Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 120 I'm your co host, Dr. Kane, and I'm Dr. Patel. And in true 2020 fashion, the title of today's episode is when it rains it pours, a succinct clinical review of hyponatremia due to si ADH. So today we're focusing on the syndrome of inappropriate antidiuretic hormone, which is a form of hyponatremia called si ADH, Dr. Khyati Patel 00:55 and Dr. Kane. I think for our audience, it would make the most sense if we kind of have some sort of a clinical case associated with this. This topic is not commonly seen unless you work in a certain practice setting. So what is our case today? Dr. Sean Kane 01:10 Sure, so our case is HN, she's a 74 year old female. She came in the ER, after she had a witness fall at home. She did not hit her head. She's not complaining of any pain. But the husband says she's more confused than normal. She's nauseated and has been complaining of a headache for the past several days, not related to her fault. They do a CT of her head that's normal, no bleeds in her brain. They do some X rays to make sure she has no broken bones. Everything is fine, except for her altered mental status. They do some lab work, and it turns out that she has a serum sodium of 119 which is quite low. Normal would be 135 to 145 so on the basis of hyponatremia, they consult a nephrologist, and that nephrologist does a bunch of lab work, including a serum osmolality, which confirms that the patient has hypotonic hyponatremia. So serum osmolality is 250 anything less than 280 is a little bit low. They do some urine chemistries, and her urine osmolality is high at 400 and her urine sodium is also a little bit high at 50 milli equivalents per liter. On physical exams, she's euvolemic. And on the basis of all of these lab findings, which we'll discuss in a little bit. The diagnosis is made for SIADH, or syndrome of inappropriate antidiuretic hormone, upon further questioning in terms of trying to figure out why she has this new diagnosis. It turns out that the husband reports that the patient started taking citalopram or Celexa recently for anxiety, again, because of 2020, and that's kind of a very typical patient scenario for someone with SI ADH, okay. Dr. Khyati Patel 02:48 And then recent year, there's been transition in this acronym, instead of syndrome of inappropriate antidiuretic hormone si ADH, it's also known as siad syndrome of inappropriate anti diuresis. So if you're looking for literature, you know, you might see a combination of both. Dr. Sean Kane 03:07 For the purposes of this podcast, we're going to stick with SI ADH. I'll be honest with you, I feel like it just makes things more complicated when we start renaming things, but you'll definitely see both in literature. Dr. Khyati Patel 03:18 So laying the foundation of SI ADH, you know, the the hormone that's at the center of this is the anti diuretic hormone, and it's appropriate that we talk about its physiology and pathophysiology first. Dr. Sean Kane 03:31 Yeah, so ADH, antidiuretic hormone, is released from the hypothalamus in the pituitary gland. It has another name too. So ADH is also called AVP, arginine vasopressin. It's the same vasopressin that we have IV for septic shock. And basically the role of ADH is that it maintains tonicity in the blood. So if the brain detects that your blood is too hyperosmolar or too concentrated, you need more water in your blood, it will release ADH antidiuretic means that it will hold on to water, that water will then be reabsorbed in the kidney, and then your blood will be diluted out by that water that you're not peeing out, but retaining in your blood instead. Dr. Khyati Patel 04:11 And you may wonder, well, how does it actually work in the kidneys for this water reabsorption? And so I love these cool receptor names, the vasopressin two, as well as aquaporin Two. The vasopressin two, the v2 receptors are located in the kidneys, you know, late distal tubule. And collecting that, basically at this receptor, it causes increase in the aquaporin two expression in the cells. And basically the aquaporin two channels then would allow the water to be reabsorbed into the blood, and so essentially, like you said, Dr. Kane, it will go ahead and dilute the blood, but at the same time, then there is little water in the urine, so the urine is going to be more concentrated. Dr. Sean Kane 04:52 And you know, we won't get too much into the physiology of this, but it's actually really neat how activation of that vasopressin v2 receptor causes the aquaporin to to be expressed on the cell membrane. It basically is sitting in the cell ready to be put onto the cell membrane, and it does that when vasopressin two receptor is activated. So there's so many intracellular pathways going on that we don't have time to talk about today, but it is a really cool example of a fairly simplistic pathway in terms of getting, in this case, a water channel to the surface of a cellular membrane. Dr. Khyati Patel 05:25 And there is other reasons why ADH would be released. So one other example is, you know, low blood pressure. Whenever there is a low blood pressure, the ADH is released. You know, lower concentration. Though, the job of the ADH is to just reabsorb the water, as we talked about earlier, at higher concentration, ADH can act as a vasoconstrictive agent, and so that vasoconstriction that results into increased blood pressure. Dr. Sean Kane 05:55 And Dr. Patel, as you mentioned earlier, the v2 receptors in the kidney. So clearly we must have a v1 receptor, right? And that v1 receptor is in the vascular smooth muscle of your vasculature. So when we hit the v1 receptor, when we agonize that v1 receptor using arginine vasopressin or ADH, then that causes vasoconstrictive property. Your blood pressure goes up. And this is actually different than some of our vasopressors that we use, like in the ICU, so norepinephrine, epinephrine, they primarily work by alpha one mediated vasoconstriction. Vasopressin is not a catecholamine. It's not working on the Alpha One receptor is not part of the sympathetic nervous system. So one potential advantage here is that this is a different modality to cause vasoconstriction in patients, especially in septic shock patients. This is a good receptor to know about, because we actually use it quite commonly in septic shock patients. Dr. Khyati Patel 06:50 And so what happens when the ADH is not balanced, meaning, you know the pathophysiology, that's where we call it the syndrome of inappropriate antidiuretic hormone, the SI ADH. It could be that there is too much ADH. So basically, the blood gets diluted, as we talked about earlier, there is more reabsorption of the water then the water should have been peed out. In some cases, you may get to see this as not a hypervolemic, but more of a euvolemic picture, like our patient is kind of coming up with, and these patients don't have that profile in edema. And the reason is because there are other compensatory mechanism going on as the body senses that there is too much volume. We have other pathways that would go ahead and, you know, increase its salt and water excretion, but maybe that this compensation is just not enough, and the sodium is still dropping. Dr. Sean Kane 07:46 And you know, on a an exam question, for example, Dr. Patel, the classic thing is going to be that this is a form of euvolemic hyponatremia, meaning that the patients aren't fluid positive, that they're not very edematous. In actual clinical practice, it's usually not clear cut. They're definitely euvolemic or not. Many of these patients will have comorbidities that kind of confound the picture, and even clinically. Sometimes it's not always straightforward in terms of for a 70 plus year old person, oftentimes they have edema a little bit in their ankles anyway, and whether that constitutes being euvolemic or hypervolemic can sometimes be difficult to discern. Dr. Khyati Patel 08:20 I 100% agree with you. Sometimes the way it's taught in the books versus what you actually clinically get to see is different, so we appreciate you kind of highlighting that difference. Dr. Sean Kane 08:31 Now you might be wondering, okay, so SIADH, is that you have too much ADH, what are some typical causes of why your body would make too much ADH, Dr. Khyati Patel 08:40 well, one of the example is certain cancers, especially that small cell lung cancer, can do that. This ADH is secreted in in the brain, basically. And so the CNS disorders like stroke, meningitis, any kind of head trauma, could result into an appropriate ADH secretion as well. Dr. Sean Kane 09:01 We can also see in patients that have surgeries, especially if they're in a lot of pain, pain can be a trigger to have more ADH released. And of course, Dr. Patel, as pharmacists, we have to talk about drugs, and there are plenty of drug induced causes of SA ADH. We'll absolutely talk more about that later, and that's going to be the emphasis of the etiology of most of the patients that we're going to talk about, but drugs are definitely a common cause here, right? Dr. Khyati Patel 09:29 And then on the flip side, you know, if there is not enough ADH involved, then it could lead to hypernatremia by not obviously having enough ADH, and so this would result into large amount of water into the urine, and not enough in the in the blood, basically. So the other way around, and these patients present with we call it either central diabetes insipidus or nephrogenic diabetes insipidus. Dr. Sean Kane 09:57 This is not Sadh anymore. It's actually the opposite, but it's. Relevant, because in these cases, these patients produce tons of urine, very watery urine. In the cases that I've seen Dr. Patel, most of these are central diabetes insipidus type patients, where they have anoxic brain injury and they're herniating, and their sodiums Go from 145 to 160 within a matter of several hours, because they're producing like a liter plus of urine per hour, and the nephrogenic diabetes insipidus is relevant, because later on, we'll talk about how we don't really do it, but a textbook answer of a kind of third line therapy for SIADH is to give drugs that cause diabetes insipidus to offset SIADH. So again, if this is the opposite of SIADH, there are some drugs that can cause diabetes insipidus and then treat SIADH. Dr. Khyati Patel 10:44 So, Dr. Kane, you mentioned earlier that the normal value of serum sodium is 135 to 145 our patient added 119 when is a normal time where patients will actually start to show some of these symptoms. Dr. Sean Kane 11:01 You know, for the most part, most symptoms will start when you get to less than 130 so that 130 to 135 typically is asymptomatic. It's numerically not normal, but clinically not that relevant. Once you get below like 125 you'll definitely start having symptoms. So around 130 you're going to start seeing things like nausea, malaise, headache. As you start going down and getting more severe, hyponatremia, you're going to see certain things like neurologic impairment. So this could be balance problems, gait problems. We'll often see falls, especially in elderly patients. And then finally, when it gets really severe, we're talking like 120 and below, that's when we start seeing seizures, and it can progress to patient being completely comatose, having respiratory arrest, where the respiratory drive completely shuts down in the brain. And people can die from this. This is absolutely a very dangerous thing, that if they have very low sodium, like less than 120 they need to be in an ICU with very close monitoring, because of the drugs that we're using and the frequency of monitoring, both neurologic monitoring, but also laboratory monitoring. Dr. Khyati Patel 12:04 And so basically, the bottom line is, whenever you have sodium of less than 120 you want to take it very seriously, because the outcomes could be very grave, absolutely and so, going back to our discussion about drugs causing this issue. I always, as pharmacists love to pinpoint drugs as differential diagnosis for any trouble that patient is having. And so it's prudent that we talk about drug induced causes. And most common one is SSRIs. You know, causes about 1/3 of all, all the SI ADH issues. And so to name some of these agents are, you know, sertraline, escitalopram, citalopram, fluoxetine, paroxetine, as we kind of go back to our patient case. Hn, you remember the husband, kind of divulged that she is started on citalopram. She's sort of taking it for some anxiety a few weeks back Dr. Sean Kane 13:02 and again, thinking about typical textbook type questions, I would assume that most NAPLEX board review type questions, or even NAPLEX questions, they're probably going to trigger SSRI as the cause of SIADH. It's such a common link between the two, but there are other medications out there that are worth talking about. So carbamazepine and oxcarbazepine, these patients actually have to have routine serum sodium monitoring because of the concern of sidhh. Not my neck of the woods, because it's chemotherapy, but high dose cyclophosphamide, apparently the higher dose is associated with sidhh. And then there are a ton of other drugs that are implicated. And if you were to pull up a list, it's not as bad as Qt prolonging drug lists, but it's pretty extensive, just to name a few, really, any antidepressant, any anti convulsant, and the typical antipsychotics, these are all CNS acting medications. So generally speaking, you're probably pretty safe to assume that it may be implicated if it's a CNS oriented medication, and that kind of makes sense too, because ADH is secreted from a part of the brain. So if drugs are kind of accumulating in the brain and interacting with receptors in the brain, crossing the blood brain barrier, they're more likely to potentially interact with the hypothalamus and potentially alter ADH secretion. Dr. Khyati Patel 14:20 And so, Dr. Kane, you mentioned that these patients will need rigorous lab monitoring to what kind of lab do we usually go for, and what are we going to find in these labs? Dr. Sean Kane 14:31 So the first thing that needs to happen is checking the serum osmolality. And the reason for that is, if you go back to like a hyponatremia lecture, it gets really confusing here, but we need to know the tenacity of the blood to distinguish from hypotonic versus hypertonic blood. And in this case, in SIADH, we want to see hypotonicity. We want to see a plasma osmolality below 280 and if you think about it, the things in your blood that give you tenacity. Sodium is one of the most predominant things that gives you tenacity. So intuitively, you would say, well, if sodium is low, I would expect my tonicity to be low. Why would it ever not be low? And the reason that we check tonicity is that if you have a low sodium value, but your tenacity is not low, it means that something else is going on, and it's probably not SIADH; it's actually a pseudo hyponatremia, where the lab value is falsely low because of other things going on. Common examples would be really high triglycerides, like in the 1000s, a lot of proteins in your blood, like abnormally high amount of protein. And then also, probably the most common example, at least in the ICU, is DKA and HHS, where their serum glucoses are many hundreds, oftentimes more than 800 or 900 and all of these cases, the actual serum sodium is not low. It's actually normal. That's why we call it a pseudo hyponatremia. But it's a lab error, because of these other components in the blood that are altering the lab value itself, Dr. Khyati Patel 16:02 as we discussed earlier, this patients could not have whole lot of edema going on, so they would appear as that they're euvolemic, although, as we discussed earlier, Dr. Kane that this is not very easy to classify because patients may have other underlying comorbidities that could muddy this picture a little bit. Dr. Sean Kane 16:23 Yeah, and then the other thing would be urine studies. So I think it's important to note that there are literally, like eight guidelines for SIADH that are out there in the literature. So in terms of specific thresholds for diagnosis, there is some variability here, but generally speaking, the urine osmolality should be inappropriately high or too concentrated in someone with s ADH, typically, this is going to be in the many hundreds milliamse per kg, but a typical threshold would be more than 100 so we might see urine osmolality being 400 500 something like that in these patients. And then also we'll see inappropriately high amounts of sodium in the urine as well. Now, if you think about it, if you're a kidney, and you know that your serum sodium is 119 you're as a kidney, you're going to do whatever it takes to hold on to as much sodium as possible. So really, if there's more than 20 or 40 milli equivalents per liter of sodium in the urine, that's not appropriate. You should be holding on to more of that sodium. So again, with urine chemistries, we're looking at osmolality, more than 100 urine sodium, more than 20 to 40. But oftentimes these will be even much higher than those values. Dr. Khyati Patel 17:31 And so this lays a pretty good background of what's considered normal and whatnot. And you know what should be looking out in terms of clinically evaluating the patient as well as, you know, laboratory evaluating the patients too. But let's dive into the treatment. And so the overview of the treatment, the bigger picture over here is that we're going to identify the secondary cause for si ADH, and try to remove that cause, or, you know, try to alleviate that cause. And so for our patient, for example, it would be appropriate to stop the newly started SSRI. Dr. Sean Kane 18:06 The number two is going to be more of a critical care type. Topic is decide whether this is acute hyponatremia, where they have neurologic manifestations of hyponatremia, or if it's severe hyponatremia, where their sodium is less than 120 which is a danger zone for seizures and other really life threatening complications. So if they have altered mental status, seizures sodium is less than 120 then in the first several hours, your management is actually focused on rapidly correcting their sodium by up to six milli equivalents per liter, so that you can avoid those neurologic complications that may arise from that acute or severe hyponatremia. Then once you deal with that, then obviously you'll transition over to the more chronic management of slowly getting them back to a fairly normal sodium value over a period of several days. Dr. Khyati Patel 18:55 And so from here on, we can probably talk about the treatment in terms of that acute, severe version versus kind of like what happens after that acute treatment is done and patient is not in that danger zone, per to say. And so starting out with the acute or severe presentation, as you mentioned, Dr. Kane, you know, this is where patients would have neurologic changes. Maybe they're having seizures, or their sodium is less than 120 if we kind of relate this back to our patient, her sodium was 119 and she did have altered mental status, and she did have a fall, we know that that's what probably caused her hyponatremia, in addition to her being on obviously, the citalopram is the new therapy. And so again, the in depth. Discussion about this treatment is probably beyond the podcast the scope, but the bottom line is that we treat this acute hyponatremia with the concentrated sodium chloride, the 3% hypertonic saline solution. Dr. Sean Kane 19:56 And for this a typical dose is going to be a 100 ml bolus. Dose of 3% hypertonic saline, and this is going to be given over 10 to 20 minutes, and then basically give a dose, and then you wait a little bit and assess for neurologic changes in terms of them improving, you'll likely get a follow up lab value in an hour or two. And depending on what you see, again, it's beyond the scope of today's podcast, but you may give up to three total doses. So 300 mls of this 3% hypertonic saline bolus, with the overall goal in the first six hours, we want to correct that serum sodium in terms of increase that serum sodium by about four to six milli equivalents per liter in that first six hour period, usually changing it that small amount. So if they're at 119 getting them no more than 125 is kind of our therapeutic goal, and that typically is enough to avoid some of the really serious complications of hyponatremia, like seizures, herniation, things like that. We don't want to correct it too quickly, but we want to move them up enough that we can avoid some of these acute problems that happen with very severe hyponatremia. Dr. Khyati Patel 21:03 And obviously, as you mentioned, Dr. Kane, those patients will be under ICU care. They're going to get frequent sodium tracts for at least first day or two, while the therapy is going and while they're getting stable, exactly. Dr. Sean Kane 21:17 And during that time, really, that's it for the acute management. It's not going to fix all of the patient's symptoms, and it won't, certainly won't fix their serum sodium back to a normal level, but it gets the ball rolling. And then, really after that comes the still a hospital, but non acute management of their hyponatremia, getting them back to normal in terms of their Dr. Khyati Patel 21:39 sidh, right? So again, going back to what we discussed about identifying the secondary causes and removing it or alleviating it, it'll be better. And then something that you mentioned earlier, Dr. Kane about the acute treatment, that we don't want to raise the sodium too quickly. What happens if we do that? Why can't we just load them up with the 3% hypertonic saline? Yeah. Dr. Sean Kane 22:01 So what happens is that your brain cells, because of the blood brain barrier, are slower to react to acute changes of really any electrolyte, including sodium. So if we dramatically change your serum sodium and make it higher, what will happen is the brain sodium. Let's say that your blood and brain are at 119 and then we dramatically change your serum to go to 130 now, all of the water in your brain cells are going to leave the brain and go into your blood to help, you know, dilute down that higher sodium level through osmosis. But it turns out your brain cells need that water, and we have a problem with that, and that problem is called Central pontine myelinolysis, or CPM, and basically what happens is those brain cells get damaged and die because they don't have the water that they need because it's gone out back into your blood because of that osmotic gradient. Dr. Khyati Patel 22:52 So this sounds like a really big deal that we make sure we don't increase the serum concentration of the sodium more than six mil equivalent per the first six hours, Dr. Sean Kane 23:04 yeah, and then beyond that. It really depends on what guideline you look at. The historic textbook answer here is that you don't change serum sodium more than eight to 12 mil equivalents per liter per day in the first day, and then no more than 18 over a two day period, depending on who you talk to, there are some sources that are a little bit more conservative, suggesting closer to no more than six to eight milk equivalents per day of change period, no more than that. Dr. Khyati Patel 23:31 And so let's say a patient came in, the serum sodium was 123 you know, they weren't having this acute or severe presentation, but they do have what we call it, si ADH. What will be that first line therapy in that scenario? Dr. Sean Kane 23:48 So again, first line is going to be figure out why they have it and stop the cause, especially if it's a drug induced cause. Obviously, if they have lung cancer, there's not a lot you can do about that, but if they recently started taking a new drug, especially like an SSRI, you're going to stop that even though you could potentially be worried about withdrawal syndrome. In this case, the risks of continuing that SSRI are almost always going to outweigh the benefits that that drug is giving you. Dr. Khyati Patel 24:13 And as far as the therapy, therapy goes, after removing that underlying cause would be fluid restriction. And for that, some reason, sounds really exciting. Dr. Kane, Dr. Sean Kane 24:24 so one thing is, when you think about sidh, you learn this really neat pathophysiology, and you're kind of waiting for this miracle drug, and it turns out that we just make the patients not drink as much fluid, and that, honestly is the mainstay of therapy for the vast majority of patients, there's no cool equation in terms of how much they're going to drink or not drink. There's no cool drug really, that is a first line therapy. Patients don't really like this that much, to be honest with you, so we're going to restrict them to about one to 1.5 liters per day of both oral and IV fluid intake. Or we can also look at a. Way and say that we want the patient to pee out 500 mls more than whatever they took in. And unfortunately, patients don't like this, because they get thirsty, and then we don't let them drink water, and it takes several days, really, for sodium to approach normal levels using this strategy. So nobody's excited to do this. It's not comfortable, but it is the safest and most effective therapy that we offer for these patients. To kind Dr. Khyati Patel 25:25 of put it in perspective to those who have heart failure, you know, generally, I mean, it's individualized, but generally, we look out for like that two liter per day restriction. And so this one to 1.5 liter per day sounds a little too extreme, and so I can tell why patients don't like Dr. Sean Kane 25:40 it absolutely. And really the next therapy, Dr. Patel, is actually a thing to not do, and the thing to not do in SIADH patients is you do not give them point 9% sodium chloride or normal saline. The reason is that it can actually make their hyponatremia worse. And this is actually counterintuitive, because normal saline has 154 milk equivalents per liter of sodium in it. So, you know, when you give this to most patients, it actually makes them hypernatremic, which is why, intuitively, you'd think that this would be a good idea, but it can actually worsen their SIADH. Dr. Khyati Patel 26:13 And why? Why Does that really happen? Because, I mean, it just makes sense that, hey, there's water, it has sodium in it. We're gonna just supplement this, you know, to the patient. Dr. Sean Kane 26:23 So it turns out the SIADH, they have a problem in managing water, but they don't have a problem managing salt. So at the kidney level, what happens is they will pee out most of the sodium from that normal saline bag, but they will retain a lot of the water. So the net effect is that they pee out more sodium than the amount of water that they took in. So the net is that they have more free water that they retain because they got rid of the sodium that you just gave them. So that is why their hyponatremia worsens, is that they don't get that much sodium and they get some free water to go along with it. Really, the key here is that these patients need to have an IV fluid that has an osmolality that is exceeding whatever their urine osmolality is. So normal saline osmolality is around 300 and typically in SIADH, we're looking at an osmolality of 400 500 something like that. Dr. Khyati Patel 27:18 And so we're gonna probably resort to like that 3% you know, hypertonic solution, which has the osmolality of, you know, about 1000 1027 that would probably help fix the problem exactly. Dr. Sean Kane 27:33 So if fluid restriction isn't working, and we have to go to kind of the next step. The next step would be giving them 3% sodium chloride, typical dose is around point five to two milliliters per kilogram per hour. That's a pretty big range. Another way to look at it is for 3% the math would be different if you're using a different concentration. But if you take their body weight in kilograms times the amount of change per hour that you want their sodium to change by that's going to tell you the rate that you want. So for example, for an 80 kilo patient, if you want their serum sodium to change by 0.5 80 times 0.5 is 40 milliliters per hour. So if you hang that 3% sodium chloride at 40 ml an hour on that 80 kilo patient, that means that every hour, their serum sodium will increase by 0.5 Dr. Khyati Patel 28:23 and in these patients, you know, sometimes they'll, they'll need that IV loop diuretic if they start to have, you know, hypervolemia. So the diuretic, like furosemide, it's going to help patients just get rid of that fluid volume. And this, this really is not needed for most patient, but if they have underlying conditions like heart failure or cirrhosis, which we know are conditions that increase that edema to begin with, then that might be necessary. Now. Dr. Sean Kane 28:51 Dr. Patel earlier, we talked about how fluid restriction is our first line therapy, and it isn't this like sexy, awesome, really targeted therapy for SIADH, we actually do have that sexy, awesome targeted therapy in SIADH, but we don't use it very often, and that drug class is called the vaptans. And the vast, vast, vast majority of patients will not need a vaptan. Instead, they'll do fine with fluid restriction, stopping the drug induced cause, and maybe giving 3% sodium chloride. Dr. Khyati Patel 29:21 And as we dive more into like what these vaptans are, become more clear as to why most patients don't need to go on this. But in general, vaptans are our v2 receptor antagonists. Remember, our ADH goes to the kidney and that late distal tibule and collecting duct and agonizes the v2 receptor. Vaptans are basically doing the opposite of that, and producing aquaresis, which is where pure water loss is induced into the urine. Dr. Sean Kane 29:50 And unlike our fluid restriction, this takes effect within hours, and it lasts all day. You only have to dose the oral therapy once a day. So in theory. These vaptans sound like the perfect therapy for SIADH, there are two vaptans on the market. We have tolvaptan (Samsca), that's a once daily tablet orally. And we also have a continuous IV infusion called conivaptan (Vaprisol). So we have IV, we have po we have a perfect mechanism that links directly back to our pathophysiology. Dr. Patel, what is not to love about the vaptan drug class? Dr. Khyati Patel 30:24 Well, so because they work so well, there is a box warning for them causing the opposite, which is the hypernatremia. And as we know, there is the consequences of causing the CPM if we over correct the sodium too quickly. Yeah. Dr. Sean Kane 30:43 So again, when you initiate a vaptan, just like with 3% you're going to be very frequently monitoring serum sodium, probably every four to six hours, if not more often, at least in the first day or two, and then after that, you know, several times a day, because these vaptans are so potent, you really should not use them immediately after giving 3% sodium chloride, you want to see what the effect of that hypertonic saline is. And then probably the most important counseling point with this is when you see a patient receiving a new start, vaptan, they should not be fluid restricted for the first day or two days. You should allow them to drink as much as they want. And the reason for that is that if you fluid restrict them, plus give them the vaptan, the amount of sodium change that they will have will almost certainly exceed what you want them to have. And then again, you're at risk for too rapidly correcting their serum sodium. Dr. Khyati Patel 31:36 And so Dr. Kane, I don't deal with vaptans in my you know, chronic practice and disease management area, but in the hospital setting, if you were to use the, let's say po tolvaptan (Samsca), what kind of dosing would we consider? We consider if they work really, really well. Dr. Sean Kane 31:55 So if you look at the package insert, it says 15 milligrams a day on day one, and then it can go all the way up to 60 milligrams, in my experience, usually will actually give half of an initial dose, which would be 7.5 milligrams, and kind of reassess at that point. You can always give more. But what you don't want to have happen is that their serum sodium overly corrects, and then you have to start something like giving them extra water or even D 5w IV infusion, because you over corrected. Now you're trying to play catch up and avoid some of those complications of over correction, Dr. Khyati Patel 32:26 makes sense. And so as we would expect, these drugs are going to cause more thirst, dry mouth and urination. And so these are kind of like the common side effects patients will report. Dr. Sean Kane 32:38 And you know, another thing about these, in terms of side effects, is actually hepatotaxicity. So again, usually for sidh, we're giving several doses in the hospital setting, but these do have a warning that you should not exceed 30 days because of the risk of hepatotoxicity. In addition to that, these are also drug interactors. So these are 3A4 substrates, so they're susceptible to drug interactions, but also they are 3A4 inhibitors, so they cause drug interactions as well. So we do have some issues in terms of why these are not core first line therapies for SIADH. Dr. Khyati Patel 33:11 And then, addition to that, you know, they're they're expensive. The average wholesale price is about $600 for one tablet. Obviously, you know, the actual cost will be lower, but that kind of goes back to the use of just half the dose. Dr. Kane, as you mentioned, that that helps to cut down the cost a little bit, exactly. Dr. Sean Kane 33:32 I mean, again, most patients are not going to be taking this for very long, so it makes sense that this would be pricier per tablet, because it's not a chronic med that a patient would take indefinitely, but still, $600 a tablet, that's pretty pricey, and something that really should be taken seriously in terms of who is going to initiate on the therapy. Dr. Khyati Patel 33:52 Basically, it's not for everyone that just like that. And then there are some other therapies that are not for everyone too. So what we talked about up until now are kind of like the common it's more like a streamlined prime line therapies, but you may hear or read in textbooks or literature additional drugs that have been used to correct Si, ADH, Dr. Sean Kane 34:15 so some examples of that. And again, this is more textbook. This is almost never done in clinical practice. There is a tetracycline derivative antibiotic called demeclocycline, and in about two thirds of patients it causes nephrogenic diabetes insipidus, where the kidney does not respond to ADH but that means that about a third of patients don't respond to it. It has a fairly delayed onset of action, so it's not even close to the onset of our vaptans. It takes about two weeks for sodium levels to get back to normal. And it's a tetracycline derivative, so you have to worry about photosensitivity. And compared to other tetracyclines, it also causes a little bit more nephrotoxicity as well. So generally, this is not used, but you'll definitely see it in textbooks. Dr. Khyati Patel 34:57 And the other drug that you may hear is. Lithium. Yes, I know lithium. It also causes nephrogenic diabetes insipidus in about 30% of the patient. So you can think in about 70% of the patient, it may not work to do what we intended it to do, but give all the lithium related side effects. So again, nephrotoxicity, hypothyroidism and hello. I mean, who wants to cause mood imbalances by giving lithium to patients just to correct their si ADH, Dr. Sean Kane 35:25 yeah, that sounds like a bad idea, that you're giving a drug for its side effect without really considering all of the other side effects that now the patient has to deal with because of that lithium that you're giving them. Dr. Khyati Patel 35:35 And this third one, Dr. Kane, was really surprising. We're talking about taking urea, urea, same stuff in your pee. Yeah, pretty much taking it orally, though. Dr. Sean Kane 35:46 Okay, so, yeah, with urea, the mechanism here is that you're giving a solute load to the patient, so they have to pee out the urea that you give them, and when they pee it out, water comes along with it, so it causes this solute diuresis, because the water is following that urea. There's also a secondary mechanism related to reducing the amount of sodium loss in the kidney as well, but its primary mechanism is that solute diuresis, Dr. Khyati Patel 36:10 something tells me that this does not taste good, no. Dr. Sean Kane 36:14 So it's available as a powder for solution, so you have to mix it with a liquid. It's actually a medical food, so it's not an FDA approved drug, and it tastes, apparently terrible, and nobody likes drinking it. On top of that, you're literally giving these patients urea. So bun levels usually increase, or they should increase. Typically, we're looking at bun doubling when you take this medication. So generally, this is not well tolerated, mostly because of palatability issues, but all of the other side effects and things like that. Really relegate all of these therapies, the tetracycline derivative lithium urea. Almost no one uses these, but you're still going to see them in a textbook, potentially exam questions and things like that, but not commonly done. Speaker 1 36:55 Yeah, we will probably just leave them in the textbook. We won't use them. Dr. Sean Kane 36:59 I agree. How about that? Well, why don't we go back to our patient case and just kind of wrap kind of wrap things up in terms of what would be a typical clinical course for that patient? So again, hn was our 74 year old female, SIADH with a sodium of 119 with some neuro changes. What are typical therapies that are going to happen for her doctor? Dr. Khyati Patel 37:16 Patel. So as we laid out, first thing for the goal of therapy is to identify underlying causes and remove it, right? We know she started her citalopram because of anxiety. We covered that they are causing si IDH in 1/3 of the cases. That's most likely the cause, and so we're probably going to stop her SSRI. Obviously, we're going to look for other options to help control her anxiety, but for now, we're going to stop this one, Dr. Sean Kane 37:41 and because she did have neuro changes, and she would be classified as severe hyponatremia with a sodium less than 120 she will get at least 100 mls of 3% sodium chloride or hypertonic saline in the emergency department. Again, we don't want to change her serum sodium by more than about six within the first six hours, potentially even within the first day if she clinically improves with that. If her sodium isn't improving, or her clinical symptoms are not improving, we could potentially give up to three total doses of the 100 mls hypertonic saline. Dr. Khyati Patel 38:12 And once that's done, then the gold standard therapy of fluid restriction is what will come in place. So we were talking about one to 1.5 liter per day of fluid. Obviously, if fluid restriction doesn't work, then we can repeat the 3% sodium chloride infusion one more time, Dr. Sean Kane 38:30 and then again, the vaptan sound like a great drug category, but because of cost, side effects, things like that, really the only scenario where she could potentially receive a vaptan is that if she's refractory to fluid restriction and more 3% sodium chloride, that would be a very rare circumstance where she would qualify for that. Dr. Khyati Patel 38:49 So I think that wraps up the episode of SIADH really well, Dr. Kane, we have a few points to kind of lay out as a key concept. And so just understanding the pathophysiology. You know, SIADH causes hyponatremia. It causes it by making the body to reabsorb too much water, and so leads to too little water in the urine, and leaves the urine concentrated and the you know, the pathophysiology, the core issue is not really a sodium issue, but a water issue that leads to a sodium issue, Dr. Sean Kane 39:24 number two is going to be the SSRIs are the most common drug induced cause of SIADH. There are a number of other CNS acting medications, but SSRIs are going to be the textbook example here, Dr. Khyati Patel 39:35 and in the acute or severe cases where you have very low levels and patient is presenting with, you know, altered CNS status, 3% sodium chloride. The hypertonic saline is going to be the quickest way to increase the sodium. We want to make sure we don't do this too quickly. And our goal will be about six milli equivalent per liter, even within the first six hours, potentially within that first. 24 hours to avoid any kind of acute neurologic complications. Dr. Sean Kane 40:04 And then finally, fluid restriction is our first line therapy for these patients. It's going to take several days for sodium to get back to that normal range, so we have to be patient, and typically around one to 1.5 liters per day is what we're looking at for that fluid restriction. So I think that wraps up today's episode nicely. We do have a couple references that are review articles if you're interested. Those are available at our website, HelixTalk.com Again, this is episode 120 we're also on Twitter at HelixTalk, and we love the five star reviews in iTunes so that we can climb the rankings and other clinicians are more likely to find the podcast. So with that, I'm Dr. Kane Dr. Khyati Patel 40:40 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 40:44 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 40:55 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.