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CME-MOC

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Show Notes

Pearl 1: Key Principles

  • Hyponatremia is a problem of excess of free water relative to solute in the body
    • Is there relative excess free water because there is not enough solute intake?
      • e.g. tea and toast
    • Is there an absolute excess of free water?
      • E.g primary polydipsia
    • Is there a relative excess of free water from ADH release?
      • Hypovolemia
      • Decreased effective circulation (e.g. CHF, cirrhosis, nephrotic syndrome)
      • Inappropriate release (SIADH)
  • Therefore, a detailed solutes/fluids history is needed to manage hyponatremia 
    • Account for all fluids that the patient is getting, including water, coffee, Diet Coke, Gatorade, etc.
    • How much solute is the patient taking in? (e.g. big or small meals?)
  • Most of the time, hyponatremia is multifactorial.
    • You can’t rely on algorithmic cutoffs because there may be multiple contributors to the direction the urine Osm may be in
      • In particularly, common issues like pain, nausea and certain medications (more in pearl 5) can increase ADH (inappropriately), reabsorb more free water and increase urine Osm
  • For more information, see 5 Pearls on Hyponatremia Diagnostics

Pearl 2: Fluids in hyponatremia management

  • Giving fluids
    • Hypovolemic hyponatremia
      • Fluid choice does not matter as long it is not a hypotonic fluid (e.g D5W) 
      • How do fluids help with hypovolemic hyponatremia?
        • Isotonic fluids or hypertonic fluids will turn off hypovolemic baroreceptors, and subsequently decrease ADH release
      • Expert opinion: for patients with cirrhosis and some component of hypovolemia, can use albumin as fluid
    • SIADH:
      • If giving fluids, the fluid’s osmolality must be hypertonic to the urine osmolality
        • FYI: lactated ringers has an osmolality of 272 mOsm/L
        • FYI: normal saline (0.9%) has an osmolality of 308 mOsm/L
      • See “Edelman Equation Overview” below transcript from Dr. Sheldon Chen
  • Withholding fluids: fluid restriction
    • Used mainly in SIADH
    • Restrict to amount less than what patient is drinking 
      • Protip: physically put their allowed amount in front of them
      • 1 hospital pitcher/jug  = ~1L
    • Predictors if fluid restriction will work: generally if patient is excreting free water
      • Urine-to-plasma electrolyte ratio:
        • (Urine Sodium + Urine Potassium)/Serum Sodium
          • if <1 (actively excreting free water), will likely respond to fluid restriction
          • if >1 (retaining free water), will likely NOT respond to fluid restriction alone
      • Urine osmolality
        • if UOsm <500 (rule of thumb), the patient will likely respond
        • if UOsm >500 (rule of thumb), the patient will likely NOT respond to fluid restriction alone

Pearl 3: Solutes in hyponatremia management

  • The body needs solute to excrete free water
    • UOsm ranges from 50-1200 mOsm/L
      • Note: We can never excrete urine that is UOsm = 0
  • Types of solute:
    • Salt tabs:  
      • Doses commonly prescribed are often not high enough, and if we increase dosing, can often lead to medical side effects (e.g. HTN)
      • Makes patients thirsty and they will just drink more water
      • Retrospective cohort study shows modest (5.2 mEq/L) improvement in serum sodium in euvolemic hyponatremia after 48 hr tx
    • Protein supplements – solute without thirst response
      • Theoretical mechanism same as urea, but it has never prospectively studied
      • Benefits: cheaper, good for patients with low muscle mass, doesn’t taste bad like urea or prompt thirst response like salt tabs
    • Urea powder –  used in Europe and some US institutions
      • Works by osmotic and aquaretic mechanisms
      • However, not FDA approved (is a medical food), costs money since regulated like an OTC supplement
      • Tastes like urine, unless flavored
      • BUN levels may increase during treatment, which does not represent renal impairment

Pearl 4: Loop diuretics in hyponatremia management

  • Basis: ADH mediated reabsorption of water requires both 
    • (1) Aquaporins and 
    • (2) medullary gradient for water flow
  • How does lasix improve hyponatremia?
    • Furosemide inhibits the Na-K-2Cl channel in the thick ascending limb of the Loop of Henle, disrupting the medullary gradient in the interstitium which is the impetus for water to flow back into the body
  • Dosing: because mechanism relies on disrupting gradient and the duration of action of loop diuretics, it usually needs to dose frequently to prevent gradient from reconstituting
  • Adjuncts: often given with salt tabs, since as mentioned earlier, still need solute to excrete free water, so need to replenish solute that is depleted by furosemide 
  • Evidence: An RCT which looked at FR vs FR + loop vs FR + loop + NaCl, there was an initial improvement in Na at day 7 for FR+loop+NaCl, but this wasn’t durable over 28d of observation
    • Experts say since small study, this needs to be followed up with larger study before it is expected to change current management, which often includes Lasix+NaCl

Pearl 5: Etiologies of hyponatremia

  • Diagnosis of the cause of hyponatremia is an important part of management
  • Specific etiologies:
    • Common stimuli for ADH release:
      • Think of situations where the body feels want to conserve water or situation where the body feels like danger
        • Pain
        • Nausea
    • Thyroid disorders (specifically myxedema coma) rarely cause hyponatremia, specifically as the only presenting sign
      • Send TSH only if high enough pre-test probability with other signs
    • Adrenal insufficiency, especially secondary, can be a bit more vague (e.g fatigue, nausea or other GI symptoms) so it is not unreasonable to evaluate
      • Protip for urine studies, think of the 2 different mechanisms for adrenal insuffiency:
        • Adrenal insufficiency can cause an SIADH-like picture due to CRH stimulating ADH release directly
        • But in severe adrenal insufficiency, there can also be a hypovolemic component due to circulatory collapse
    • Medications: antiepileptics and antipsychotic medications are common culprits
      • However, any drug can do it and almost all drugs have been associated with it
  • When should imaging be obtained? (expert opinions)
    • Chest pathology is common, so review old chest x-rays or CTs, or if there are none, it is not unreasonable to obtain 
    • Brain imaging is a bit more costly and invasive, so really depends on if there are abnormal neurologic findings on exam

 

Transcript

Dr. Hwang: Like if you checking one set of urine studies and trying to decide what’s happening to the patient is kind of like seeing where a planet or a star is in the sky. And just deciding based on where it is at that moment, like what its orbit looks like and where it’s going to be like, you, you can’t do that. Right? The management of hyponatremia by definition a dynamic thing. You’re trying to predict or change the behavior of a system that changes over time and studies are kind of static.

S: That’s Dr. John Hwang, a hospitalist at Bellevue and assistant professor at NYU. This is the Core IM 5 Pearls Podcast, bringing you high-yield, evidence-based pearls. I am Dr. Shreya P. Trivedi, a hospitalist at BIDMC. 

T: I’m Dr. Tim Rowe, a pulmonary critical care fellow at Northwestern in Chicago – it’s so great to be back and talking osms!

C: And I’m Dr. Clem Lee, a hospitalist at Beth Israel Deaconess along with Shreya.  

S: Today we are talking all about hyponatremia management part 1, which means there will be a management part 2 on all things thiazides, overcorrection, vaptans, ICU management — things that get Tim really excited!

T: Yes and if you haven’t done so already, make sure to take a listen to the hyponatremia diagnostic episode where we broke down each diagnostic test and what its tell you about the patient’s physiology.

S:  And our approach to this management episode was similar in that  we wanted to break down each hyponatremia management intervention that we have in our arsenal … with that idea that if we can understand what that intervention is doing in hyponatremia and why we reach for it then we can be more savvy with the tools we have in arsenal we have because in the real world there are often multiple insults for the hyponatremia and it not as clear cut.

C: Let’s get into those pearls we’ll be covering in the episode. Test yourself by pausing after each of the 5 questions. 

S: Remember, the more you test yourself, the deeper your learning gains.

T: Pearl 1: Key principles in management of hyponatremia

 –S: What is your approach to understanding the fluid-  solute balance a patient is in? 

T: Pearl 2: Fluids & Fluid restriction

— S: How do you gauge what type of fluid you can give in SIADH? What can you use to tell you on day 1 that fluid restriction alone will not work?

T: Pearl 3: Solutes

— S: What are the 3 types of solutes you can use in hyponatremia? What are each of their drawbacks?

Pearl 4: Loop diuretics

— S: How do loops help in hyponatremia management?

Pearl 5: Etiology-driven management 

— S: Do you really need to send off a TSH and cortisol for each patient with SIADH? What do you do when there isn’t a clear cut cause?

Pearl 1: Key Principles

T: Ok guys, before we get into each of the tools that we have to manage hyponatremia, i think its good to step back and go over some big picture principles that play into our mgmt

S: and the first thing is going back to how all hypotonic hyponatremia comes down to relative excess of free water in the body! Something that is emphasize on day 1 but somehow I still appreciate every time I hear it. 

Dr. William: I make them stand up, I make them shout it from the rafters: “Hyponatremia is a water problem”…. it’s very unusual for someone who has hyponatremia to have anything wrong but their water balance. 

T: That’s Dr. Jeffrey William, a nephrologist at BIDMC you may remember from the hyponatremia diagnostics episode.

C: And to be a little bit more precise with that, true hyponatremia is really an imbalance between water and solutes in someone’s body and the ability to excrete that water is impaired or overwhelmed.

Dr. William: You know, I’m imagining how much water is going in and how much solute is going in because the, solute that goes in, helps to eliminate that water. And if they’re not in balance, then there’s a chance for water overload or the appearance of hyponatremia.

S: So if we really sit with that idea of imbalance between water and solute, we have to ask ourselves is there too much free water because is not enough solute to balance out the water, like in tea-and-toast state?

C: Or is there is just too much water because of the patient is drinking too much of it, like in psychogenic polydipsia?

T: Or is there a lot of ADH floating around, which makes the body reabsorb extra free water and as a quick reminder from episode 1, that ADH can be either appropriate in a hypovolemic patient, or can be inappropriate, like in SIADH. 

Dr. William: Part of the management for me is thinking about two things separately. One is how do I manage this patient right now, which is often finding the balance between fluid and solute and how do I manage the underlying disease if there is one, if there is a reason for, ADH to be in excess. I think that the most important part of it first is understanding even if they have excess ADH the only way they would develop hyponatremia, if they were drinking water in excess of their ability to excrete it.

T: Just listen to Dr. William describe the detective work he does to figure out what’s tipping the water-solute balance in his hyponatremic patients

Dr. William: I will often ask them about their fluid intake.  And I make sure  to include all fluids, because I think there’s a fallacy out there that this only applies to water, whereas it really applies to all fluids. And I definitely, you know, had patients who drink pots of coffee and that’s water, you know, that’s water, even though there’s coffee in it, it’s still water and juice and diet Coke is a popular one.

C: Uh oh…, who would’ve thunk those 3 cups of coffee I had today counted as fluids?

S: Right… and the other fluid we should be asking our patients about is gatorade… its another big one, especially when patients come in feeling unwell,  chugging gatorade because the marketing makes them think its filled with electrolytes but its actually a hypotonic fluid and really mostly water.

Dr. William: And then once I have a sense of the water that’s coming in from the fluids in general, I try to ask about dietary intake, just from a sense of what I would call solute, or just the things that they’re eating and how often they’re eating.

S: Dr. William told us about one quite memorable story.

Dr. William: And her son tells me all she eats are dove bars, like the ice cream with the chocolate on the outside. And I was like, Hmm, I think this is a tea and toast diet. You know, if there ever was one, you know, she’s not like eating tea and toast, but she’s drinking plenty of fluids and she’s eating dove bars… so clearly her fluid intake was outstripping her solute  didn’t take because she wasn’t really taking in any true solute uh, it was just ice cream and chocolate.

S: Now that i appreciate how through I/O history can be in hyponatremia, I think its interesting how aggressive about I/Os we are with heart failure but now I’m convinced that we need to be even more hands-on with In/outs in hyponatremia. 

T: Ahh I&Os…so important but so elusive!! That actually leads in perfectly with the second big picture pain point in hyponatremia management, which is its frustratingly multifactorial nature. As convenient as it is to think about patients in neat little buckets like “SIADH” or “tea-&-toast” and follow the diagnostics, that’s not always the way it goes in clinical practice.

S: Dr. Helbert Rondon, a nephrologist from University of Pittsburgh gave an example of someone with a low solute intake-tea and toast picture so classically you’d expect a really low UOsm, right? But people are more complicated than that…

Dr. Helbert Rondon: Usually the cutoff is not that crystal clear a hundred, because sometimes, you could see somebody who has low solute intake hyponatremia, and the U osmolar is 150 or 160 on the low side, but not less than a hundred. Then when you ask the patient, you know, um, the patient might have some nausea from drinking too much or something like that. So you see those overlapping picture sometimes.

S: I love this example bc things like nausea, pain, meds can all cloud the picture by releasing all that inappropriate ADH, cause water reabsorption and kicking up that  urine osmolality and clouding what we’d expect our urine studies to be.

C: The last big picture point we wanted to stress is that in the mgmt of hyponatremia, sometimes not do anything as you are still waiting for data to come back is something

Dr. Hwang: A lot of times the urine studies, which often aren’t collected in the ED, right? They’re collected by the overnight resident or by us in the morning, um, they’re collected at a very awkward time in which they’re, they’re confounded by the effects of what has happened to the body over the initial 12 to 24 hours. Um, even if the intervention is doing nothing like nothing is something right, like withholding beer, withholding free access to water is something.

S: This goes back to the Dr. Hwang’s initial point that hyponatremia is dynamic and we need figure out how this timepoint of urine studies fits in with the context of what’s going in and out of the patient’s body so we can interpret it a bit more correctly.

Dr. Hwang: One example of this is sometimes the urine OSMS are kind of low-ish right, that they’re elevated, but they’re not super elevated. They’re like 200 or two 50. And the urine sodium is kind of low, you know, 15 or 20 or 12 or something like that. And you might try to finagle that into, oh, this is, this is hypovolemia. But an equally plausible explanation is you’ve collected urine studies at the moment where the body is actually correcting the right. The stimulus for the, you know, ADH releases has, has been removed and their body is transitioning into making a more dilute, urine, large amounts of a dilute urine.

S: What a great example of trying to understand where in the trajectory you are catching this patient’s urine studies. Why don’t we summarize… I think we’ve covered a lot of ground. You’ll be able to manage hyponatremia much better if you get a detailed fluid and solute history to understand where on that water-solute balance your patient falls.

T: Right – & not just obtain the history & forget it, but keep track as you try interventions in the hospital.

S: Be mindful that there can be multiple insults going on and last “doing nothing is something”  in the management of hyponatremia and that in and of itself can impact the sodium.

T: Alright, so we’ve discussed the relative imbalance of solutes and fluid that leads to hyponatremia states. So it should come as no surprise that most of hyponatremia management is just targeting those inputs – fluid or solutes! What should we tackle first, Clem? 

C: What was that? I’ll take fluids!

Pearl 2: Fluids in hyponatremia

T: Okay let’s jump right into this – you’re taking care of a clearly hypovolemic patient who also has hyponatremia. The nurse is about to spike a bag of crystalloid and asks what you want to use. What do you think Shrey?

S: This is a great question… Do I go with a balanced fluid like lactated ringers that seems to be more kidney protective, or normal saline, since NS has a little bit more sodium content.

Dr. William: No. As long as they’re isotonic or hypertonic, it doesn’t matter.

S: Hah.. maybe it would help briefly remember how fluids help hyponatremia and to be specific how do fluids help in true hypovolemic hyponatremia.

Dr. William: In these situations you’re actually providing the volume and then the volume expansion shuts off ADH, right? The expansion of the volume within the vasculature is going to, you know, turn off those baroreceptor responses will shut off and that’s actually what makes the serum sodium better is as shots off your kidneys, start to excrete the water that is in excess in the body. And that’s how hyponatremia gets better in the setting of true hypovolemia with an isotonic fluid.

S: Got it. So with true hypovolemia causing hyponatremia and fluid choices, the tiny differences in salt content likely are negligible and don’t matter in the grand scheme of things.

C: Ok but I feel like in the hospital there’s another common confusing situation– we often get patients with unclear histories, who may very well end up having SIADH. What do we do about fluids in that case?

T: Oooh, that’s a little bit more tricky. This may be a cop-out, but I’m gonna let Dr. Hwang take this one 

Dr. Hwang: It is a misconception that if you give intravenous fluid to somebody with SIADH you will make the sodium worse. When I teach hyponatremia to my residents, that is just something that I start off with and when I get a bunch of quizzical looks, that’s my opportunity to then get into the, the explanation a little bit.

C: Oh wow thats a plot twist. I think in residency we all get drilled into our heads that SIADH is treated with fluid restriction and salt tabs. So how can fluids actually help?

Dr. William: I’m really comparing the fluids osmolality to the urine osmolality. And if you are giving a fluid that has a higher osmolarity than the urine, then you will be able to excrete the free water or the extra water. If you’re giving a, a fluid that has a lower osmolality than your urine, then you are going to hang on to water. 

C: So the big take away is if you are going to give fluids, even in SIADH, make sure the osms of the fluid you’re giving are higher than the urine osms. 

S: Yes its much more nuanced than “all isotonic fluids are bad for SIADH”

Dr. William: The classic SIADH example, where you assume that the ADH release is relatively constant. And let’s just say, it’s creating a urine osmolality of 600. So in this case, you would need to give a fluid that has osmolality greater than 600 in order to improve the hyponatremia. There’s only a few fluids that do this. And this is when we give 3% saline or hypertonic saline, and it works right, cuz it has an osmolality of over a thousand. So it’s going to work at, you’re going to excrete for rewater as a result, you’re delivering extra solute to excrete water.

T: On the flip side, if the patient has a UOsm of 600, giving a fluid with a lower osmolality like with isotonic fluid, which has an osmolality around 300s would make the sodium worse

Dr. William: You’re creating a situation that’s actually worse where you’re giving extra water. Um, and this is even worse if you give half normal saline or D5, which are even more hypotonic

T: And if you’re like me and have a tough time memorizing the osmolality of different fluids, be sure to check out the infographic from our recent fluids episode – that’s got all laid out nicely

S: One last thing that our reviewer  Dr. Sheldon Chen pointed out, is that the rate with which you infuse the fluid matters too. Its a lot to cover on the episode but if you are interested check out the show notes where uses the Edelman equation to shows the difference of infusing isotonic fluid at 40ml/hr in an example patient with SIADH vs. 100ml/hr. 

C: I know that will go over my hear, but I’m sure Tim is going to look that up

T: Alright, enough on fluids – lets take a hard pivot. We talked about using fluids to treat hyponatremia, but how do you guys think about fluid restriction?

C: I’m not sure it’s elegant… If I feel like my patient by my gestalt is drinking too much free water, I start a fluid restriction.. And then i just keep restricting until my patients get mad…

T: Oh man, I know that struggle. Everything you do is elegant .But actually Clem, it turns out that approach isn’t completely wrong–

Dr. William: In terms of how much of a fluid restriction is worthwhile… I guess what I would say is as much as possible? you know, you have to drink something … So let’s just say they take in three liters of fluid every day. If they have hyponatremia and you say, you know what, I’m going to restrict you to one and a half liters a day. It’s gonna get better! 

C: Amazing. Love it when medicine is intuitive and the math makes sense. Or as the Gen Zs say– when the math maths.

T: The math maths! No cap, that slaps 

S: You guys will have to translate all of that to me… maybe someone can leave a comment and explain that! One thing I felt really good about was hearing how um Dr. William sets up patients for success with fluid restriction because often times sticking a paper on their wall saying  “fluid restriction” and not looping in our patients.

Dr. William: The way that you do this is you, you tell the patient to fill up a pitcher to an amount of fluid. You say your restriction is 1.2 liters for today. And that is the only fluid they drink the whole day. And when it’s done, it’s done.

S: Since this interview, I started getting out those gray pitchers from the pantry, showing them this is a L and I’ve found patients actually following through with fluid restriction so much better. It’s helpful all around since it’s hard to conceptualize how much a liter is.

C: Not to rain on your patient education parade here but I’m kinda of a pessimist… but are we sure fluid restriction is even going to work?

Dr. Helbert Rondon: Rather than, you know, waiting to see if fluid restriction will work or not, we have certain predictors that can tell us if this patient will respond to fluid restriction or not. 

Dr. William: So one rule of thumb is measuring the urine osmolality. If this urine osmolality is really high, say more than 500, then it’s telling you that most of the water that you take in is going to be reabsorbed. So it’s going to be very difficult for a patient to restrict enough water so that they’re not gonna worsen their hyponatremia.

S: So the way I think of this is if the urine osm is >500, that means there is just so much ADH around that, reabsorbing free water that fluid restriction alone wont be enough

T: So UOSM >500 is a good general rule – but I know nephrologists, they’ve got a ratio for everything. Is there any more accurate way to predict in these scenarios?

Dr. Helbert Rondon: The main one that that we could use is, um, this urine to plasma electrolyte ratio, which we calculate by adding the urine sodium plus potassium and divide it by the serum sodium.

S: If you missed that we will link how to calculate the ratio in the show notes but just remember to order both a urine Na and urine K for the ratio.

T: I always forget to order the urine potassium.

S: Yes dont forgot!

Dr. Helbert Rondon: So if the ratio is less than one, it means that the patient is actively excreting free water in the urine. And all you need to do is restrict the fluid to less than what they’re excreting in the urine plus insensible losses. those patients, you know, usually, will respond to fluid restriction.

C: Yeah and what Dr. Rondon is saying is a throwback to Pearl 1, if that ratio is less than 1, they are on the side with more fluid than solute, so that’s why restricting fluids will help.

Dr. Helbert Rondon: The great majority have a ratio more than one, meaning they will have a negative free water clearance, which means that they’re retaining water. And even if you put them on zero fluid restriction, they might get worse. So in those patients, rather than waiting, we know that they’re not gonna respond the first day. So we add a medication.

S: And that medication we will get to in our next couple of pearls. So with that, why don’t we bring it home for the listeners?

C: Ok to recap this pearl; if your patient needs fluids, what type of fluid doesn’t matter much, but you do want to make sure whatever fluid you’re giving is more osmolar or to say in other words, has a higher electrolyte concentration than the urine.

T: Yup – and with fluid restriction you’ve gotta set your patients up for success. Don’t just tell them the fluid limit, go raid your unit pantry and bust out those gray water pitchers to educate them!

S: and we can look at the urine osm to see if its >500 or more specifically if urine sodium plus urine potassium are greater than serum sodium, and if thats the case your patient is probably not going to be responding to fluid restriction alone 

Dr. William: The times when a fluid restriction really does work is when that patient has been drinking a lot of water beforehand. The tricky part now is like, what if they weren’t drinking a lot of fluid then what is the fluid restriction going to do? 

T: The answer to Dr. William’s rhetorical question there is unfortunately not a whole heck of a lot. But in pearl 3 we’ll talk about something else we can sprinkle into the mix.  

Pearl 3: Solutes in hyponatremia management

C: So now we all know that hyponatremia is all about a relative imbalance of solutes and fluids… it’s time for us to talk about the other half of the picture, solutes 

T: Right, this is where we need to remember the old aphorism – excreting free water isn’t free – we need some solute to make our pee!

C: Dr Seuss has entered the chat.

Dr. William: So how does this work? So remember that the urine osmolality has a range, right? It like ranges from 50 to 1200 and the human kidney or whatever. So what that tells you is that yes, urine is never straight up water. Never. It can’t be because you need solute to excrete water. I don’t know if I have a great explanation as to why that’s true. I’m sure that there is but it should stand to reason that if the lower end of a urine osmolality is greater than zero, that you need some sort of solute to get rid of water at all times.

S: Thats so interesting ….so if we need some solute to pee out free water, then are salt tabs just acting as a solute?

Dr. William: That’s why the the hyponatremia improves. It’s not because we’re introducing more salt, it’s because we’re introducing solute and that solute helps the excretion of water and the excretion of water results in an improvement in hyponatremia.

T: Oh man this is great – Clem, I know that you’re fixated on fluids, and not just because you measure your daily coffee intake in pots, but I’ve got to admit – I’ve always been more of a solute guy myself. 

S: Where’s this going, Tim? 

T: Hear me out here, Shrey! You see, solute is the underdog, the real MVP, the G.O.A.T. of hyponatremia management. Anyone can bolus a liter of saline, or…remove the handle on the water tap.  But solute administration? It’s nuanced. It’s cerebral. And sometimes, it’s actually kinda gross. 

C: Oh boy, I think I know where that’s going

S: haha yess is this urea?

C: But I think he is alluding to urea, lets hear about the OG, the alpha, the Adam and Eve of solutes. Yup, I’m talking about the salt tabs.

S: Yeah salt tabs seem great in theory providing that solute but have you guys ever seen those sodium chloride tabs actually work on its own? 

Dr. Helbert Rondon: The regimens that we use for salt tablets are, have a very small, solute load. Like the two grams three times a day is about less than 200 milliosms per day of solute load. That’s very small, um, compared to, for instance, urea, which if we use the usual regimen, which is 15 grams, twice a day, that’s 500 milliosms. So to, to match that solute load, you have to get 15 grams or more of sodium chloride to match that. Solute to force water out. So, and 15 grams is something that is not practical for patients to take on a daily basis, 15 tablets of salt. Um, so therefore when I use salt tablets, I don’t use it as the main therapy for hyponatremia.

S: Bummer I think I’ve been under dosing salt tabs with the usual 1-2g TID. All this time, I guess I really wasn’t giving that much solute for my patient to pee out free water.

C: Aw Shrey, don’t beat yourself up too much. The other downside of salt tabs is that they inherently make our patients really thirsty, so  this backfires because they end up drinking more water, tipping back that balance of excess – of excess water and solute.

Dr. William: So if you end up taking in salt tabs and drinking more fluid, it’s kind of a zero sum game, right? Cause you’re just introducing more solute. You’re matching it with more water and you’re just increasing volume. So if you are going to prescribe salt tabs for someone’s hyponatremia, the most important thing about that treatment is the fluid restriction. If they cannot maintain a fluid restriction with salt tabs, you might as well stop it. You’re only going to make their hypertension worse. Their volume status is going to go up, and the salt will be doing absolutely nothing helpful for you.

S: I really appreciate this reminder that salt tabs are not without risk –   and honestly makes me think of all the patients that come in for have heart failure or hypertensive urgency get put on a low Na diet (which is debatable thing to do) but while they’re on that 2g Na diet also get put 3g TID of salt tabs for their hyponatremia!

C: Thats actually sad to think we can be making our patient’s hypertension worse but I imagine happens more often than we think

S:  Makes me wonder if there other options for solutes than salt tabs?!

Dr. William: I often turn to protein instead. Um, and I ask patients to supplement their diet with a protein shake or some sort of protein powder. They can mix their own little protein shake, whatever is economical for them. Instead of buying the, you know, the tiny bottles at the pharmacy and protein is solute, but protein doesn’t necessarily make you thirsty, not like salt will. So patients are often able to do this a little bit better.

S: You know, using protein as a solute kind of feels like genius – 

C: You guys might be wondering why that would work – the reason is that protein is broken down into urea, which is a great solute for free water excretion

S: This has been practice changing for me. I’ve started to ask my patients when they call down to the cafeteria to order more protein or meat meals and order less carbs cause thats not gonna end of as a solute cause that doesn’t end up as a solute

T: Speaking of protein breaking down into urea, let’s hear a bit more about the new kid on the block in the solute game. 

Dr. Helbert Rondon: Urea basically works as an osmotic diuretic. It makes you secrete water. And one extra benefit of urea is that urea actually makes you retain sodium. So if you measure natriuresis in patient with SIADH when you give urea they retain sodium. 

T: Whoa, so urea is pulling double duty – it’s a solute to help eliminate free water and actually promotes sodium reabsorption. Sounds like all of the things we want our hyponatremic patients to do. But then why aren’t we ordering this more often?

Dr. William: So urea, they use it a lot in Europe actually, and it’s, it can be quite effective. Um, it is challenging to get here in the US I’m not exactly sure why it’s classified as a medical food, not a drug. Um, so it’s never covered and, um, it’s actually kind of expensive. It turns out it also, you may not be surprised, tastes funny, like sort of a urinary quality to it, perhaps? Um, and they’ve tried to flavor it, you know, make it lime, but it’s still, you know, it’s like drinking urine a little bit.

C: Well, not to say i told you so but I told you so– that is kinda gross. But more urea might be on the horizon, especially with Dr. Rondon research!

Dr. Helbert Rondon: All the data that we have is retrospective at this point. But I think that if we can show that it’s effective in a prospective trial, perhaps it can become officially a drug and maybe the insurance companies might be willing to pay for it.

S: Nice, would love to use some urea, it wont make people more thirsty, it doesn’t cause worsening high blood pressure or Gi irritation like salt tabs – I’m kind of jealous of Europe. Regardless im so glad we went over 3 types of solutes we can use in hyponatremia mgmt – lets recap

T: Sure, I’ll give it a shake. We need to have solute to eliminate water. Most of us reflexively go for salt tabs as solute. But there are so many limitations – the doses we have to use are often higher than our patients can stomach, they tend to provoke a thirst response that can be counterproductive because -remember- we are in the business of trying give less fluid in hyponatremia mgmt 

C: Right, then there is protein as a solute, which really is game-changing for me. I’m already ordering many Ensures for my malnourished elderly patients, so I like hearing that this also helps increase their solute intake. The last solute– urea, as gross as it sounds, it doesn’t come with the side effects that salt tabs do and can be just as effective if its available to you.

Pearl 4: Lasix in hyponatremia management

T: Lets move on to lasix! Pop quiz  CLEM! how do loop diuretics work? Clem?

C: That’s easy! It blocks the Na-K-2Cl cotransporter in the medulla – does that sound right

T: Right but how does blocking that Na-K-2Cl in the medulla improve hyponatremia?!

C: …cytokines?

S: I didn’t know either before this episode but its kind of cool – furosemide basically takes away ADH’s ability to reabsorb free water

T: Wow, this is huge. Reducing ADH’s ability to reabsorb free water? That’s like taking away the hammer of Thor!

C: Right, or taking away iron man’s suit

S: Exactly to really understand how lasix prevents ADH from working, we have to understand that ADH actually needs two things to happen to reabsorb free water (1) insertion of aquaporins and (2) there needs to be a gradient so water will want to move back in the body 

Dr. Hwang: ADH leads to the insertion of aquaporins in the collecting duct. And once the aquaporins are in place, water can move from the urine in back into the interstitium of the kidney. It can, but aquaporins are passive, right? They don’t actively transport water. There has to be a gradient to make the water, want to move the urine into the kidney that gradient exists because of the loop of Henle. So when you give somebody a loop diuretic, and you mess up the function of the loop, you’ve messed up the gradient. And you’re basically inhibiting water reabsorption.

T: Another way to think about free water transit – aquaporins are like the door, but its the medullary gradient that pulls water through. 

Dr. William: In short, basically we say that loop diuretics wash out the medullary interstitium. So what does it do? Well, if the urine osmolality is 300, then the medulla is also 300. So no matter how much ADH you have, you can have SIADH like crazy the water won’t be reabsorbed.

T: So without a gradient, the poor little aquaporins are just basically hanging out by their lonesome.

C: That makes a lot of sense and agree the physiology is pretty neat. But arent we taught that Lasix only lasts for a few hours…? Maybe… six?

Dr. William: You need a fair You need a fair amount of loop diuretic to do this. Um, people say that you often need like up to TID, at least 20 milligrams of furosemide to do this. 

S: I have seen this quite a bit as a rookie move and teams uptitrating the lasix from 20mg to 40mg daily but really its about increasing the frequency and getting patients on a low dose TID to make sure that gradient is washed out  throughout the day

C: So lets bring this all together, how do loop diuretics fit together with the other tools we have in hyponatremia mgmt?

Dr. Helbert Rondon: So loop diuretics is the main drug and salt tabs are just a compliment.

C: Oh ok, so we knock out the channels so there’s no more gradient, but still need solute to excrete the free water

S: I’m still thinking of how Dr. Rondon say loops are his main drug of choice and salt tabs are just complementary. Idk what algorithm was drilled into my mind especially for SIADH where you do fluid restriction then reach for salt tabs and then reach for lasix. But clearly we should be rethinking that paradigm 

T: Yep maybe we should be reaching for lasix earlier in SIADH management, instead of on day 4 or 5 after seeing fluid restriction and salt tabs didn’t help.

Pearl 5: Etiologies

S: Ok I feel like I’m in a much better place thinking about tools we use to correct hyponatremia, but reality is that the etiology of the hyponatremia is such an important part of management, especially when we find ourselves in the inappropriate ADH secretion, because there’s just so different causes

C: So while we are trialing lasix, fluid restriction and protein supplementation or salt tabs, what sort of diagnostic tests should we be sending off to narrow down the cause of SIADH?

T: I don’t know about you guys, but I’m almost reflexively sending TSH and am cortisol…it was deeply engrained in my primordial med student brain. Is this really a helpful practice?

Dr. William: Right? Everybody checks a TSH… it’s somewhere in some algorithm, it made it to whatever handbooks people carry. I don’t know, but everybody checks it and it’s mostly normal. But even if it’s abnormal, like when have you ever seen somebody with thyroid disease, causative of a hyponatremia? If you look in the literature, actually, it’s extraordinarily rare. And they’re even case reports of like profound hypothyroidism, myxedema like coma and their normo-natremic. So I think that we check it way more often than we really need to.

S: I really appreciate Dr. William calling out something we probably do for no reason in most cases. For so long, I haven’t thought twice about that what are the chances that this patients has significant thyroid disease and their only presenting sign is a low sodium.

Dr. Hwang: And that is what makes me question why, you know, we would even consider asking this question, right? saying that hyponatremia is a feature of thyroid disease is not the same thing as saying, you know, hyponatremia in isolation, unexplained can be a classic presentation of, you know, otherwise occult thyroid disease. Like I would pay attention if the latter was the case, but to, in my experience, that is, that has not been true.

C: So maybe the takeaway here is we really should apply some Bayesian principles and only send a TSH only if we really have a high pretest probability of a thyroid disturbance, not just someone with isolated hyponatremia

T: That makes a lot of sense – if you have a low sodium from hypothyroidism it’s probably not going to be a subtle presentation. But what about cortisol levels? Do we need to send this on all of our hyponatremic patients?

Dr. William: So first of all, you know, so first of all, you know, if you, if you think someone has adrenal insufficiency, you would expect them to look a certain way clinically, right? 

S: Yep without all that cortisol, clinically these patients usually are really fatigued, maybe have some nausea, weight loss, adrenal insufficiency causing hyponatremia is certainly a thing but in a similar sense you have to use your pretest probability for it.  

C: I do find I send cortisol a bit more often than TSH since most of the signs and symptoms of adrenal insufficiency are so vague and nonspecific and i don’t want to miss it

T: I was always taught that the urine studies in adrenal insufficiency look like SIADH since the mechanism involves CRH stimulating ADH release, is that really what causes it?

Dr. William: So this, this gets a little bit tricky. So is it really the hypovolemia that’s leading to a volume stimulus to cause ADH release, or is it this more endocrinologic pathway of CRH (or cortisol releasing hormone) being a secretagogue of ADH.

S: So this is where distinguishing primary and secondary adrenal insufficiency can be helpful. Primary adrenal insufficiency – both aldosterone and cortisol take a hit leads to more of a hypovolemic picture from aldosterone deficiency, compared to secondary adrenal insufficiency which is only a cortisol deficiency, without cortisol, there is all this all this unsuppressed ADH around and so secondary adrenal insufficiency looks more like an SIADH picture   

T:  Wow, I’m learning so much about endocrine causes of hyponatremia. Dusting off a part of my brain that I havent used in a while. But while we’re waiting for the AM cortisol to cook, lets turn our attention to a notoriously tricky cause of hyponatremia – medications.

Dr. William: I mean, anyone who has hyponatremia secondary to SIADH requires a thorough review of their medication list, especially new ones, if the hyponatremia is new, um, and if their hyponatremia is chronic, then everything’s fair game. The case reports are boundless about drugs that people have surmised may have led to SIADH, which of course is, is difficult to ever really prove. 

C: Well that gives me anxiety– to hear that almost any drug can do it

S: Yep thats why i felt strongly about grilling our experts ones are the most common offenders that should be on our radar, meds commonly associated with hyponatremia.

Dr. Hwang: I would say that the, that anti, the anti-convulsants and the anti-psychotics, I feel like I’ve seen a fair number of cases where we’ve been fairly confident that that’s, that’s the reason why. So there’s a patient who was on psychiatry. Then they were started on valproate for a bit, and the resident notices, Hey, why is this person hyponatremic you think to yourself? Oh, maybe it was the valproate. 

T: Ok a truly harrowing number of meds can do it but really lookout for anti-convulsants and antipsychotics. What if we don’t uncover an endocrine cause or any offending medication and are left scratching our head. Then what?!

S: I think its tough and here i find myself thinking of the other potent stimuli for ADH release  – one of our reviewers put it nicely as thinking of things that would make the body feels want to conserve water or situation where the body feels like danger like when it feels Nausea or  pain

Dr. William: Once it sort of gets, um, you know, somebody posits an explanation like, oh, well, they’re post-op and they’re in pain. So that must be it. Or, you know, oh, they’re so nauseated. Like that’s why they have excess ADH, like these sort of non-specific reasons. But I guess the one caution that I would say is that, you know, have they had any recent imaging, right? And, and mostly when we’re talking about imaging for SIDH, we’re mostly talking about the lungs and the brain.

T: Ahhhh the lungs the lungs! I’m so glad he brought up the chest XR. 

S: Said like a true pulmonologist — here is where I struggle, especially if there isn’t a clear cause,  I can do all the management tricks with fluids restriction, lasix, salt tabs to make the numbers look better but realistically thats not a great discharge plan to send someone to rehab on TID salt tabs, how much do I chase the lung and brain imaging

T: What I do if I have a patient with SIADH without a clear culprit, I typically look to see when the last time they had chest imaging. If they’ve got normal chest imaging during while they were hyponatremic, then I don’t typically feel like that SIADH warrants re-imaging in itself. 

C: Right, and if my patient doesn’t have focal neurologic findings, confusion or a history of intracranial pathology, I don’t think it’s that crucial to get brain imaging upfront. 

S: And that is where your friendly nephrologist come in to help think which may be best in more nuanced cases– Clem why dont you recap some of things we hit on

C: So to recap this last pearl– the causes of hyponatremia are boundless, but high yield things may be to review their med list, their past imaging, think about adrenal insufficiency, which is notoriously tricky to diagnose, and finally– if there are other signs of hypothyroidism, send a TSH.

S: And that’s a wrap for today’s episode. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! Please tweet us and leave a comment on our website page, on instagram or facebook page. Thank you to our peer reviewer Drs. Richard Sterns, Tomas Guerrero, Sheldon Chen.

Thank you to Daksh Bhatia for the audio editing and Dr. Michelle Lo for the accompanying graphics. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

 

Edelman Equation Overview:

The Edelman equation says that the serum sodium is the (total body Na + total body K) divided by TBW, or: 

You can legitimately use this equation such that the numerator tracks all of the Na/K solutes and the denominator tracks all of the water volumes. Let’s compare NS to an SIADH-driven urine. NS has a [Na+K] of 154 mEq/L (all sodium, no potassium; with the Cl anion the osm is 308 mOsm/L). Suppose that SIADH makes a patient’s urine [Na+K] become 180 mEq/L (U Osm at a minimum will be 360 mOsm/L which is greater than 308; ignore UUN and glucose contributions to the urine osm). Urine output rate is 40 mL/h. Also, let’s say the patient currently has a [Na]=120 mEq/L and a TBW of 42 L. Assume no other I’s/O’s like drinking.

 

First, let’s give NS at 50 mL/h for 24 h. According to Edelman, the future [Na] will be

 

So, NS that is less concentrated than the urine made the serum sodium worse. Not a surprise, but also not a dramatic drop like you might expect. The big drops in [Na] when giving NS in the setting of SIADH are usually due to the patient drinking water (liquids in general).

 

But now, let’s increase the NS rate to 100 mL/h:

 

So, the serum sodium actually went up, even though NS is still less concentrated than the urine.

 

It’s not that NS (or other isotonic fluid) always makes hyponatremia worse if the IV fluid is less concentrated than the urine (although you should compare urine to serum, as you point out). NS can still raise the serum sodium if you infuse it fast enough. In the above, 50 mL/h was too slow and made things worse, but 100 mL/h was fast enough and made the sodium slightly better. FYI: the stalemate point (between NS and urine) is to infuse NS at about 70.6 mL/h. This can be calculated (70.5882…), but trial-and-error works too.

 

By the way, using Edelman as an accounting tool is how all of the sodium equations, like Adrogué-Madias, work. Just wanted to demystify A-M, Barsoum-Levine, Nguyen-Kurtz, etc.

 

A-M is the most famous, and simplest, and it says that giving a liter of 3% saline will increase the serum [Na] in our example patient by

 

The Edelman accounting trick says that the new serum [Na] will be

Well, the delta [Na] is , exactly as A-M said. The precision down to the last decimal point tells you that the A-M formula was mathematically derived.

References

 

 

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