimes will have a high anion gap metabolic acid doses. They obviously will come in with usually elevated blood sugars, although in the setting of S-JLT2 inhibitors, sometimes we're seeing eoglycemic DKA. But the answer to the question is you should use the actual measured sodium concentration to calculate the anion gap when you have hyperglycemia. The reason you adjust the sodium and hyperglycemia is essentially to evaluate the level of dehydration or water losses due to the osmotic shifts, because of the hyperosmolarity from the sugar. But you have to remember that glucose is electrically neutral and doesn't affect the anion gap. So the corrected sodium can estimate the magnitude of water loss that has occurred due to hyperglycemia. So you have basically shrunken, extra vascular, or sorry, increased extra cellular water because of the osmolar shifts. And the way you would correct that sodium is usually by adding 1.6 millimoles per liter for every 100 milligrams of desoleter increase in glucose. The other way I think about this and the reason you should just use the actual measured sodium rather than the corrected one is that if you're concentrated because of water shifting, all the components of the anion gap would be concentrated. And so your anion gap really shouldn't change, right? The chloride, the bicarbonate, and the sodium all would be concentrated or diluted. So if you did end up correcting the sodium but you didn't correct quote for the chloride in the bicarbonate, you would actually overestimate your gap. That's a great point and I just feel like I'm getting cerebral edema here from all the great anthropology learning. So thank you. I'm going to follow that up with another sort of similar question. So we talked about which sodium we should be using. What about which bicarbonate should we be using? You mentioned before, we have one on the gas and we have one on the serum chemistry. Which one do we trust? Yeah, so I trust both of them and we'll talk about the concordance rate a little bit. But basically what we're alluding to is you can obviously directly measure bicarbonate, like if you get a BMP or a renal function panel, the bicarbonate is there. Or you can indirectly calculate the bicarbonate using the pH and the PCO2 from a VBG or an ABG based on the Henderson Hasselback equation, which we don't have to go over. But- Oh, thank you. No PTSD for our listeners here. Yeah, I mean, Nick, if you're already getting cerebral edema there, we really don't want to push you over the edge. Yeah, we can't have them hurting eating on air. Yeah, I listened to the high Pune Trimia pod with Joel and you know, that's the last thing we want is to cause osmotic demalination for you right now. Essentially, when you look at any study that's looked at concordance of the directly measured or the calculated bicarbonate, I'd say 95% of the time or more, you're usually within two to three millimoles per liter of each other. So there hasn't been much difference. Now, there are some outliers where you might get like a five or six difference, but I'd say they're outliers. And I'd say in those outliers, what I typically do because I'm biased as an efferologist, I'm not the one in the ICU getting VBGs and ABGs. I'm usually looking at the measured bicarbonate blood. But I think if you're spending your time in the ICU and you're getting point of care testing VBGs over and over, I would just go kind of with whatever you're doing consistently. There've been some arguments that the reason there are differences in potentially the VBG or the calculated bicarbonate is that if you don't send the sample immediately and you expose it to air or to bubbles, that that would affect the CO2 levels and therefore it would affect the calculated bicarbonate. But I would say for the most part, they're pretty much the same. Yeah, I think that's a great point. And I think in the era of fast point of care blood gas testing, I think a lot of those concerns are alleviated. I think you do have to be very mindful to not have a bubble in there because that can have an effect quickly. But as we've talked about on past podcasts, a lot of the things you used to worry about with sending a blood gas to the lab, that's not the reality anymore. The idea that leukocytes are eating up all the O2 and they're making more CO2, it's just probably not a real issue anymore. I nod to leukocyte larceny. I love it. I know. I love saying leukocytes larceny, but we seldom get to see it. One thing that's really interesting here and I'm showing my age by mentioning this was like back when I was in the last time I was actually doing the primary work in the ICU when I was a resident and that was 15 plus years ago. And at that time, we would do ABGs and send them to the lab. And I see people now just using VBGs all the time and actually making good clinical decisions on them, but that's not something that I did back in my day. Back in my day, the only time we sent a VBG was to check it mixed VNSO2. And now you can actually depend on the pH and the PCO2 and things like that in the VBG, which I think is completely different. And I think that's such like a great point to make because I think like Nick and I that are working in ICUs like we rely on that point of care testing a lot and having high fidelity point of care testing that comes back quickly is like the crux of a lot of the decisions that we make. Whereas sending things to the lab, I mean, you're risking delays in the lab and basically outdated information from the second you get it. And then there's also this idea of like when you are doing point of care testing, the ability to repeat that kind of quickly and effectively, for example, if you're man, it could decay patient is very helpful. And finally, the last point, I'll really foot stop because I think it's so important is that Venus blood gas is really powerful. And there are risks associated with sticking a patient for an arterial blood gas if they don't have an a line. It's painful for one thing. You could have, you know, heatatoma formation, you could cause an aneurysm pseudo aneurysm by doing that. And so I think, I don't know, Nick, if you would agree or if you have a different perspective on this, but very rarely am I, if I have a good pulse ox emitter, very rarely am I like, oh, I really need that ABG. I need it and I need it. And that's, you know, that's the hill I'm going to die on. Absolutely agree. And people where they have pulse tile flow and the pulse ox, you don't need an ABG very often. The VBG is often all you need. Awesome. All right, let's go, let's go. It's still deeper on this. Another question that that comes up, you know, not infrequently, trainees get mixed up about all these gaps. So let's talk about, we've talked about anion gap. Now let's talk about Osmolar gap. And then maybe we can talk about urine anion gap too if we really want to go all in on this. Yeah. So let's talk Osmolar gap first because I feel like that one's a little bit easier to get our head around. Basically, just like the bicarb, which can be measured and calculated that like we just talked about, the osmolarity can also be measured directly. So you could send a serum osmolarity or you can calculate it by taking sodium, the urine and glucose sodium times two, the urine over 2.8 and glucose over 18. And those factors are there because of the molecular weight. Those are US units by the way to our international US units. Yes, yes. Thank you. You're in a different country. Yes, thank you. And so basically when you take that calculated and measured the difference between those two numbers is the Osmolar gap. And usually those should both be right around 290 milli-osm per liter. But if there is a large difference in that large difference arbitrarily is usually said greater than 10, then we have a difference between the measured and calculated osmolarity. It means that there's something contributing to osmolarity that is not our typical substrates like sodium, bu and and glucose. So other substances could be present, which aren't included in our calculations most of the times these are some kind of alcohol. So it could just be regular ethanol, right? If someone comes in drunk, they can have a high Osmolar gap and it's just from ethanol and as the ethanol kind of cleans out of their system, their Osmolar gap will close. But there can be other more dangerous substances like methanol, ethylene glycol, isopropyl alcohol. These can all cause Osmolar gaps. And it gets a little tricky because some of those intoxications can also cause an anion, gap metabolic acidosis. Isopropyl alcohol or rubbing alcohol is the one that can cause an Osmolar gap, but typically doesn't cause a metabolic acidosis. So long story short, when do I send an Osmolar gap? I do this when I'm dealing with an unexplained and I get metabolic acidosis and I'm worried about toxic alcohol ingestion. Or sometimes I would do this even before I know I'm dealing with the metabolic acidosis. If someone is just like found down, unresponsive, and maybe they ingested something that I might send an Osmolar gap to see if something's there. And I'll just say that for anyone taking their critical care boards, learn that formula and you will get 10 extra questions in the life because it's on there just over and over again. And that fact you mentioned about Isopropyl alcohol that it causes a Osmolar gap, but not an anion gap. That's like five more points right there. So. High yield studying here folks. No hyperbole in all there. No hyperbole in all. Yeah, I mean, and thank you for correcting me on the US units. But I think it's really interesting. And this is not something I knew until way later, but the glucose over 18 is because the molecular weight of glucose is 180. And it's in milligrams per deciliter, so it converted into 18. And your area is 28. So that's why it's the 2.8. So if you have difficult reasons, maybe that helps people remember. I don't know. For people who know molar masses, that is a great fact. The other question on uran anion gap is a little bit trickier. And I would say it's completely separated from the Osmolar gap. So usually I check, or I'm thinking about getting a uran anion gap in the setting of a non anion gap metabolic acidosis. So at its most basic level, what we're trying to do with the uran anion gap is estimate whether the uran is appropriately getting rid of excess protons in acidosis. If you have an acidosis, the kidneys' healthy response should be to dump out protons and get the acidosis back to normal. And the way it does that is by generating ammonium. So if you, for example, develop diarrhea and you're pooping up by carbonate and you develop a non anion gap metabolic acidosis, the kidneys' response is to excrete protons, ramp up ammonia genesis, and increase ammonium excretion. But if the kidney is actually the problem and the driver of the acidosis, this is usually seen in RTAs or renal tubular acidosis, then maybe it is dumping by carbonate or it can't generate that ammonium. So with that in mind, the uran anion gap estimates ammonium excretion. The calculation is uran sodium plus uran potassium minus a uran chloride. You have to factor in uran potassium into the uran anion gap because unlike the serum, you can have very high levels of potassium in the uran. So it's a very prominent cation. Whereas in the serum, we don't factor in potassium into the serum anion gap because it's always three to six or something. It doesn't have a huge range. Whereas in the uran, it could be five. It could be 150. So you do factor it there. So just like in the serum anion gap, your cations in the uran have to be equal to the anions. And if you kind of visually imagine the cations on one side, anions, and another, if you have a much higher value for uran sodium and uran potassium in a very low level of uran chloride, this would be a very positive uran anion gap, which would tell me that there's very little ammonium in the uran on the cation side, or that there is a very high unmeasured uran by carbonate. Both of those would suggest an RTA, either a proximal or distal. If on the other hand, you had a very small value for the uran sodium and uran potassium, but a very high uran chloride, then you would end up with a very negative uran anion gap. And this would tell you that there's a lot of unmeasured uranary ammonium sitting in the cation space. And the kidney is acting appropriately to correct the acidosis by getting rid of these protons. So in real life, how useful is this? I personally don't use it very frequently, because usually a good history will tell you if a patient is having diarrhea. You don't need to make this differential. You can spin the urine to find out if you're having diarrhea. If you're doing it the wrong way. Yeah, only nephrologists would spin urine and do complicated equations to figure out if a patient is having diarrhea. But a good history will also do the same thing. And the other thing is they've looked at this a lot, which is that there actually is not very good association between uran anion gap and direct measurement of the uranary ammonium. It's supposed to estimate it. You can measure uranary ammonium. It's just not very frequently standardized in a lot of tests. So there's this big push amongst nephrologists to actually move away from the uranion gap, because one, it's not great. Two, it confuses everyone. And it varies a lot between institutions. So our trainees should take away-- yeah, that they should remember the osmolar gap, because it's lots of points, and it means potentially life saving diagnosis. And they should forget all about the urine anion gap, because even the phrologist don't like it anymore. Basically, basically. Except it's definitely also tested on the critical care board. I can assure you that it is. So-- OK, so Jeff, I want to get you kind of wrote back into this. We've been kind of digging now through metabolic acidosis. I think we've touched on a lot of really important key points that often trip up trainees. I can already tell I'm going to be-- We're already testing this. We're attending. Really everyone. I was trying to just like protect myself, but yes, I get confused all the time on this stuff. So now I've got this great resource that we're working on right now that I'm sure I'm going to reference 1,000 times before I'm done practicing. So with that being said, we've introduced hagmas, or high anion gap metabolic acidosis, and hagmas, or non-anyod gap metabolic acidosis. We sprinkled a little nuance in there for dramatic effect, talking about some of these various gaps. But now I do want to refocus on metabolic acidosis in the ICU, and I want to do that with a case, OK? So let's say we've got a 62-year-old male with sepsis in the ICU. He's coming in with a pH of 7.1. He's got a bicarbary 12, a PCO2A27. And we'll also say that they've got an oligiric AKI to boot. And despite a bicarbated infusion, their pH is not budging, and the patient's hemodynamic instability due to their septic shock is suffering as a result. So you've got your attendings on rounds, they're posing the question, is it time for renal replacement therapy? And we'll say that you're a resident. We'll turn back the clock a little bit. We'll say you're a resident. You're not really sure what to say exactly. You're not really sure if all the other options have been exhausted. You're a little worried that perhaps the cart is being placed before the horse here. And frankly, you haven't really thought through every element of this person's acid-based arrangement in totality. And so I know we're going to talk about CRT a little bit. And for our listeners, we've got a CRT episode that is coming up very shortly. But I was hoping, Jeff, that perhaps we can apply some of what we've already talked about towards approaching this patient in a mindful way and coming up with a good game plan. Yeah, absolutely. I mean, that's great setup. This is something that is all too common. And I see it's all over the world. As you pretty much said, you know, I mean, God Acidosis is a metabolic component to it, the bicarbonate slow. But we don't really have a great cause of the acidosis. We don't have-- and without a cause, you can't really put a treatment plan into place. Again, this is diabetic ketoacidosis. Well, bicarbonate and fusion, renal placement therapy, are necessarily going to be fixed. It's just as simple as an insulin drip. That's going to be your mainstay of treatment. Again, I think Tim mentioned this earlier. But if the patient's having a lot of diarrhea, well, bicarbonate and fusion probably should-- in this case, it's not working. So it's probably not diarrhea. But bicarbonate and fusion should be the mainstay of treatment because they've just got a bicarbonate deficit. So the cause of the acidosis is really going to change our approach. It's possible that they may need a renal replacement therapy. But we can't really fully say without really delving into the rest of the chemistry. So I guess I'll ask you guys, what is the rest of the chemistry shell? Yeah. So for the sake of argument, we'll say that we've got a sodium of 138, a chlorid of 100. So if you do the math, that'll give you an anion gap of 138 minus 112, so 26. And we'll say that they're in the ICU. So of course, they've got a low albumum. So their albumum is three for the sake of argument. And that would give you an expected gap of 7 1/2 to 9 1/2. OK. So it's obviously, if I high anion, got metabolic acidosis. As you said, anion, got to 26. So going through kind of the breakdown of what we did before, let's talk about compensation. And here, we're going to bring back Winchers formula. So again, we said our expected PCO2, it's 1 1/2 times our serum by carbonate plus 8 plus minus 2. And in this case, that's going to be 24 to 28. So he's got a PCO227. So he's compensating. He doesn't have any respiratory acidosis. He doesn't have opalosis. He's compensating for his metabolic acidosis. And as we said, we'd like to make things complicated. So let's check the Delta Delta. The patient's anion gap is 26, which will subtract from his expected anion gap, which will just average it out and just say 8. So 26 minus 8 is 18. And that's going to be a little low relative to his normal serum by carb. So this is going to suggest the presence of a non-anion and got metabolic acidosis in addition to his anion and got metabolic acidosis. a ball like acid obesis. Excellent. All right. Well, that's that's great. And I was struggling to remember a fact that I just thought our listeners might enjoy. I think that winter actually developed this formula by injecting med students with dilute acid and then measuring a change in respiratory status. I remember hearing some story like that. I don't know if that's true. We should probably fact check that. But anyway, no, no, we shouldn't. Would that happen out there the other day? I mean, that's what you got to do to get a formula named after you. That's true. Yeah. You want an everyday formula in the ICU. You got to work for it. All right. So, so sorry. So you give us a great case here. We we have a double disorder now. So we want to talk about, you know, kind of the treatment and addressing our RT question. But before we get into that, then we should discuss the differential diagnosis for someone who has both a high anion, get metabolic acid doses and a non anion, get metabolic acid doses. So Tim and Jeff, how do you guys how do you guys approach this? Well, I'll start. I'll start on the anion, get metabolic acid doses. And so this one is, you know, depends on kind of, I think in what era you were trained in. I think when I was in med school, I learned a nomonic called mud piles. And I think that's still kind of ubiquitous when you say mud piles. People know what you're talking about. But the issue with mud piles is that it includes a couple things which are kind of obsolete nowadays, like the paralysis and the isonize. We really don't see anion, get metabolic acid doses related to medications like those anymore. And so in addition, it's also missing a couple newer more rec, not I went to newer, but now more frequently recognized causes of anion, get metabolic acid doses. So the one I teach is called goldmark, G-O-L-D-M-A-R-K. And just quickly going over G stands for glycalls. So we talk about ethylene glycalls. But there's also things like propylene glycalls, especially in an ICU. Propylene glycalls can be something that's a vehicle that's used in like IV benzodiazepine drips. And so patients who are on, you know, long-term sedation can develop this. Oost is for oxoproline, which is a metabolite of Tylenol overdose or oxoproline is also called pyroglutamic acid. L is lactic acidosis. D is lactic acidosis, not very common, but something that can be seen in like short gut syndrome or patients who have a ladle of bowel surgery. M stands for methanol, A stands for aspirin, R stands for renal failure, NK stands for keto. So keto starvation, keto acidosis, or diabetic keto acidosis. So I would say that's usually the mnemonic that I would recommend teaching when dealing with an anion and get metabolic acid doses. And really all I do is just go through them, take a look, which of these might be high based on the history, which of these can I subsequently test for? Yeah, I like that a lot. And I just to emphasize the oxoproline, I think it's probably one of the most overlooked causes of anion get metabolic acidosis. And you know, I think people get confused because they're used to seeing the acute toxicity of Tylenol, which has one picture, but there's a very different picture, which is the chronic use of Tylenol, which can give you this this metabolic acidosis. Great. And then Jeff, I think you were going to maybe talk a little bit about non-GAP acidoses. Yeah, so that one's a little more straightforward. As we said, it's now down to the loss of bicarbonate, usually via the GI tract, or from the kidneys, or in the case of a type 1 RTI, it's the inability to actually secrete acid. An uncommonly more, but actually something we seek quite a bit in the hospital. And there's unfortunately a fairly common, you know, nephrology console, there's actually hyperploremic metabolic acidosis in the setting of large volume of administration of normal saline. And you know, I mean, I think you can get into, you know, a little bit of the, which fluid is better with this discussion, because I think one of the things that people think about the drawbacks of normal saline is it does induce acidosis. And we know acidosis does have negative consequences. And you know, this is a little bit demonstrating the surgical literature where, you know, and there was a study that compared normal saline to LR for post-op fluid resuscitation. And on arrival to the sick year, the normal saline group had lower pH, which is again, not unexpected and lower bicarbonate compared to the LR group. There are a few other causes, which, you know, paper elementation. So in those individuals, you're kind of introducing feeds to, that is something that you can certainly possibly expect to see. And then a C is all in my, they guess, you know, it's the diuretic that I think is becoming a little more, you know, commonly used. I think sequential nephron blockade is kind of becoming something that we're starting to see a little bit more in the ICU is another, again, it's carbonic anthydrogen inhibitor, a box of your absorption of bicarbonate in the proximal tubule. So essentially, introducing a proximal RTA. So that is another non-gap acidosis cause that we could potentially look for if the medication is there. Great. Yeah, I think just to emphasize a point for our listeners, you know, I really like the use of mnemonics here. You know, as Tim said, goldmark or gold market is great for one. I like rages for the non-anionic gap. That's RTA. And then there's like three A's. So ammonia, acytazole, my hyperalimentation, G is GI losses, E is endocrinopathy is an S is saline, which is usually what the answer is. You know, and I also like their approach to sort of tick through and sort of which of these can I blame it on, which of these should I test for? Yeah, there's one, there's one more in the non-gap acidosis, which isn't that common, but in the right population, which is patient who have had an ilioconduit. When you have an ilioconduit and you have basically a neoblatter that's made of the ilium, you have a chloride bicarbonate transfer and those patients can basically dump bicarbonate it to the urine. But again, that's usually pretty evident from the history of the patient having an ilioconduit. Oh, great point. So maybe you have to make it instead of rages, maybe rages or something. I don't know. I don't know. I work the eye into there somehow. All right. I'm on it. That's a great point, Tim, because I know a lot of mixed Ic use or surgical Ic use, it's not infrequent, especially in folks that have like bad pelvic or abdominal cancers who have had these significant surgical alterations to their anatomy. It's a good thing to keep on the radar. So one, kind of moving along, as far as the different ideologies for high anion gap and non-gap acidoses, do you think either, you know, Tim or Jeff whoever wants to handle this, are there certain patterns that we should be able to readily recognize to help us reach that diagnosis faster? I know we've talked now probably a dozen times about the history and the importance of the history. So I don't think we need to necessarily belabor those relatively obvious cases, but are there certain things on labs or imaging or other physical findings that may help us hone in on what's going on a little bit faster than we might otherwise? Yeah, absolutely. I mean, I think when you just take goldmark and you break each of the letters out into individual diseases and illness scripts, you think about, you know, how those patients present. So patients who have had toxic injections of ethylene glycol or methanol, typically will come in altered and unconscious and not be able to give a history. You know, the ingestion issue also maybe raises concern for Tylenol overdose and that's something that you can send levels for. And as Nick mentioned, I think it's really important, which is that usually the anion gap metabolic acidosis of Tylenol toxicity is not a acute overdose. It's like a slow chronic congestion. Patients who have, you know, sepsis or infections or Schemi or in shock, I mean, lactic acidosis is usually the big one that I think about. I think lactic acidosis is one that should always be considered basically every patient because you can be surprised. Those cancer cells can start, you know, shifting over to anaerobic like colitis and create big amounts of lactic called the warburg phenomenon. So that's something that happens even in the absence of sepsis and ischemia. Patients who are malnourished have a history of alcoholism or starvation, high risk for starvation ketoacidosis, patients who have diabetes or high glucose, DKA. The renal failure is usually pretty obvious from the labs and it usually needs to be pretty severe, you know, if it's causing a a metabolic acidosis. So those are the big aspects from kind of like history and physical that would, you know, usually make me send one tester or another. Awesome. Great. Yeah, and, you know, I think, I think it's important to keep a broad differential when you see that because it's easy to sort of fixate on one thing. Oh, they're septic and potentially miss that ischemic limb or ischemic gut or something else. And I think it's a great point you make about cancer too that often lactic acidosis can be a sign of malignancy. All right, well now that we've talked about physiology, the differentials and workup, maybe we found some clues to make the diagnosis. Now we got to really double down and talk about treatment. So we have we have this case where a patient was placed on a bicarb infusion. What do you what do you guys think about that? You know, bicarb thumbs up thumbs down, you know, where do we land? Thumbs up thumbs up. Yeah, but yeah, I mean, there's obviously new ones. I'll let Jeff talk about it first. Yeah, no, I mean, I think I think overall, it's never, well, that's just it can be a bad thing in certain circumstances, but if you've got true metabolic acidosis and their pH is low, you know, you're kind of in a situation where your pH may be life threatening you out of you got to bring it off somehow. In terms of it, but it's not really a straightforward decision in terms of just going for, you know, pH is low, let's just start it by carptophase. How low is low enough? Typically, we're kind of looking somewhere in the 7-1 to 7-2 range. And a lot of the studies, which we'll talk about a little less than 7-2, is kind of to find this severe acidosis. There's data from animal studies that pH less than 7-1 affects your left ventricular counteractility and also can produce--you see increased production of vasodilators that can cause vasodilagia. Obviously, these are horrible outcomes, especially in your RICU patients, you're trying to prevent these. Humans, however, we don't exactly have the same matching data that hasn't really been fully replicated. We do have some trials. There's a small one, which had patients with malevolc acidosis from black to acidosis. All of whom actually had pulmonary artery catheters, which is great in terms of the ability to actually measure our ingotinamphics. So these--there's 14 patients, pretty small. They're given by carbon infusion to increase their pH, which it did. But they didn't actually see any of changes in their hemodynamics. Even the severely acidotic group, those whose pH really range from 7--excuse me, 6-9 to 7-2--was their severely acidotic group. They're actually where no change in hemodynamics despite improving their pH. It's a small study, but again, I think if your pH is 6-9, a bicarb ship, it's not unexpected that that's not going to solve all your issues if it's due to lactic acidosis. But at that point, I think you just kind of have to do what you have to do. There was a metanalysis, which identified a few more studies about 12, which again, we're looking at a pH less than 7-2, as our severe acidosis. These are people who again have lactic acidosis. And a lot of the primary outcomes are mortality driven. We know that in an ICU population, it's very hard to prove that anything is going to improve mortality. Immunizations are incredibly sick. But really, in a bicarbonate, it didn't affect mortality in premodalities studies. It didn't really affect the hemodynamics and the studies that looked at that. There was one study that did actually find a benefit in liberating somebody from the ventilator and decreasing length of stay in the ICU. But that's really the exception as opposed to the rule. And I think this is actually the most interesting line of our--of this study. We actually had to refer to a survey data between nephrologists and intensivists from 2006 in terms of who started biotarb trips when. And nephrologists were more likely to start biocarb trips for lactic and ketoacidosis, which is hopefully something that I think has changed, because especially for ketoacidosis, that's not really the standard of-- So it's due, as I say, not due as I do, that's what you're saying. Yes, exactly, exactly. But hopefully, that was almost 18 years ago somehow. So hopefully, we've evolved a little bit. The biggest randomized trial that we have was called the Bipar ICU trial. And this was the French ICUs. They do a lot of our ER-Big studies. The French ICUs had a lot of our AKI, EMOTA-Ls, send initiation studies in the ICU. But this is a pretty large study, almost 400 patients with severe lactic acidosis, pH less than 7-2. And again, they kind of looked at mortality in biparbonate infusions. And despite the actual treatment group, compared to a control group, maintaining a higher pH, there actually was no difference in mortality. The one thing that they did find-- and the study wasn't powered for this, but it still is I think important-- was that patients with AKI actually did experience the mortality benefit and actually had a reduced need for RIT, kidney replacement therapy. So again, it wasn't powered for that, but I think it's an interesting data that maybe, again, we can tailor it to use towards our patients. Yeah, that's another win for French critical care research. I mean, if you look at all of the-- seems like the majority of steroid studies in septic shock were also done in France, or a lot of the big ones. I know there are other ones. So yeah, I guess I need to move to France if I really want to become a high-level IC researcher. I mean, in the US, we're like five hospitals teamed up to do a study in France. It's like 360 hospitals teamed up. Correct. Yes. We had two hospitals in the US, and they were all doing a different protocol, whereas these like, you know, ANZICs or French studies are like absolute formatting over the entire country. Yeah, they're like military adherent to the study protocol, and they have like 50,000 patients in each arm of a forearm study. But we're leaving you without the French. That's right. Sorry, so I'm sorry for that aside, Jeff. So what's the bottom line here? Yeah, so I think the data ultimately is lacking again. We maybe have a population with acute kidney injury, who maybe there's a benefit, but ultimately it's lacking. But I think we've touched on this a couple of times, but I think it's important. Again, we have to go back to why does the patient have acid? The above acidosis in all these studies was due to lactic acid, and lactic acid is usually a subpolytic acid. It's not, it is a subpolytic acid, some pathology that is obviously causing stress on the body. So we'll by carbonate fix the acidosis now. It may increase your pH, but it's not going to actually fix the cause of your lactic acid osis or ketoacidosis. Again, if the patient's pericode, you know, acidemia, you have to do what you have to do. Bicarbobb is obviously makes a lot of sense. But I don't think it's surprising that there's not strong data for bicarbonate infusions in these settings. Again, if it's due to like, you know, as we said, several times RTA or GI losses makes sense. But in lactic acidosis or really anion, gap acidosis in general, there's something else that we have to take care of. Bicarbonate is just a bandaid. Awesome. So just to kind of briefly summarize that, common theme of the ICUs, you've got to do what you've got to do. And so in the event that you're dealing with hemodynamic instability, a peri-arrest situation, the fog of war still may be thick. You might not know exactly what's going on, but giving someone a few boluses or putting them on a bicarbated drip to try to just write the course of that ship in the acute phase, very reasonable intervention with the giant caveat that, well, two giant caveats. One is that you're going to continue to try to figure out exactly what's going on. And B, this really is a bandaid over a bullet hole. It may help for a short period of time, but you are not remedying the underlying acidosis. So as a friend of mine said, bicarb is the spanks of the ICUs. It makes things look better, but it's really fixed the underlying problem. Oh, my goodness. Oh, man. That's good. That's going to get stolen. That's amazing. So, you know, I guess maybe Tim, if you would shed some light onto the dirty little secret of those spanks here and tell us maybe, you know, what are the downsides to using bicarbated in the setting? A lot of patient ICUs will need the bicarbated, just like you said, but it's always good to just be aware of what that bicarbonate is going to do outside of just the direct effect on the pH, right? So just like every other sodium containing solution, when you're giving a bicarb drip, which is usually isotonic, if you give three amps in D5W is 150 milicotlins, if you're giving several liters of that for a severe acidosis, you're giving several liters of an isotonic sodium containing solution. Patient to have sepsis, probably a good thing, right? But patient to have heart failure, you have to be a little bit careful about. So it's volume. I think that's the important thing to remember is when you're giving bicarbonate, you're giving volume. So you have to be aware that you might run into issues with volume. If you're giving straight amps of it, those are hypertonic and you can develop hypernatrimi, it's not uncommon, like Jeff mentioned, a code situation. In a code, you're pushing a couple amps of bicarb, you stabilize them, you get rosk, you get them back down to the ICU, the next set of labs are sodium 160. That's just because of all the sodium that you gave them, but not a big deal, you can lower that. Also important to also just remember that bicarbonate has effects on other electrolytes, so it can drop your potassium, it can drop your calcium. Usually when I'm dealing with a patient with hypochylemia or hypochylcemia and metabolic acidosis, I'm thinking about giving bicarb too. I personally would rather repeat the potassium and the calcium first because once you kind of get behind the eight ball, it becomes really challenging to keep up. So those are just the things to always keep in mind, volume, effects on other anions. And then another thing that sometimes gets asked of us, which I don't love doing, but it's like, can you just correct the acidosis for this patient who has a respiratory acidosis? Can you give bicarbonate for this patient? And I usually say, no, that's not indicated because it's not a bicarbonate loss issue. It's not a metabolic issue. And it's always important to remember, kind of, Jeff alluded to this H plus bicarb moving to a bicarbonic acid moving to water plus CO2. So when you give bicarbonate, you're also generating CO2. It's really important to remember that if you give bicarbonate, conpatient with respiratory acidosis, you will risk raising their PCO2 if they can't ventilate. I think that's a really crucial point and that's a point that I always like to make to people that just like, you know, the alkyceltor commercial or you drop the tablets into the water and it starts, you know, pop-pop fizz fizz. The, you know, alkyceltor is sodium bicarb and that gas coming off of CO2. But if you can't, if you can't ventilate, if you can't get that CO2 out of there, the pH won't change, right? CO2 will go up, but they won't be able to excrete it. And there are some studies, you know, in the emergency room setting or like in patients who are coding or pericoding, where you push bicarb and it basically doubles your end title from like 20 to 40 for seven minutes, which is a pretty good argument to not give bicarb pushes frequently because they're going to be stacking on one another. Another sort of point that I like to make is that bicarb can fool you in terms of oxygenation because if we remember our friend the oxyhymoglobin dissociation curve, the curve left shifts and right shifts depending on pH and the idea here is that like your red blood cells want to unload oxygen in tissues where there's acidosis, right? That facilitates delivering oxygen. If somebody's blood has got an acidosis, right? Their spO2 will be low because they're unloading oxygen in the blood. If you push bicarb and you raise the pH, well now their sat will go up. But you haven't actually increased the amount of oxygen in the body, you've just shifted oxygen from tissues back on to hemoglobin. So it makes the sat look better. You often see this, somebody has a low sat, you push bicarb, the sat goes up, but you haven't improved oxygen delivery. In fact, you've made it worse. Especially what you're doing is you're making that person more hypoxic at the tissue level potentially. Exactly. This is the difference between hypoxia and hypoxemia. You've made their hypoxemia a little bit better, but potentially made their hypoxia worse. So just remember, it's spanks, not a cure. Now that we've now that we've, you know, bashed on it a little bit, maybe we could talk about one of my favorite drugs. What is an alternative to bicarb? Yeah, so this came about, you know, I want to say 20 or so years ago, people were like, well, can we give a buffering agent that doesn't have all these issues? And so they developed this synthetic one called fam, which stands for Tris hydroxyl, hydroxy methyl amino methane. Basically, it's a buffery, it can buffer protons without producing all that CO2, without leading to as many of these other electrolyte abnormalities. But the problem with fam is that it's excreted by the kidneys. And so as you know, and patients in the KII and ICU, I mean, in ICU with sepsis and lycobagasos, oftentimes the kidney function is normal. And so you can't use them in those patients because it'll accumulate toxic levels of that drug, which can actually cause hypotassium. Full disclosure, personally, I have never used it in the last 15 years. I remember one time in residency. I had a patient who was put on this IV infusion, but I have almost exclusively never used it. I'm curious to know, do any of you have experience using fam? Well, I've got good news and bad news. So I've used it before. I've used it maybe like two or three times. So like a lot of experience, right? But unfortunately, they don't mean a facturating more. You can't get it anymore. So maybe that will change at some point. Maybe somebody will listen to this podcast and start manufacturing fam. But I think for listeners, it might be an answer on a board question, but it's not an answer in real life in the moment because it doesn't exist. You can't get it at this in the United States. Season seven of Critical Care Time brought to you by the makers of fam. So hopefully, hopefully we'll hear a call. So I know with the time that we have left, I do want to talk a little bit about how we might definitively treat this person in the ICU. This was, obviously, we've had a fantastic discussion of acid-based thus far, really hit hard some concepts in bicarbonate administration. I really hope our listeners will come away from this with a lot of new knowledge and a lot of deep understanding on the method behind the nephmatenous, if you will. And I'm sorry, I just couldn't help myself. So okay, getting back to the case, Jeff, so we'll say that this patient has proven to be refractory to bicarbonate infusion. We've got an uptrending pressur requirement. Now that oliguria has evolved into anuria and the pH is at seven even. So seven on the nose. In your estimation, would this be an appropriate time to start real replacement therapy? And I'll caveat this by saying, I don't want to get into the weeds on RRT because I know we're going to talk about that again in the very, very near future. But really, I'm wondering, RRT, yes or no. And if so, is this someone we would be writing CRRT orders for? Is this someone for whom we would need to talk to a nephrologist about intermittent hemodialysis? Yeah, so given the scenario, try to bicarb drip, start working, they're a nerick. We don't want to give a lot of volume. So bicarb drip is not really going to be super effective and their ulcers still very acidotic. So yeah, we have to have the dialysis talk at this point. I think the biggest thing to remember is that dialysis is really just a big bicarbonate drip. You can get a lot of bicarbonate in a little bit, though it does depend on obviously which modality you're using. It'll clear toxins like metabolites of alcohols or metformin toxicity, which just create a lactic acidosis. This is really very effective for that, though it doesn't do a great job of throwing lactic acid itself. It does clear it a little bit, but the rate of production is actually going to be greater than clearance. So the bicarbonate and pH may get better with dialysis, it's not actually going to improve our lactic acidosis. But at this point with this patient, yeah, we'd probably be talking about dialysis. With hemodialysis or another diffusive clearance such as sled, the bicarbonate concentration is going to be somewhere in the 35 to 38 milaclubl per liter. What we're talking about, convective clearances, which is our CBVH, replacement fluid, it's going to be a much higher biocryon concentration compared to serum, which is going to be about 35 milaclubl per liter. But I think the important thing is, in terms of selecting our modality, is how quickly do we need to get this pH up? Hemodialysis will provide a quicker improvement in our pH than continuous kidney replacement therapies. So if somebody can tolerate hemodialysis from a hemodanemic standpoint, it probably should be preferred. And then maybe you can trade it just into a continuous therapy once you've gotten your pH up. And really the reason for that is that our our dialysis, a fluoride hemodialysis is much quicker like the units are milliliters per minute. In continuous therapies, we're looking at like liters per hour. So you're going to be able to get much more bicarbonate into the patient quicker from hemodialysis. What we're doing, the continuous therapies, again, you'll start kind of in your, and you guys I'm sure we'll have a lot of this discussion in your upcoming CRT podcast. But we generally aim for about an efflomerate of about 20 to 25 cc per kilogram per hour. That's usually where you start. But if the patient's very acidotic, you sometimes just have to go about that. That's how you're going to get them enough bicarbate. And I will say, you know, acidosis is one of our indications for dialysis. But we don't really actually have a great idea of when we should actually start for metabolic acidosis. There's no trials that have discussed that. We don't even have a great idea of when we should start kidney replacement therapy and they ask you to begin with. So, you know, it would be great to obviously have a trial that would point towards that. But, you know, right now we just don't. Thank you, Jeff. I think that was a really nice overview of how we might consider a renal replacement therapy in a patient like this. And the one thing that you mentioned that really sticks out to me, and this is something like I'll teach my trainees is that if you see a significant change in the patient's serum lactate while they're on CRRT, a significant improvement, let's say on at the 36 or 48 hour mark as you've been continuing to treat their septic shock, that is much more indicative of an improving clinical picture than it is the CRRT taking the lactate off. Like yes, it clears lactate. I get that. But the extent to which it's going to normalize or significantly remove lactate and kind of quote unquote fix the labs is, I think it's sometimes overstated or misunderstood by folks. I mean, just just as a quick aside here, I think it makes sense when you think about the fact that like athletes can raise their lactate and their kidneys work normally. Their kidneys, which normally remove about 20% of the lactate, cannot compensate for like running a marathon. Your lactate is going to be high, right? So it would be crazy to think that a kidney replacement could do better than the real thing and correct a super normal lactate, right? It's an unfair expectation of renal replacement therapies to expect them to fix a lactate acidosis. Yeah, no, that's exactly, I think at the point I want to make too, which is that people assume that when the dialysis machine is in the in the room and the patient is hooked up and blood is circulating through the filter that the numbers are going to look good the next day. And that is not the case in lactate acidosis. I recently had this a patient who had a really severe lactate acidosis in AKI and I had her on CRRT at a dose of 45 ml per kilo per hour like the high dose. It's a really high dose. I could not get the pH above 7.1. I couldn't bring the bicarbonate up despite that tried hemodiallysis high flow could not get it. I was talking to a colleague, an older colleague of mine about this and he was like, yeah, it's the the lactate acid production is really severe. You cannot keep up with it with dialysis and he told me this hilarious story where you know, this is an older guy who said back in the 80s, he had a similar patient and the patient was on hemodiallysis and the surgeon came and said, you haven't fixed the lactate acidosis yet. And he said, I can't. I'm giving as much dialysis as I possibly could. And the surgeon asked for dial two dialysis machines to be put into the room and to run the blood in series. I was like, that's not gonna help. It's not gonna fix the problem. I mean, you have two kidneys. Obviously, you need two dialysis machines if they both do all right. I don't understand. I mean, more is always better. More is always better. So that's why like two ECMO circuits, two CRT machines. Well, I mean, I don't know Nick. I usually use two ventilators one for each lung. So I actually have done that before. Yeah. I mean, oh my goodness. Well, guys, I thank you so much for spending time with us. I know we're getting close to pretty much the end of our time. Here, this was I think just a phenomenal discussion. I do want to again, plug Neff madness for our listeners. It's really awesome kind of resource and this current kind of like bracket that you guys put together is really fun. Hopefully Metabolic Acidosis will win. And then also plugging kind of Neff JC and a lot of the great work that's done by you guys. I don't know if Tim or Jeff you guys want to talk about that real quick. I know that we're going to post a copy of the the early versus late initiation of RRT comparison graphic that you guys have, which I think will speak nicely to some of like Jeff was looting to. But do you guys want to take a minute or two to also to just kind of like plug, plug Neff JC Neff madness any of that good stuff? Yeah, absolutely. I can do that both. So by the time this podcast launch launches, you will be able to play part of the Neff madness game and read all about it. It's a JKD blog.org all the information and the right ups will be there and it'll link you to kind of where you can fill out your bracket if you want to formally play the game. Neff JC dot com is where you would go to to see the main site for the online nephrology journal club. It's every two weeks. It's usually hosted on Tuesday evenings for the US chat at around 8 pm central time. And they are and that's also where you could find the freely filtered podcast, which a Joel and company host every few weeks as well. Beautiful. Thank you so much. All right. So guys, I know this was a little bit of a longer episode to our to our audience, but we covered a lot of super high yield content with our friends of representing Neff madness. So today we talked really about all things metabolic acidosis and our goal was to to take this, you know, hour and 15 hour and 20 minutes to create this one stop shop for you guys, which we can pair with infographic. Like I said, that we're going to share from death madness, potentially our own infographic and our show notes to give you guys a place to go to for your metabolic acidosis and the ICU needs. We talked about all things metabolic acidosis, our general repost to diagnostics. We talked about the non gap versus the gap acidosis. And then we did this deep dive into lactic acidosis. We we talked a ton about by carbon at the pros and cons. And then we talked about real replacement therapy and kind of scratch the service on that, recognizing again that we're going to have another episode coming up soon to discuss that very topic. I want you guys to obviously feel free to come to the website. So critical care time.com. If you want to learn more about this and all the other topics we cover, certainly if you want to view our show notes and infographics, that's the place to go. And then if you want to learn a little bit more about nephrology from from these fine folks, feel free to visit www.ajkdblog.org. And for those of you that don't know our website, sorry, is www.criticalcaretime.com. Any of those resources should do you just fine. Yeah. And now we've come to the part of our show. We like to say thanks. First off, big thanks to Jeff and Tim for being outstanding guests, teaching us so much today. My brain is still swelling, but I think I think I'll survive. No, herdeation, Nick. You cannot. You guys, you guys gave me knowledge at a steady rate. It wasn't. It wasn't perfect. So thank all our listeners. Thanks to the people who left us reviews, comments, given us a shout out on social media. We read what you say, especially when it's a five star review and we appreciate it. Come to our website, subscribe, subscribe to our show on whichever podcast app you like and be sure to tweet at us at crit care time or at nick M mark or at askins underscore razor can also follow us on Instagram threads or YouTube. We'd also like to say a big thanks to our sponsor C star medical. We are fortunate and grateful that this episode and all episodes in season one of critical care time are sponsored by C star medical. C star medical is advancing the science of cell directed extra corporeal therapy to help restore the balance of a dysregulated immune system, in acute kidney injury and sepsis. Check out their website, cstarmedical.com to learn more. And that's going to be www.sea starrmedicl.com. Before we go, we want to thank our whole team. So first off, the members of pod paste for helping us edit the show and put it together and production making it sound good and look good. I also thank all of the members of our team who have helped behind the scenes, getting a script together, planning, just to thank Kurt Bellnap for our awesome theme music, which is planning over me right now. And now time for some disclaimers. So this podcast and all related media, including the infographics you're going to love, our property of critical care time. You can share our content, but please just acknowledge where you got it from. And the views expressed within this podcast and any associated media do not necessarily reflect the views of our employers, all references to patients or encounters have been modified to be hipocompliant. And thus any similarities to real world cases or purely coincidental. Finally, this podcast is for educational and entertainment purposes only and should not be used in lieu of seeking medical advice with that. Thanks for listening. I'm Dr. Cyrus Askins, so long and I'm Dr. Mark. See you next time.