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 107 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is, you're going to go bananas over this brief review of hyperkalemia. And in this episode, we're going to be covering some typical treatment approaches to both acute and chronic hyperkalemia. Speaker 1 00:49 So first and foremost, let's define what is hyperkalemia, right? It's sometimes all about the numbers. So talking about the serum potassium, generally above 5.5 millequivalent per liter would be considered elevated potassium or hyperkalemia, although institution specific thresholds are different. Sometimes I've seen some studies Dr. Kane, chronic hyperkalemia is defined as 5.1 and above. So it really depends on the institution, and Dr. Sean Kane 01:14 it probably also depends on your patient's renal function. As an example, where you might be less inclined to tolerate a slightly higher potassium level in someone with chronic kidney disease because they're more prone to getting that hyperkalemia, especially if you're titrating meds that will cause more hyperkalemia, Speaker 1 01:31 the thresholds for starting the treatment is a little bit higher. So yeah, we watch the potassium if it's, you know, 5.5 or 5.1 and above. But really, when it gets to the level where it surmounts to, some signs and symptoms are some of those higher levels, probably, I would say around six to seven milliequivalents per liter, and really bad is considered when it's above seven, yeah. Dr. Sean Kane 01:53 And I mean, this is a medical emergency, especially once it gets above seven. And it may be a medical emergency when that potassium level is in the sixth range, it kind of depends, again, on the patient, the acuity of it. Certain dialysis patients, as an example, may be able to tolerate more of this chronic hyperkalemia and be able to tolerate a slightly higher potassium level, versus someone who typically does not have hyperkalemia and now suddenly develops hyperkalemia Speaker 1 02:17 Absolutely And so talking about some of the signs and symptoms of the acute hyperkalemia. We're worried about the cardiac issues, talking about arrhythmias, like bradycardias or ventricular arrhythmias can happen. Dr. Sean Kane 02:30 And in terms of like the classic EKG findings, I think most pharmacy students know about peaked T waves, where the T waves are taller than they're supposed to be. And yes, that happens, although it's not a black and white issue. Of you'll always see that happening. Other EKG findings are basically get widening of stuff. So you'll get a widened PR interval, a widened QRS. As hyperkalemia progresses, you'll get a loss of P waves. But what's really important is that these are not incredibly specific and always seen in hyperkalemia patients. So you may find EKG changes, you may not and sometimes it's hard to tell if it's a true change or not. And in those cases, you know this is a data point among all of the other data points that we're looking at for that patient. Speaker 1 03:10 Yeah. But anytime you have a patient with cardiac abnormality, or we can correlate that the potassium in the lab is high and the EKG changes are happening like you described, then it almost always wants some sort of an intervention. Dr. Sean Kane 03:23 So in terms of why this happens, at least in the acute setting, the number one cause of hyperkalemia is acute kidney injury. We'll repeat that again. The number one cause of hyperkalemia is acute kidney injury in the acute setting. And the reason for that is that, literally, 80% of your body's potassium is excreted through your kidney, so when your kidney stops working as well, you're going to accumulate more of that potassium. Speaker 1 03:46 And this is very common within those patients who are taking the RAS agents. Basically, those are the ACE inhibitors, the ARBs, the RNA, the aldosterone antagonist, or even potassium sparing diuretics. Dr. Sean Kane 03:59 And of course, if someone's taking potassium, like a potassium supplement. A typical example might be that they're on lasix for heart failure plus potassium, and if that lasix is removed, meaning that they don't need that diuretic anymore, but the potassium stays. Potentially that could be a scenario where you'll see hyperkalemia induced by potassium. But the much more common scenario is going to be acute kidney injury, causing the patient's renal function to deteriorate to the point where they don't eliminate potassium as well. Speaker 1 04:27 And in certain cases, in the acute situation, severe acidosis is also associated with the acute hyperkalemia. And this has to do with that hydrogen ion and Potassium pump, where the hydrogen enters the cell and then the potassium basically gets out of the cell. So now you have the intracellular potassium, which is much higher than your extracellular coming out in the extracellular space. Dr. Sean Kane 04:49 And we'll see this in someone with, like, very profound metabolic acidosis, where their PH is 6.9 because they have a high lactic acid level, or some other meta. Like acidosis, and really, if you can fix that acidosis, you can shift that potassium back into the cells. But again, this is a fairly rare circumstance for acute hyperkalemia. The much more common scenario is acute kidney injury causing hyperkalemia, right? Speaker 1 05:14 So talking about the causes and how patients would present, let's talk about what are some of the treatment options for these acute cases. Dr. Sean Kane 05:22 So the number one treatment is stop the thing that caused it. So if they have any nephrotoxins or things that cause acute kidney injury, then we should remove those and not give them back to the patient. Classic examples are going to be NSAIDs, Aces, ARBs, arnies, aldosterone antagonists, diuretics, things like that. Speaker 1 05:39 And that's a no brainer, right? You want to obviously stop the precipitating causes. But let's say you did that and the potassium is still high, or they're still showing the cardiac changes. Dr. Sean Kane 05:50 Well, as much of a no brainer it is of to stop the precipitating cause, I would argue it's not a no brainer what the number one treatment is. So the number one treatment for acute hyperkalemia is calcium. It is not any of the other strategies to get rid of potassium in the body. It's actually giving calcium. And the reason for that is that calcium is going to stabilize the myocardium to prevent cardiac arrhythmias, and that's really what's the life threatening complication of acute hyperkalemia. So the calcium will make it so arrhythmias are less likely, and that is a huge benefit, and that's why this is the number one treatment, is IV calcium for these patients. Speaker 1 06:28 So you're saying, Dr. Kane, that calcium is almost like the protective factors for the heart, the myocardium. It doesn't really necessarily do anything to the amount of potassium in the body, it just helps stabilize the membrane Dr. Sean Kane 06:42 absolutely correct. And that's why this is an easy one to forget. Because when we think about a patient with hyperkalemia, we always think about, how do we get that number better? And in this case, the calcium has no impact on your serum potassium at all. The impact is preventing those arrhythmias. Speaker 1 06:57 And there's about a couple different ways we can give the calcium calcium gluconate IV and calcium chloride. Again, this is going to be given in the central IV form. Dr. Sean Kane 07:09 We would also give calcium chloride peripherally in someone who has a cardiac arrest, because we want to give a highly potent calcium very quickly for those patients. Really, the difference here is that calcium gluconate is not as damaging to the veins. Calcium Chloride causes plenty of phlebitis. And the other difference is that calcium gluconate is a third of the potency. So for every one gram of calcium chloride that you give, you'd have to give three grams of calcium gluconate in order to have the same amount of elemental calcium that you're giving the patient. In terms of dosing, if you look at a code cart, you're gonna find calcium chloride, because, again, calcium chloride is what we'd give in a code blue scenario, regardless of what the patient's IV access is. And that code card, you're going to find a one gram pre filled syringe of calcium chloride. So theoretically, if you were giving the equivalent of that, you'd be giving three grams of calcium gluconate. And you will see that in the literature, you'll also just see people giving a gram of calcium gluconate for a non Code Blue scenario at the end of the day, we actually don't know what is the optimal dose of calcium for these patients, as long as we appreciate that there is a difference between these two dosage forms and that there is not one best answer, just knowing what our dosage forms are and why you might give one over the other, I think is the important thing here, and Speaker 1 08:19 I guess the time with which you deliver this doses, it's also important, and it depends on whether you're looking at Code Blue versus non. Code blue situation, absolutely. Dr. Sean Kane 08:30 So again, in a code blue scenario, you don't have the luxury of time to, you know, slowly infuse that calcium over five to 15 minutes. So in a code blue scenario, you're gonna give that calcium chloride IV push. You're going to ignore the risk of phlebitis and just give it in a non Code Blue scenario, where you have the luxury of time to some extent, even though this is still a medical emergency, you're going to put it in an IV bag and infuse that bag over five to 15 minutes. And again, the reason for that is you want to give it quickly. Normally, we wouldn't give it that quickly, just if we're repleting Calcium, but we want to give it quickly enough that we can hopefully stabilize that myocardium as soon as possible. Speaker 1 09:05 And once it starts to work, it lasts for about 30 to 60 minutes. So think about this, if you're if you haven't removed the total body potassium yet, you might have to redose this in order to keep that myocardium at stable pace, Dr. Sean Kane 09:19 exactly, really beyond that, all of our other therapies are targeting potassium in terms of redistributing the potassium, or, in fact, getting rid of the potassium. The next most common therapy that is given for acute hyperkalemia after calcium, is going to be IV insulin with IV push dextrose in terms of dosing. It kind of gets a little bit interesting here. Dr. Patel, so we're using IV regular insulin, which is the only insulin that you would ever give IV anyway. But what's interesting is that we're giving the insulin regardless of what your serum glucose is, so we are able to actually redistribute potassium from your blood back into your cells regardless of what your serum glucose is. Dosing wise. Is a typical dose is going to be 10 units. However, for patients with renal impairment, we'll actually give half that. We'll give five units. And the reason for that is we see plenty of hypoglycemia, even when we give this with dextrose, that occurs several hours once that dextrose is gone, but the IV insulin still hangs around because of that renal impairment. Speaker 1 10:17 And so that's why almost always do the regular IV insulin along with the dextrose, this is going to be IV Dr. Sean Kane 10:24 push, yep. And just to clarify that dextrose is 50% dextrose, pre filled syringe, typically 25 grams or 50 mls of this pretty large dextrose vial. And really importantly, this insulin, we don't give it sub q. The reason we don't give it sub q and we give it IV is that we want it to work now. We don't want to wait for subcutaneous absorption, even though that's fairly quick. We want it to work right now, not in, you know, 10 to 15 minutes. Speaker 1 10:48 And in the case of regular insulin, as the listeners should know it, if you give subcue, it forms the hexamers, right? And that's why it takes about 30 minutes for it to start working. We don't have that time, so that's why we have to do IV in order for it to work start faster Dr. Sean Kane 11:00 and just for kind of clarity of what is actually going on on a kind of biochemistry standpoint, insulin will activate a pump called the sodium potassium ATPase pump, mostly in skeletal muscle. And by activating this pump, it draws potassium from your blood into the cells, and that is redistributing that potassium that now won't go to your heart cells and cause an arrhythmia instead. Yeah. Speaker 1 11:22 And so effect of this intervention will last for about four to six hours. Again, this is going to be very equivalent to how long the regular insulin functions in the body, which is about that Dr. Sean Kane 11:34 and again, that D 50 that you're giving the 50% dextrose, does not typically last four to six hours. And for that reason, we actually see a good amount of hypoglycemia, even when you're giving dextrose, even when you're reducing the dose to five units in a patient with renal impairment, we're looking at roughly about 10 to 20% incidence rate of hypoglycemia. So you definitely have to recheck blood glucose probably every one to two hours in these patients, and you need to be aware of this adverse effect and probably not redose them if their potassium is not moving in the direction you want, because you're probably going to cause hypoglycemia if you give them more Speaker 1 12:08 of this, it makes sense. The other agent we have in our playlist with shifting potassium back into the cell is albuterol. Usually we give it via the nebulizer route, so it will be 10 to 20 milligram nebulaized over about 10 minutes. Think about this dose, though, it's much higher dose than when we use it in asthma patient, we use maybe, like, what, 2.5 milligrams in the asthma patient. Again, we need this because it's an acute situation, and higher doses can work a little bit more effectively. Dr. Sean Kane 12:38 And for me, at least, I typically don't see this done as often. You'll definitely see it in the literature. I'm sure it's done in clinical practice that dose is so high, and if you think about why is it working beta two stimulation. So albuterol is a beta two agonist. Beta two stimulation causes a shift of potassium from the blood into cells. So we're using this adverse effect of albuterol to our benefit. The downside, though, is that excessive beta two stimulation is probably not good for the heart and in someone who is at risk for arrhythmias, my personal bias is that I'm not excited to give them four to eight times the typical dose of albuterol and potentially increase the risk of arrhythmias in these patients by over stimulating the beta receptor. Speaker 1 13:18 And just think about all that Albury causing the jitteriness, right? You'll be shaking off the, you know, patient bed. Dr. Sean Kane 13:25 Our third agent that we can use to redistribute potassium is sodium bicarbonate, and this is really only restricted to that kind of nuanced patient that has severe metabolic acidosis. And the acidosis is what is driving that hyperkalemia. Really. The intent here is, if you fix the acidosis, you can potentially shift that potassium back into the cell. In terms of how you would give this. You know, we do have pre filled syringes of sodium bicarbonate. It's 50 ml equivalents in one syringe. You might give one or two of those. You could also potentially select this preferentially as an IV fluid option for patients that do need IV fluid, which is not uncommon in like a pre renal, acute kidney injury type patient, we're basically put in 150 mEq of that sodium bicarb into a liter bag of D5W Long story short, this is relatively controversial. We don't have a lot of data supporting this, helping with acute hyperkalemia, but we do know that acidosis can worsen hyperkalemia, so most of these patients with very severe metabolic acidosis may need bicarb anyway, so we might just kind of cover two birds with one stone in terms of saying we can fix the acidosis or help the acidosis, and it may or may not help with the hyperkalemia as well. Speaker 1 14:34 Yeah, and I think that's what I discovered when it talked about using po bicarb, which we'll talk about, you know, using the chronic hyperkalemia as well, is that it may not fix the hyperkalemia, but it may help fix the acidosis portion of it. Dr. Sean Kane 14:48 Now, really, up to this point, we haven't talked about getting rid of potassium, and many of these patients do have too much total body potassium. We've protected the myocardium with calcium. We've redistributed the potassium into the. Cell. But again, that we haven't gotten rid of it, the three final agents are focused on getting rid of total body potassium, and the one that is kind of the most obvious one is a loop diuretic, so something like 40 milligrams of IV, Furosemide or lasix. This basically makes it so that the kidney wastes electrolytes, including potassium. The problem, though, is that this only works if you pee. Many of these patients have acute kidney injury causing their hyperkalemia. Many of those acute kidney injury patients are oliguric, where they don't produce urine, so you may or may not be able to get any benefit out of an IV dose of lasix for these patients, and if they don't pee, they're not going to get rid of that potassium, and this won't be very effective. Speaker 1 15:39 And the other option in those patients, and could be dialysis. So basically, you know, hook them up to a dialysis machine, and it's going to basically remove, filter out the body's, you know, blood, and take, get rid of the potassium. The only issue here is that we have to worry about putting in the catheter and getting the consult from the nephrologist, and this may take a little bit of time, so we have to consider some time sensitive option as well. Dr. Sean Kane 16:06 Really, the only way that this could potentially be a little bit quicker is in a patient who already is a dialysis patient that already has a dialysis catheter or a fistula, where they already have access, and they already have a known nephrologist that knows about their case and things like that. But even in those situations, you're still looking at several hours from start to finish in terms of getting dialysis started on that patient. So you still do need to do the other therapies that we've talked about as a temporizing measure until dialysis can be initiated. Speaker 1 16:32 And last but not the least, in our pocket, we have the cation exchanger, or sometimes we like to call them the potassium binders or raisins. And these are given basically there are raisins that sits in the gut, and they basically soak up the potassium in exchange of something other because that's why they are named cation exchangers. We've got three agents available. The oldest one that we have used in acute situations like this is the sodium polystyrene sulfonate (Kayexalate). It's probably the only potassium binder used in the acute situation because the other two are Veltassa (generic patiromer) or Lokelma (generic sodium zirconium cyclosilicate). They are fairly new in the market, so the SPS is not really used in the chronic situation as much as it's used in the acute situation. Dr. Sean Kane 17:19 What's unique about these is that, yes, they do have an acute effect on potassium, but they're not going to have an effect on potassium within, you know, an hour. These are going to be a longer term therapy. It probably doesn't hurt to give these agents, but it's also not going to do a lot in that very acute scenario where you have a patient with EKG changes with a potassium seven and a half that you can't get dialysis initiated, yet you do need to use these other therapies, in addition to considering a cation exchanger as well. Speaker 1 17:47 All right, so shifting the gears from acute hyperkalemia, let's talk a little bit about chronic hyperkalemia, and what really it is. It's very similar presentation as the acute hyperkalemia, although this is some with somebody who has consistently elevated potassium levels. So we immediately patients like CKD or ehrd come to mind who are potentially also on one of those RAS agents that they have to take because of the compelling indications. Dr. Sean Kane 18:14 Usually, this is going to be asymptomatic, just like with acute hyperkalemia. They can have some symptoms, muscle cramping, muscle weakness, really, they're not going to see kind of those emergent or urgent symptoms like EKG changes, unless they have a sudden change where their potassium goes from five and a half to now seven and a half. That's where it becomes an emergency, and you go back to that acute hyperkalemia protocol instead. Speaker 1 18:37 Yes, that's absolutely right. So acute on chronic issues can be managed just as like the acute hyperkalemia. The treatment for the acute hyperkalemia we talked about, Dr. Kane, you said, remove the precipitating factor like, let's talk about some of the causes or radiology of the chronic hyperkalemia. So as we talked about certain diseases like CKD or other conditions that results into aldosterone unresponsiveness, such as sickle cell anemia, lupus, Amyloidosis can cause it, but CKD stands out the most, and this is again, because it's kidney's inability to excrete the potassium from the body, because of the pool filtration and redistribution of potassium into the extracellular space, that those are The two biggest mechanism happening. And as the patient progresses through various stages of CKD. So going from stage one until stage five, which is basically end stage renal disease, the risk of hyperkalemia just exponentially increases. And as the risk of hyperkalemia increases, so does the associated morbidities of the CKD increase as well. Dr. Sean Kane 19:39 We've already kind of covered the medications, but just again, to review, we have RAS agents that will increase potassium. These are ACE inhibitors, angiotensin receptor blockers or ARBs, direct renin inhibitors like aliskiren (Tekturna), aldosterone antagonists like spironolactone or eplerenone, and then the ARNI drug class, like Entresto (sacubitril/valsartan). All of these are working at some point in that renin–angiotensin–aldosterone system. Blockade of that system is responsible for causing an increase in potassium. Speaker 1 20:09 Yeah, and think about chronicity of the use when we talk about medication induced, you know, chronic hyperkalemia. So NSAIDs, we talked about how they could be associated with acute hyperkalemia. But somebody who's taking NSAIDs, you know, on a regular basis, outpatient, it can also result into decreased urinary potassium excretion. And as we also talked about, in somebody who is taking potassium supplements, where probably they don't need to anymore, they need to dose adjust, or completely stop it, it can result into it too. Dr. Sean Kane 20:38 Of course, we have dietary sources of potassium, bananas is the main thing that people think about. It's like a medium sized banana gives you about 10 mil equivalents, or, you know, one cater tablet worth of potassium. But there's a lot of other dietary sources of potassium that aren't bananas as well. Speaker 1 20:54 Yeah, think about green leafy vegetables, your dried fruits, like apricots, dates, grapefruit, some citrus fruits, melons, potatoes, both regular and sweet potatoes, coconuts, beets and some of the unusual sources that we don't think about are things such as iced coffee, who knew right, or milkshakes and fruit juices or salt substitutes, right? We have a lot of these patients who are using the RAS agents. Arni agents are patients who have high blood pressure or CHF, and they're asked to limit their sodium. Well, they go out in the market and will buy salt substitute Well, guess what the salt substitutes will have? They'll have potassium, if not sodium in it, right? So this, these are really good sources that can increase potassium. We have to be careful, though, the dietary intake in itself does not result into chronic hyperkalemia. These are usually in combination with either them having CKD or them using one of these medications that can increase the potassium levels. The dietary potassium is mostly absorbed when consumed, but 90% of the time it's really excreted. So this really drives the point, it's something has to be wrong with the kidneys for it to not excrete the way it's supposed to. Dr. Sean Kane 22:06 So in terms of treatment, no surprise, the number one treatment for chronic hyperkalemia is to figure out why they're hyperkalemic and fix the underlying cause. This could be a dietary change. Could be that if they're on a potassium supplement that you get rid of it, you do some dose adjustment, you have some change of their chronic medications like NSAIDs or RAs agents, potentially could mean that you get rid of them entirely. It could be that you hold them for some period of time and then resume them at a lower dose. Kind of depends on why they're taking it and what other alternative options you have. Speaker 1 22:35 And I think that's becoming the biggest debate. Right? We talked about how patients with CKD, as they advance in their stages, the risk of hyperkalemia increases, and so do the morbidities of the CKD. Now we know that, you know, some of the RAAS agents, such as ACEIs and ARBs, are very useful in patients with CKD to help mitigate that proteinuria. So we have that clinical indication that's warranted, that we use these agents, if we can continue patients on the RAS agents at the doses that they're supposed to be on, that's a good thing with the lack of available agents to create hyperkalemia. And the outpatient setting, we used to typically go with the approach of either temporary hold it or decrease the dose. Obviously, in the acute situation, you're going to temporary hold the doses of these agents, and then come back to think about whether you want to start with the lower dose or start at the initial dose. And starting at the initial dose, most clinicians probably would not be comfortable with even though, clinically, for example, patients who have heart failure, they need to be on a certain doses of ACE inhibitor, right and certain doses of ARBs too, that may not happen. So that was the concern, and hopefully, with the some of the newer agents available, the clinicians are now feeling a little bit more comfortable continuing these therapy at the right doses, also treating hyperkalemia with other agents. Dr. Sean Kane 23:55 And those other agents are going to be those cation exchangers. So exactly we talked about sodium polystyrene sulfonate (Kayexalate). This is more common on the acute setting, just because it's been around for a long time and cost reasons, it's given orally or rectally. If a patient can't take orally, works a little bit slower if you give it orally, onset is roughly two hours, versus rectally is about one hour. And again, this is more for that acute setting, not as common in the chronic setting. It's kind of gotten a little bit of a bad rap because of concerns about intestinal ischemia, and that may be one of the drivers for some of these other cation exchangers that are now in the market that are fairly new. Speaker 1 24:30 Yes, exactly. And even though, when we talk about the onset differences between po and, you know, PR administration, we don't really have that confirmed time to normal cleana. So again, this is going to be patient specific. How high is the potassium, how well functioning their kidneys are, you know, etc, etc. So it's a little bit different response. It's not very predictable response. And so with the hope, hope is that with the new agents develop that are in the same category. And. May get to see some definite and predictable answers. And this first one is patiromer, brand name Veltassa. Again, this is not studied in acute hyperkalemia settings, so it's only approved for chronic hyperkalemia. And what it does is, again, it's a raisin, it's a cation exchanger, but exchanges for the calcium in the gut. It's taken by Po. It starts to work seven hours after giving the first dose, and the time to normalkalemia, or eukalemia, is about seven days. So give or take a week. So like you said earlier, some of these measures even take a long time to stabilize the potassium. And if you think Dr. Sean Kane 25:36 about it, if you have someone who has systolic heart failure who can't tolerate an ACE inhibitor because of hyperkalemia, that's a mortality benefit in therapy in a systolic heart failure patient. So potentially, if you could give them patiromer or Veltassa to allow them to have that target dose of their ACE inhibitor and have that mortality benefit, this could potentially be a win for a patient, as long as cost was appropriate for that patient's individual circumstance Speaker 1 26:01 cost, and then think about the side effects in step two that we will cover. So usually, this one started, you know, once daily, 8.4 grams, and it's increased up to 25.2 grams, depending on, you know, your serum potassium level goals. The evidence for Veltassa or the patiromer comes from a couple different trials. We have a phase two open label trial and a phase three randomized control trial that was done basically in similar patient population where they were CKD, so eGFR of 15 to 59 had mild to moderate hyperkalemia. So we're looking at 5.1 to 6.4 and some of most of these agents were on some of these RAS agents, whether they were on ACE inhibitors ARB or the aldosterone antagonist. So they looked at efficacy of these drugs and presence of these RAS agents. Maybe different doses of pet humor were kind of evaluated in both of these trials. So looking at the open label phase two trials at four weeks, the difference in potassium was anywhere between point three five to point five, five. This was in patients who had mild hyperkalemia. In those patients who had moderate hyperkalemia, we saw reduction to a little bit larger level, so almost to one equivalent per per liter. Dr. Sean Kane 27:18 So what you're saying is that by taking this agent, if your hyperkalemia is not terrible, so your let's say a potassium of five and a half. If you take this agent at four weeks, your potassium is going to drop by roughly about point four. And if you take this agent and you have a much higher potassium, let's say 6.4 it should drop you almost a full milk equivalent per Speaker 1 27:38 liter, perhaps. And in this trial too, they looked at long term outcome at 52 weeks, they found the patients who were remain on patiromer Veltassa against the placebo. Those who remain on Veltassa, their potassium remained within the normal limit compared to those with placebo. The other trial was the phase three trial, which was a randomized control trial, and this showed at four weeks, the average reduction in potassium was about that one milliquivalent per liter. They also did further eight week randomization, and found that potassium remained the same in patients who were on the active treatment group, versus an increase by point seven milli equivalents in those who were taking placebo. Dr. Sean Kane 28:20 And it looks like in that study, most of the potassium decline happened over the first three days. And once you stop therapy, it kind of goes back to where it was after about three days. So we'll call it steady state in three days for this agent. Speaker 1 28:31 Yeah, that sounds like fair idea. Yeah. So these were the efficacy outcomes and how fast it started to work. And you know, how much it lowered the potassium by et cetera, et cetera. This, again, it's looking at purely the numbers. This is not looking at some of the other outcomes, such as if they had any cardiac issues, or, you know, where there were these agents were able to prevent that safety issues on the other side, the most common one, again, this is common with any cation exchanger, is constipation to anywhere between 6.8 to 11% between the two different studies and hypomagnesemia, interestingly enough, was also very common. Some cases of severe hypomagnesemia where the level was 1.4 or below were also noted. Dr. Sean Kane 29:12 And that may not be that surprising if it's also exchanging with magnesium in addition to potassium within the gut. And it should be noted that this was in comparison to placebo, right? Dr. Patel and not kaxley. Speaker 1 29:23 Oh, that is correct. These agents were both the studies studied patiromer against placebo, and Dr. Sean Kane 29:29 it sounds like they also did not include dialysis patients in either of these studies, because the minimum eGFR was 15, so no data on dialysis patients. Speaker 1 29:38 That's correct. That's correct. And also in both of these studies, they did not ask patients to be on the, you know, the low potassium diet that is usually the measure that we take in clinical practice. And none of these trials really reported use of diuretics, which we know can be used in help controlling hyperkalemia. Dr. Sean Kane 29:59 So then our. Or agent that is fairly new to the market is sodium zirconium, cyclo silicate, or low calma. This was approved in 2018 for both acute and chronic hyperkalemia, and this exchanges sodium and a hydrogen in exchange for that potassium. Speaker 1 30:15 Yeah, it starts to work fairly quickly, I would say quickest among the three cation exchanger exchangers that we talked about about one hour post the first dose and time to normal callemia can be as fast as about 24 hours. For most patients, about 84% of the patients responded within 24 hours Dr. Sean Kane 30:35 terms of dosing. So it's 10 grams orally tid for up to 48 hours, and then after that, it's 10 grams daily. You basically titrate the dose based on the potassium level of the patient. Speaker 1 30:46 Yeah, and the data for low Calma comes from two different randomized control trials we have harmonized, which included about 250 patients. Again, these were also patients who had CKD, who were on one of those raas agents, and who were defined to have hyperkalemia anywhere about 5.1 Interestingly enough, this also included patients who had some comorbidities, such as diabetes and CHF, where these patients are normally going to be using these raas agents for additional benefits. They had to do the 48 hour open Run in because you have to take the doses in a higher quantity, and then they randomized it against placebo, and then three different doses for four weeks. So basically, efficacy at four weeks, they found dose dependence, statistically significant reduction in potassium minute compared to placebo. So different doses of low Calma resulted into reduction up to 4.4 4.5 and 4.8 versus 5.1 in Dr. Sean Kane 31:44 terms of safety. So this does have a sodium component to it, so the patient is going to get sodium as a result of that, as it exchanges with potassium. So in the higher doses, we saw some edema. So at 10 and 15 gram doses, we saw six and 14% incidence rates of edema versus placebo was only 2% so that's something that could be relevant for, like a heart failure patient as an example. Speaker 1 32:05 That's true, they didn't directly study but they did a subgroup analysis for the 87 patients who had a heart failure in this trial, and found that eight patients with the treatment agent had edema versus only one patient with placebo had that. So that could be significant. And we have to be careful in patients with CHF. There was another study that was done in maybe a little bit larger patient population. We're looking at about 750 patients. There was a defined hyperkalemia range. It was anywhere between five to six and a half. Again. They also did the same thing 48 hour open label run in and then randomizations for four different dose ranges, and they were looking at two week randomization, found that sustained potassium reduction happened with the five and the 10 milligram doses and not with the lower doses. So this is more of a dose comparative study. I mean, that's where we were getting the recommendation of using either 510 or 15 gram doses going forward. Dr. Sean Kane 32:59 Then there was another study looking at 12 month open label trial, and this particular study, they had 88% of patients that were able to achieve potassium levels of five or less. 87% of patients were able to continue their RAS agents like ace or arbit, and 14% were able to initiate a RAS agent that couldn't take it beforehand. Speaker 1 33:21 That's absolutely right. And I think I like this outcome a little bit better, because this is more clinically meaningful outcome. Yes, we want to lower the potassium, that's the ultimate goal. But in addition to this agents, how are we able to use some of these therapies that are, you know, associated with mortality and morbidity benefits, such as the RAS agents? And so this is, this is a really good outcome that shows that some maybe we can continue this agents and continue them on the RAS agents. This agent, in particular, lo Come on, was studied in end stage renal dialysis patients. So the name of the study was dialyze. About 200 patients getting hemodialysis were randomized for eight weeks against placebo, and what they found is that the pre dialysis levels for potassium were better in those patients who were taking low Calma on chronic use during the last four weeks of the trial. But really we were looking for the interventions that needed to be taken in those who would have urgent who would have the need to reduce the potassium urgently. And this, this episodes happen very infrequently in both the groups, and therefore there was no statistical significant different noted. Dr. Sean Kane 34:29 So what you're saying then is that this would not be a routine agent given dialysis patients to prevent acute hyperkalemia from occurring in the future, just because it's rare enough that you'd probably have to have a very large trial to be able to detect that Speaker 1 34:41 difference, absolutely right? Yeah, some general points to keep in mind when it comes to cation exchangers, that we have some rare but fatal side effects, as you mentioned, Dr. Kane earlier, is the intestinal necrosis or colonic necrosis that have been reported. We do have some drug interaction concerns that we have to keep in mind to these. These agents are sitting in the gut, absorbing potassium. They can absorb other drugs too. And so for patiromer, this is significantly documented that it has interaction with ciprofloxacin, metformin and thyroid supplements, and the recommendation is to separate patiromer either three hours before or after. And the same thing with Lokelma should be separated two hours before or after. Fairly new agents, we might see more drug interaction data, you know, populating. But the three agents we mentioned with pateromer are somewhat established drug interactions. So we talked about, you know, all these different trials and looked at, you know, how fast they stabilize potassium and by what degree they lower potassium. All in all, these cation exchangers are no more beneficial in lowering potassium than it would be laxative treatment, right? We're not going to treat a patient with a laxative when they have hyperkalemia in a chronic setting, but this is just going – it's saying that the benefit is not that great compared to some of the other treatment agents out there, such as laxative agents. These agents, however, are not studied directly. They're all studying against placebo, like we discussed Dr. Kane. They're not studied with other standard of care that may exist, such as use of diuretic therapy. Dr. Sean Kane 36:17 Really, I think the main benefit for these agents is going to be to be able to initiate or increase the dose of your aces, ARBs, things like that, especially in patients that have mortality or morbidity benefits from those therapies? Speaker 1 36:30 Yeah, that's right, and that's where perhaps the use of oral diuretics come in play too, especially in you know, CKD or CHF patients, where the use can be directed to treat hypervolemia or hypertension. We could use loop diuretics, and that could help us get rid of some of those extra potassium that's coming from the RAS agents. Dr. Sean Kane 36:51 Bicarbonate has also been studied. You mentioned that earlier, this is typically given on the acute setting when patients have severe metabolic acidosis. On the chronic setting, really not enough evidence to support the use of oral sodium bicarbonate to help with chronic hyperkalemia, but it may be used in CKD patients that have low bicarb levels to supplement their bicarb. So different indication probably won't help with the potassium, but you may see it for other reasons. Speaker 1 37:17 Yeah, helps, you know, stabilize their acidosis as well. So talking about treatment, it was good, but let's talk also about prevention, right? So as we talk about prevention, we talk about, or think about bananas. Don't eat bananas, right? So that's good, especially in CKD and ESRD patients. Dietary modifications are imposed, where we will limit the potassium intake less than, or equal to three grams per day, no more than that. But interestingly enough, avoiding periods of fasting can also prevent that insulin response that can also result into hyperkalemia. So that's something that's specifically recommended in patients who have CKD and ESRD, and then obviously patients who are taking the RAS agents. We want to make sure we are starting at the low dose and titrating to that optimal dose. You know, with appropriate lab monitoring in place, we want to make sure they're restricting other sources or sources of potassium, mainly the dietary sources or soft substitutes, avoiding other and offending agents such as NSAIDs and then use of diuretics whenever possible, in combination with the RAS agents can be helpful. So Dr Dr. Sean Kane 38:25 Patel, I think that last point is really important in terms of monitoring. So when you have a high risk patient, let's say someone with chronic kidney disease who also has systolic heart failure, and now you're initiating Lisinopril on them as an example, how might dose and monitoring play a role in that particular patient. As an example, Speaker 1 38:43 I probably would go as low as 2.5 to five milligrams to start out with. That's the definition of starting low, for example. And in this high risk patients, I probably would want them to check their potassium and serum creatinine in about 10 to 14 days, about couple weeks, perfect. Dr. Sean Kane 39:00 Well, to kind of summarize some of the key points from today's HelixTalk, for me, one of the most important points for acute hyperkalemia is calcium either calcium gluconate or calcium chloride, is the most important therapy for acute hyperkalemia because it prevents arrhythmias from occurring. It doesn't change potassium, but it prevents those arrhythmias Speaker 1 39:19 the intravenous insulin. We're talking about the regular insulin. Usually this is combined with the 50% dextrose. Is also commonly given to redistribute the potassium back into the cells. In patients with hyperkalemia, we're going to consider lower doses, five units instead of 10 units, and frequent blood glucose checks, especially in those who have poor renal function, because we're also worried about that delayed hypoglycemic episodes later on Dr. Sean Kane 39:44 for that chronic hyperkalemic patient, where they're right on the cusp of, you know, having to intervene on them, the first therapy for those patients is going to be get rid of underlying causes, like dietary sources, either holding and or reducing renin angiotensin aldosterone system, drugs like. Aces, ARBs, things like that, potassium supplements, NSAIDS, all of these really need to be closely addressed and monitored to see if it really needs to be continued on that patient. Speaker 1 40:10 Various new cation exchangers are available, such as the paternomer brand name as well Tessa and sodium polystyrene sulfonate (Kayexalate), as well as the sodium zirconium cyclo silicate, the Lokelma. One thing to consider about these agents is that their chronic use may allow the use of the RAS agents without the dose reduction at the optimal doses, which again confirms morbidity and mortality benefit. But they're not really studied against some of the other treatment agents that we have available, such as the use of diuretics. They're studied against the placebo, and they're fairly new in the market, and time will only tell whether we're going to be seeing these used chronically in practice. Dr. Sean Kane 40:52 Well, that wraps up HelixTalk, 107 quite nicely. If you want to see show notes, they're available at HelixTalk.com we're also on Twitter at HelixTalk, and we love those five star reviews in the podcast app or iTunes Store, so do take a look and find us there and give us that nice five star review. And if you want, you can even leave a very nice comment to help us stay motivated in the year 2020, for future episodes. So with that, I'm Dr. Kane Speaker 1 41:17 and I'm Dr. Patel, and as always, study hard. Happy New Year. Narrator - Dr. Abel 41:21 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 - ? 41:32 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.