Episode 88 – Three Types of POTS with Dr. Pederson

00:01 Announcer: Welcome to the Standing Up to POTS podcast, otherwise known as the POTScast. This podcast is dedicated to educating and empowering the community about postural orthostatic tachycardia syndrome, commonly referred to as POTS. This invisible illness impacts millions and we are committed to explaining the basics, raising awareness, exploring the research, and empowering patients to not only survive, but thrive. This is the Standing Up to POTS podcast.

00:29 Jill (Host): Hello, fellow POTS patients, and most appreciated people who care about POTS patients. I'm Jill Brook, your hyper adrenergic host, and today we're going to explain what that means. We are covering a topic that was requested by listeners: the types of POTS that sometimes get discussed - hyperadrenergic POTS, hypovolemic POTS, and neuropathic POTS. Our guide through this topic today is the ever-wonderful neurobiology professor, POTS researcher, founder and president of Standing Up to POTS, Dr. Cathy Pederson. Dr. Pederson, thank you so much for being here today.

01:06 Dr. Pederson (Guest): I'm glad to be back. Thanks for having me, Jill.

01:08 Jill (Host): So, we had a listener write in and ask that we speak about hyperadrenergic POTS, and we thought it was a good idea to maybe speak about that and the other subtypes of POTS. And I think that some doctors use these distinctions, and some do not. So, it's not essential for getting good POTS treatment, I think. But we hear about these sub types of POTS all the time and I think they might be useful for shedding light on the underlying processes of POTS, but POTS patients should not worry if they have not been assigned any subtypes of their POTS, right? Does that fit with how you think about it?

01:48 Dr. Pederson (Guest): Yeah, that's exactly right. In fact, I think my daughter fits into all three categories in parts. As you listen to this episode, maybe talk about that a little bit. And she has never been named hyperadrenergic or neuropathic or hypovolemic. But other folks like you, Jill, talk about being hyperadrenergic, right? That's... for you, that's part of the label and identity of your POTS. And I think a lot of people, especially with the hyperadrenergic POTS feel that way, too. So I think this is really important just to talk about. But I think we should say upfront, as you were sort of alluding, to not all the doctors agree on this. You know, not every doctor uses this, but it could be a good way to just sort of think about different POTS symptoms and different needs of POTS patients.

02:42 Jill (Host): OK, great. So, before we get started on the three categories, perhaps we should review a little bit about the autonomic nervous system and remind our listeners about the sympathetic and parasympathetic nervous systems. Do you want to just give us a reminder of that?

03:01 Dr. Pederson (Guest): I think that's a really good idea. For listeners that want to hear more about this, one of our first episodes - episode four - was autonomic nervous system 101. And we're not going to go into that kind of detail today, but if this is something that you're thinking, boy, I need to know more about that, go back to episode 4. So when we talk about POTS, we talk about the autonomic nervous system and we all know that term, right? That's the automatic part that takes care of things that we're not really aware of or thinking about until they go wrong, and there are two branches of that. So, there's the sympathetic, which is the fight or flight. People talk about adrenaline, right? The body thinks you're in danger or there's a reason for you to be fearful. Adrenaline is the old name for that neurotransmitter. We call it norepinephrine now. So norepinephrine’s job and the sympathetic nervous system job is to get you into action, to fight off the danger, to fight off the bear, or to run like heck and get out of there, right? To fly out of that dangerous situation. And so, when norepinephrine is released, its job is to get blood and oxygen and nutrients to your muscles. So, it increases heart rate, it increases blood pressure, it can cause constriction of the blood vessels, so it makes it easier for that blood to get back to the heart, and it increases respiratory rate. So the opposite of the sympathetic nervous system is the parasympathetic nervous system, and sometimes people call that the rest-and-digest system or the housekeeping system. This is sort of when you're laying low, you're relaxing. Maybe you just had something to eat. And so, your body's in what we call homeostasis. It's just doing its normal metabolic activities, and it also - the parasympathetic nervous system - also has a neurotransmitter. This one is called acetylcholine. And so, when acetylcholine is released, it sort of does the opposite of norepinephrine. So, it increases digestion. I have to say my daughter and I just had dinner before we started to record this. I'm definitely in parasympathetic mode right now, right, digesting my dinner. And it also, though, is going to, as we rest and digest, decrease my heart rate, lower my blood pressure, dilate those blood vessels, and decrease my respiratory rate. So think about how you just feel very relaxed after you've had a nice meal. So, sympathetic - fight or flight - norepinephrine. Parasympathetic - rest and digest - acetylcholine. We're going to come and talk about those as we go through the episode. The last thing I want to say is a reminder before we get down to it, is that the sympathetic nervous system and parasympathetic nervous system are always talking to virtually all of the organs in your body. And so, it's about this balance, the balanced response at the heart, let's say, or at the respiratory system between sympathetic and parasympathetic, and the one that has the stronger pull wins. So if it's sympathetic, heart rate goes up. But if parasympathetic is winning, heart rate goes down. OK. So those are the basics that I feel like we need before we delve into these types of POTS.

06:40 Jill (Host): OK, and I think you said an important word there which was "balance" - that a healthy body can go back and forth between the parasympathetic and the sympathetic and, as needed, spend some time in each state.

06:55 Dr. Pederson (Guest): Absolutely. And we know in POTS that that doesn't happen. And the one that tends to win in POTS is the sympathetic nervous system, that fight or flight. So people are feeling that anxious and tremulous and tachycardic and high respiratory rate. All of those things.

07:14 Jill (Host): OK. So let's get into the three major categories of POTS and start with the one that is named for that adrenaline - hyperadrenergic POTS. What can you tell us about that subcategory of POTS?

07:31 Dr. Pederson (Guest): This one is really interesting, I think, because as I was studying up for the episode - I always study to be sure that I give good information to our listeners - this one by far has the best diagnostic criteria of the three. So, if folks have had a tilt table test and they put the IV in for that, and they're taking samples of blood out at different times when you're laying down and then also through standing, that's probably what they're looking at. They're drawing what's called plasma norepinephrine. Plasma is the watery part of your blood, but norepinephrine, we just remember is the neurotransmitter of that sympathetic nervous system. And in order to get this diagnosis, there has to be an increase of 600 picograms per milliliter. That's just a unit of measure I know, drives you crazy. So, they're looking for a substantial increase, though, of norepinephrine when you go from laying to standing, and you have to have at least a 10 millimeter of mercury rise in pressure for the systolic blood pressure. So, you know when you have a blood pressure there are two numbers, might be 120 / 80, that top number, the 120 is the systolic number. So, in order to get this diagnosis, the norepinephrine levels have to go up, but the systolic - that top number of the blood pressure - also has to go up at least 10 millimeters of mercury during the standing part. So, very specific criteria in order to get this this particular diagnosis. Another thing that, frankly, I learned when I was reading some of these papers that I hadn't realized and I'm interested in your opinion on this is that the onset is often more gradual. Was yours a gradual onset, Jill?

09:36 Jill (Host): Very much so, like a decade or two. Yeah, that's interesting. I did not know that.

09:41 Dr. Pederson (Guest): I didn't know that either. My daughter is primary probably, after doing this research, is probably neuropathic, which often comes right after infection. So she got sick and never got better, but that tends to not be the case in the hyperadrenergic POTS, which I think is really, really interesting. And there are several causes of this hyperadrenergic POTS. One is a genetic mutation. So one could be passed through the families, and I think some of our listeners may be in that situation where maybe a parent has POTS and now the offspring may be siblings, that sort of thing. And there's a single point mutation that can happen in something called the norepinephrine reuptake receptor. So norepinephrine, I'm hoping everyone going to say this with me, is the neurotransmitter of the... sympathetic nervous system, right? The fight or flight. A reuptake receptor is the one that helps us recycle that norepinephrine. So, these neurotransmitters are released from one neuron onto the next into a little gap that's called the synapse. But what's supposed to happen is the neuron that released it, recycles it. They pick it back up again through this reuptake receptor. But if you have a mutation in that receptor and it doesn't pull enough norepinephrine back into the cell, you end up with big amounts in the synapse that are not supposed to be there. So you're releasing normally, but you're not recycling it normally.

11:13 Jill (Host): I just have to laugh because I'm trying to imagine the family where they have a genetic mutation that makes everybody in their family as high adrenaline as I am, and I feel bad for that family. [Laughs]

11:28 Dr. Pederson (Guest): So, the people marrying in need to be very patient. Is that what you're saying? [Laughs] Yeah, it's interesting to think about and we do know families - in our support groups we've got families of people - where multiple people have POTS. And that's not to say that they necessarily have that specific mutation, but it's possible. There are other causes. So, our regular listeners might think that Jill's cause is mast cell activation syndrome. So mast cell activation syndrome can be tied with any kind of POTS, really. But there's a really big relationship between mast cell activations syndrome and hyperadrenergic POTS. And so, we all know as big fans of you, Jill, that you have both of those, both of those give you a lot of issues. So that would be my guess as to what's maybe ticking underneath of your hyperadrenergic POTS. Another potential cause is what they call baroreflex. A barometer measures...

12:36 Jill (Host): Pressure.

12:37 Dr. Pederson (Guest): Pressure, right. Measures pressure. So, we have these little pressure reflexes, pressure receptors, inside some of our major blood vessels. If the pressure receptors in these big arteries don't work correctly, it throws off blood pressure, which throws off heart rate and causes all sorts of issues.

12:58 Jill (Host): So, are you saying that, for example, your baroreflex response might be to think that there's more pressure than there really is, and so your body thinks that you're getting more blood flow than it really is? Is that what you're saying?

13:15 Dr. Pederson (Guest): I think it's the other way. So, what a baroreflex would do is as the pressures go up, it would cause dilation, right, to lower that blood pressure. And as the blood pressure drops, then it's going to cause those blood vessels to constrict to keep the blood pressure in normal range. So, if they've failed or they're not working very well, they're just not responding as quickly or at all in the way that they should be.

13:44 Jill (Host): OK.

13:45 Dr. Pederson (Guest): And then the last potential cause is very rare, and it's called pheochromocytoma. And I know that this was one of the tests that my daughter had early on. Did you have that one, Jill?

13:58 Jill (Host): Yep, mm hmm.

13:59 Dr. Pederson (Guest): OK. So, I think lots of folks that are running through their paces of diagnosis are tested for this. But my daughter did this at Cincinnati Children's and the neuroendocrinologist that ran it said she's run it on many, many children, never seen a case of it. So, it's really, really rare. Pheochromocytoma is a tumor on the adrenal glands. They're really small glands right on the top of your kidneys, but they can also release norepinephrine. So we usually think about sympathetic nervous system doing that, but the adrenals can also release norepinephrine and that could cause that hyperadrenergic state.

14:42 Jill (Host): OK. So, lots of norepinephrine, lots of hyperadrenergic state. What are the typical prominent symptoms associated with all this sympathetic activation?

14:55 Dr. Pederson (Guest): OK, I bet our listeners are guessing. What's going to happen with blood pressure?

15:00 Jill (Host): [Laughs]

15:01 Dr. Pederson (Guest): It goes up. The tachycardia may be even more extreme for people with the hyperadrenergic POTS than it is for people with other subtypes, because, again, they've got that norepinephrine there. Their sympathetic nervous system is working like crazy. They may have more heart palpitations. A palpitation is different from tachycardia. Palpitation is when you feel like your heart skips a beat or you feel like your heart is beating out of your chest. So that's more common in people with the hyperadrenergic POTS. And then I think you were sort of joking a minute ago, but that anxiety, sort of maybe tremors in the hands, and then, especially when people are standing up, their hands, their feet will be cold and sweaty just from that effort, from that overstimulation of the sympathetic nervous system. A lot of people get migraine headaches that have hyperadrenergic POTS. And interestingly, and I know you mentioned this one in not too many episodes ago - increased urinary output, especially after being upright. And so, I think it was one of the diary episodes where you were talking to a college kid and said, man, I don't know how I'd sit through the classes anymore, right? Or a three hour lab or something like that. And then the last one is nausea and vomiting. So to our listeners, if you're like, check, check, check as you go down through here, hyperadrenergic POTS may be the predominant form that you have. It's common the estimate is about half of people with POTS have a hyperadrenergic form. Now let me hedge a little bit and say, if you add up as we go through this episode, it adds up to way more than 100%. There's overlap, OK? So, these are not staunch boundaries, but again, these are descriptions of clusters of symptoms and then help the practitioners to think about potentially how to treat them.

17:04 Jill (Host): Right, and there's one more phrase that comes to mind to me that gets used to describe this type, which is the ‘tired but wired’ feeling. And I think the idea is that most POTS patients are tired, but the hyperadrenergic ones are somehow simultaneously tired and wired. I'm an outlier. I'm just wired.

17:28 Dr. Pederson (Guest): [Laughs]

17:30 Jill (Host): [Laughs] But we hear that a lot. So, what are the typical treatments for addressing POTS from this angle?

17:37 Dr. Pederson (Guest): Yeah, absolutely. So, I'm just going to give a couple that are the really common ones. So, Clonidine is one, and Clonidine is a little different type of drug than the beta blockers which are going to be my second one. Clonidine goes right into the brain, so it goes right into the central nervous system, and it busts the sympathetic nervous system. So, in the brain is where we're generating this fight or flight response. We're causing the release of norepinephrine in the brain, but also throughout the body. And Clonidine goes in there and shuts it down. And so when we decrease that centrally, it shuts it down in a lot of the body as well. My daughter takes this one. She only takes it at night. Brain fog can be a problem as it shuts down lots of other things as well. But I'll tell ya, we were talking about sleep before the episode started. If she forgets to take her medicine at night, including this Clonidine, she has insomnia. Three o'clock in the morning she'll think, "Oh my gosh, I better check and see if I took that medicine." And almost always she hasn't taken it. So this one really helps her sleep, get that wired feeling down a little bit. Probably more common than that are the beta blockers. I think lots and lots of POTS patients take these beta blockers. And both of these are going after the sympathetic nervous system. Both of them are going after norepinephrine. So, when we say ‘beta blockers,’ the full name is beta adrenergic receptor blockers. Adrenergic is talking about norepinephrine and epinephrine, sort of its kissing cousin. And so, we're going and we're blocking those norepinephrine receptors. Clonidine's going and shutting down so we're not releasing the neurotransmitter, we're not releasing the norepinephrine. But the beta blockers, the norepinephrine may be there, but we're blocking the receptors, so the signal is not getting through to those tissues, to your heart, let's say, and it prevents that sympathetic activity peripherally. So that'll help you to decrease your respiratory rate, your heart rate, your blood pressure, all of those things.

20:02 Jill (Host): OK. So I think that's about it for hyperadrenergic POTS. Is there anything else to say about that or should we move on to the next one?

20:12 Dr. Pederson (Guest): I think I'm ready to go on to the next one, but I would urge people if this sounds like you, your doctor hasn't maybe mentioned this term, maybe just ask them about it and ask them what medications might really fit some of these symptoms for you.

20:28 Jill (Host): And you know, you're reminding me that even though, for example, caffeine can help with vasoconstriction and it can help with energy, I know that for some of us the caffeine puts us over the edge just psychologically. And I wonder, you know, caffeine can keep the adrenaline around a little longer in your brain, I believe. And so that's why I'm very careful about when and how much caffeine I dare to do.

20:57 Dr. Pederson (Guest): Yeah, absolutely. Caffeine is a stimulant, and so when you're already wired, you don't want to add a bunch of stimulant on there. Absolutely.

21:06 Jill (Host): OK. Moving on. The next one is neuropathic POTS. Can you tell us about that?

21:13 Dr. Pederson (Guest): Absolutely. I don't think we hear this term as much. I think when people identify with the type of POTS, it's almost always hyperadrenergic, but there are two other subtypes. Neuropathic - neural means nervous system. And often we think first about brain and spinal cord, but here we're really talking about out in the periphery. So peripheral nerves that are going out to your heart and your lungs and your muscles and your sweat glands and all of those things. And so, what we see in neuropathic POTS is a decrease in the sympathetic innervation. So again, that sympathetic nervous system is coming in here again. So we have less nerves out in our tissues than we should. And what we know is that this is particularly predominant in the legs. So, if you have small fiber neuropathy, you likely have neuropathic POTS, right? So small fiber neuropathy is associated with neuropathic POTS. And I know a lot of our listeners have been tested for this. And know what that term is, but I'm not sure we really understand. So, there are large fibers that go down through your legs and there are these small fibers. The large fibers, those are like the motor neurons that are sending the signals down to your legs. These small fibers, though, instead are really helping with things like constricting our blood vessels. So, if you think about having less sympathetic innervation, the small fiber neuropathy in the legs in particular, now we're not constricting the blood vessels the way that we should. And so that's going to lead us to things like blood pooling, particularly in our abdomen and down in those legs. So, let's run through the scenario: So, when the sympathetic nervous system is activated - that fight or flight - we get the release of norepinephrine. And down in our legs - the lower extremities - we've got less small fiber innervation than we should, which means that those nerves are releasing less norepinephrine because we just don't have as many there. So, one thing I'm not sure I said, so let me be sure that I say this clearly: norepinephrine is a vasoconstrictor. So, it causes our blood vessels to get smaller to constrict, which helps us push the blood back up to the heart. So, if there's not as much norepinephrine because we don't have as many of these small fibers in our legs, we don't get as much vasoconstriction. We get excessive blood pooling. So now we've got this blood that's sitting in our abdomen and in our legs and the classic POTS sign of blood pooling, right, is after a shower or a bath and those feet turn blue, right, or purple or red. But if the blood is sitting down in the lower parts of the body, then there's not enough blood coming back up to the heart. And the blood coming back to the heart - we call this venous return. So, if you have low venous return, you don't have enough blood coming back up to the heart. That causes your heart rate to increase.

24:51 Jill (Host): And I think this is where some of the experts believe that there could be a vicious cycle, right? So, you get not enough return to your heart or to your head, which puts you in a heightened sympathetic state, which can lead to release of more of that norepinephrine. And this might be where people start being both the neuropathic POTS types and the hyperadrenergic POTS types, and if your body is putting out more adrenaline, but your nerves are not reacting correctly and not putting it to good use, you can kind of have the worst of both worlds and a vicious cycle, right?

25:28 Dr. Pederson (Guest): Yeah, that's absolutely right. Physiology is really interesting. I love Physiology. But it can also be really complicated because everything is related to everything else and that's a perfect example of that. So now when you've got that low venous return, it sets off a whole cascade of issues.

25:48 Jill (Host): Right, OK. So when do we tend to see neuropathic POTS? Is it associated with certain triggers for POTS?

25:56 Dr. Pederson (Guest): Yeah, it actually is. Neuropathic POTS is really common after viral infection. So, my own daughter caught, we think Mono - Epstein Barr virus - and never got well. And so that's really a common scenario for people that have this neuropathic POTS. It also seems to be really associated with surgery or trauma. So, a car accident, something like that can also lead to this neuropathic POTS. So what's interesting about this, especially with the viral infection, is that we think that this may be one of the leading forms that might be autoimmune. So you think about that viral infection and, you know, you were sick like everybody else was sick, but why don't you get better? Something’s going on with that immune system, right? Maybe now it's been triggered into high gear, you get this autoimmune form of POTS. We know that there are a number of autoantibodies. So, antibodies are made by your immune system to help you fight off infection, an autoantibody is now targeting your own healthy tissue. So we never want those. We want antibodies, but we don't want autoantibodies, and we know that in POTS there are some autoantibodies that are present, and again that tends to be related to this neuropathic form of POTS, although it could be found with others as well.

27:32 Jill (Host): OK, fun times. So, what are the symptoms that are sort of the cardinal signs of neuropathic POTS?

27:39 Dr. Pederson (Guest): Yeah, so loss of sweating, particularly in the extremities - in the arms and legs. So, if you notice that you're sweating on the torso, but not so much on those extremities, that could be a sign. Again, because we don't have the nerves, so we don't sweat as well on those extremities. That blood pooling that I mentioned before. And then there's a term for that blood pooling in the feet when the feet turned that blueish purplish color. It's called cyanosis, right? Cyan is a form of blue. And so those are the symptoms of neuropathic POTS. And again, if this sounds like you, they estimate that about half of POTS patients have this neuropathic subtype.

28:29 Jill (Host): OK. So, what are the typical medications for neuropathic POTS type then?

28:35 Dr. Pederson (Guest): Sure. There are a couple, and again, I'm going to stick with the ones that we hear about and that I think our listeners know. So midodrine is one of those, and this is another one that goes and binds that adrenergic receptor. And again, adrenergic is talking about norepinephrine, so it's binding these norepinephrine receptors. It's called the A1 adrenergic receptor, and it's an agonist. It turns that on. OK, it doesn't matter. For our purposes, what we need to know about midodrine is it's a vasoconstrictor. It causes those blood vessels, the peripheral blood vessels, to constrict. And when you do that, it helps to increase the blood flow back to the heart. We call that the venous return. So, it increases that venous return, which in turn is going to settle your heart down and slow that heart rate down again. So it helps to balance things out. So midodrine, and that's the one my daughter tried it for a little while, I think maybe you did, too. This is the one that I think gives that funny tingling goosebumps in the scalp. My daughter did not like that at all. It turned out it didn't help her very much, and she was pretty happy to get off of that one. [Laughs] The other one that we see here is called pyridostigmine. [Transcriber’s note: pyridostigmine is the generic version of Mestinon.] And this one is different. So virtually everything that I've mentioned before has had to do with norepinephrine and sympathetic nervous system. Pyridostigmine is an acetylcholinesterase inhibitor. Acetylcholine is the neurotransmitter of the parasympathetic nervous system - that's the rest and digest one. So here we're looking at sort of the opposite side of things. So, there are two ways to balance our autonomic nervous system. If our sympathetic is too high, one is to knock the sympathetic down. That's what we've been talking about. The other one, and this is what pyridostigmine does, is to elevate the activity of the parasympathetic nervous system. So the idea is that acetylcholinesterase is an enzyme that breaks down acetylcholine in the synapse. And so, if we inhibit that, it leaves acetylcholine in that synapse longer. So that acetylcholine goes and it binds to its receptor and it sort of bounces off, and what usually happens is it gets broken down and recycled into the neuron bed, just released it. But in this case, it doesn't get broken down. We've inhibited that enzyme. And when we do that, the acetylcholine can go and bind to its receptor again, OK? So we're increasing parasympathetic tone is what it's called, and getting that parasympathetic nervous system working better. So, this can cause our baroreceptors - those pressure receptors - to be more sensitive. And as that happens, as the parasympathetic nervous system comes up, the baroreceptors start behaving themselves. We see that decreased heart rate upon standing. So that can help to lower or eliminate that tachycardia. So pyridostigmine is an interesting one. My daughter takes this one as well. It really helps her, but again, it's sort of the opposite mechanism from the other medications we've talked about so far.

32:09 Jill (Host): Right, OK. So, some are dampening down the sympathetic, but this one is increasing the parasympathetic.

32:17 Dr. Pederson (Guest): Exactly.

32:18 Jill (Host): OK. So, anything else to say about neuropathic subtype of POTS?

32:25 Dr. Pederson (Guest): I just want to emphasize, there's a lot of overlap between these. So if listener said well, well, I checked every box for hyperadrenergic, and Gee whiz, you know, I checked every box for this one, too. That's OK. That's OK. That's perfectly normal. These can definitely be overlapping.

32:44 Jill (Host): OK and I think this third one is something that a majority of pots patients have as well. What is hypovolemic POTS?

32:53 Dr. Pederson (Guest): Right. Hypo means below, right, below normal on something. Volemic is talking about blood volume. So, the name is telling us that their blood volume is too low, and this is actually harder to measure than one might think. So, it could be from red blood cells. That's easy to measure. We just do a CBC and POTSies have their blood taken all the time. So that's a really common test. The one that's harder is plasma - to estimate how much plasma is in that body. But when they do the test, and again it's sort of extensive and expensive, the typical POTSies has a plasma volume deficit around 13%. So that's a lot. We only have about 6 liters, 4 to 6 liters of blood in a human adult. And so, if you're missing 10% of that or 13% of that, that's an issue. So, what causes that? You know, when we look at people that have hypovolemic POTS, there are some abnormalities in some hormones. It's... it's sort of interesting. So, some hormones are too low. So there are two hormones that are supposed to be released when our blood volume and our blood pressure get too low. One is called renin and the other one is aldosterone. So renin and aldosterone are hormones that are supposed to be released as we're getting to the bottom edge of the window that is our blood volume. So it's supposed to keep us in that normal range to bring that blood volume back up again. On the flip side, there's another hormone called angiotensin 2, and so this gets complicated. I'll try to try to be as clear as I can. Renin and angiotensin 2 are related. So, there are things that I call hormone cascades where one hormone activates the next one, and the next one, and the next one. So, renin is the first hormone in the cascade - that one's low. That's what we just said a minute ago. The last hormone in the cascade is angiotensin 2, and what’s a little bit crazy is that angiotensin 2 is two to three times higher than it should be in the body. So, what that tells us is the body is not responding well to the fact that our blood volume is too low. We're not releasing enough renin and aldosterone, but we have too much we're not breaking down because our body is in crisis. We have too much angiotensin 2. So it's like type 2 diabetes where they don't need insulin because it's the receptor that's the problem. Maybe this is that sort of thing.

36:06 Jill (Host): Oh, interesting. So maybe your body keeps making more angiotensin 2, trying to get it to have an effect, but it's not having an effect because, for whatever reason, your cells are resistant to it?

36:19 Dr. Pederson (Guest): Right, right. Or it's not breaking it down, it's not breaking the angiotensin 2 down when it should. And so, in either case, what's happening is that we're not holding onto enough sodium. So, in the kidney, where we control how much sodium and how much water we pee out, or we reabsorb back into the body, we don't retain enough sodium. So the sodium goes to the urine, and I tell my students over and over - they recite it - I'll say, "Where sodium goes..." and they’ll say, "Water always follows." So, in the kidney the trick to water 90% of the time is manipulating sodium. So, there's a lot of this manipulation of sodium. So anyway, we're not reabsorbing the sodium. That's what the angiotensin 2 would have us doing and aldosterone would have us doing. And so, we leave it in the urine and then we lose a ton of extra water as well.

37:20 Jill (Host): Now I remember when I learned this, I thought, "You, too, kidneys?" Your kidneys are in on this as well. And it's a good reminder that POTS is really a whole body issue, and we always associate it with the heart. But the whole body is involved. So, OK, stupid kidneys.

37:39 Dr. Pederson (Guest): [Laughs] Yeah, that's right. That's right though.

37:43 Jill (Host): OK, so then what happens then? So, you're peeing out too much sodium and the water is following. And then what?

37:51 Dr. Pederson (Guest): Right, so now my blood plasma, the watery part of my blood, is dropping. Remember we said when they do the test - they don't do it very often, it's expensive, it's nuclear medicine that they use - but it causes lower plasma, which means you have less blood to move back to the heart. And we called that blood going back to the heart venous return. So, there's less venous return, but your body still needs blood. So if not enough blood is coming back, the heart panics and it starts to beat faster trying to get more blood coming back again, right? So, it's increasing that heart rate to try to compensate for the fact that you don't have as much blood as you should.

38:32 Jill (Host): OK. And so, then what symptoms are thought to be associated with that problem?

38:39 Dr. Pederson (Guest): So, when I looked in the literature, they only listed two, which surprised me. So, they listed weakness and decreased tolerance for exercise. But it seems to me like there would be a lot of things that are going on with this hypovolemia, but I'm sticking with what I saw in the literature. So I think a lot of our POTSies are saying, "Yep, that's me," right? Exercise intolerance is really, really common, and weakness and fatigue and muscle weakness and all of that together. And for this one - they estimate that up to 70% of all people with POTS are hypovolemic - their blood volume is too low.

39:21 Jill (Host): Yes, and my understanding is what you said - that this could then feed into so many of the other symptoms, maybe indirectly. But, for example, if you don't have enough blood volume now, your GI tract and your brain and your heart all have to compete for blood, and that might be why some people feel so bad after eating, and that might be why there's some nausea and some digestive issues when you're when your GI tract is not getting the circulation it deserves and all kinds of other things. But I think this one gets the most attention because it's the one that's the easiest to do something about.

39:59 Dr. Pederson (Guest): That's exactly right. And so, when folks talk about nonpharmacological treatments, this is what we've been preached before maybe we even had an actual diagnosis, right? So, they say increase that salt. Salt has sodium. Not all salts, but most of the salts that we have are have sodium in there. And so, 6 to 10 grams of salt. So, lots of people use Thermotabs or Salt Sticks or electrolyte drinks to try to get that salt in. They may heavily salt their food. And then increasing the fluids. So it depends on what article you look at. Two to two and a half liters is what I saw in the articles that I read for this episode, but I've seen as high as 4 liters - 2 to 4 liters per day. And so, when we're increasing the salt, and remember there's sodium in salt, where sodium goes, water always follows, right? So as we move more of that sodium into the blood, the fluid then also moves into the blood so that it helps expand your plasma to increase the amount of plasma that's there.

41:13 Jill (Host): OK, that makes sense. In addition to the salt in fluids, what else can be done about the hypovolemia specifically?

41:21 Dr. Pederson (Guest): Yeah, the compression garments that are commonly either prescribed or encouraged can be very helpful with this again. And again, the idea is venous return. So when we've got these compression garments, they're graded, they're trying to push the blood from your feet up the legs, trying to prevent that blood pooling in the lower limbs. You mentioned a long time ago the bike shorts, and my daughter wears those now and thank you to you for that. That abdominal compression and the compression of the upper legs, the thighs, and the butt has made a world of difference for her. So not just the leg compression garments, but also something like those bicycle shorts can be really helpful at, again, moving the blood back up to the heart, helping us with that venous return. Another one that seems kind of wonky is raising the head of the bed, and again I've seen a variety of numbers, but the articles - the published articles - that I looked at said 6 to 10 inches. And so, you want to take the headboard essentially and put a couple of bricks under it or pieces of wood so that you're raising the whole head of the bed on an incline. And so, you may slide down towards the foot of the bed, right, by the end of the night, but the thinking is that this affects the kidneys, being at an angle like that as you sleep. And so it reduces urine formation, and then if you're not making as much urine and having the urine in the bladder, that means you have more plasma in the blood. So that's the thinking. I think there are mixed messages on that. Try it. What does it hurt? Try it for a month. If you feel better, great. And if you don't, you tried. We've done it several times. I don't know if it really helps her or not. And then the last one that I know a lot of POTS patients have tried or use or wish they could try are IV fluids. Now, this doesn't help everyone. We tried it with my daughter. She hated it and didn't feel any better. In fact, going to the hospital and getting hooked up was very stressful for her. It was just made it much more tiring. So maybe she's not super hypovolemic, right, may be what that says. If IV fluids really work for you, then maybe you fall into this particular category.

43:56 Jill (Host): Right. And then I think some patients - this happens to me - where you feel great for a day or two after the IV fluids, but then it feels like you get some sort of a rebound effect where maybe your body forgot how to hydrate itself because it was relying on the fluids or something. And so that two good days isn't worth the seven bad days that follow. But I guess everyone’s is different.

44:19 Dr. Pederson (Guest): That's what a lot of physicians worry about, especially going long term, is that your body will lose the ability to absorb those fluids or deregulate it themselves. But if it really helps, I know people that get it daily, you know, or every two or three days. So, you have to do what works for you and there are risks to that, if you have a PICC line or a port, infections are big issues. So there are risks, but it's worth talking to the doctor about, I think.

44:52 Jill (Host): OK, great. What other medications might help increase blood volume?

44:58 Dr. Pederson (Guest): So, if you're not getting enough benefit from those nonpharmacological treatments, there are medications that can help this. Probably the most common one that lots of POTSies try at one point or another I feel like is fludrocortisone. The brand name for that is Florinef. And essentially that's targeting the kidney. It works like aldosterone does - one of those hormones that I said was a little bit low. And so, it helps you to reabsorb sodium into the blood at the kidneys. And where sodium goes... [pauses] ...water always follows, and I'm hoping that people are listening and saying it with me, right? Water always follows. So, lots of folks take that. The one caution, and this happened to us, actually, is that this can deplete potassium. And so, you'd need to be careful that you don't get your potassium levels too low. Might need a potassium supplement, or take a Thermotab or something that has potassium in it to be sure that you're not depleting that too much. Another one - so, I think fludrocortisone is the most common one in this category, but there are two others. One is desmopressin. And this is a synthetic version - a pill version - of a different hormone that's called anti diuretic hormone. And this also targets the kidney and helps us to reabsorb water to move it from the urine essentially back into the blood. And so, this one is actually independent of sodium. So, if that person maybe has high blood pressure already, you wouldn't want to give them fludrocortisone, you might try desmopressin instead. So both of those fludrocortisone and desmopressin are trying to increase the fluids in the body, which is increasing the plasma part of the blood. The last medication is erythropoietin and this is a hormone that's normally in the body as well, but it increases the blood volume differently. This one stimulates the body to make red blood cells. And so, if when they do the CBC, they see that your red blood cell count is too low, that you're becoming anemic, they might give you erythropoetin to try to get that number of red blood cells back up again.

47:29 Jill (Host): Now, is this the drug that Lance Armstrong was using?

47:33 Dr. Pederson (Guest): Yeah, this can be used in blood doping. I don't remember if this is the exact one, but this could be used for blood doping, for sure, yeah.

47:33 Jill (Host): OK. So, POTS or Tour de France championship.

47:47 Dr. Pederson (Guest): [Laughs]

47:48 Jill (Host): OK. Anything else to say about the hypovolemic form of POTS?

47:54 Dr. Pederson (Guest): I think this one is super, super common and a lot of POTS patients really benefit from increasing fluids, increasing salt, the compression garments and maybe that IV fluid. So, I'm thinking most of our listeners are... are agreeing and saying, Yep, that sounds like me here, again.

48:16 Jill (Host): Right. So many of us will be saying that we are three for three or two for three. I guess everybody is at least one for three, is that correct? Nobody is without any of these things.

48:28 Dr. Pederson (Guest): Yeah, I would think that everyone would identify with at least one of these, 'cause we've really talked about a wide range of the POTS symptoms. And one reason that physicians like these subcategories is it explains why some people have nausea and vomiting and other people don't, or some have more tachycardia than others. So, they're trying to look at the basic physiology to understand the differences between these in hopes of better treatment for folks, more targeted treatment.

49:01 Jill (Host): I'm just thinking about some of the symptoms like brain fog or headaches which seem like they might be explained by anyone of these three, because if your brain isn't getting the circulation it wants, it doesn't matter why. You could have some of those symptoms.

49:19 Dr. Pederson (Guest): I think so. Absolutely, absolutely. And again, this is... these are all tide together and they're overlapping, for sure.

49:27 Jill (Host): OK. So maybe we can just emphasize one more time: after patients have heard all of this, they might be worried that they have not been assigned a subtype or two or three. Is it important that patients be given a subtype?

49:40 Dr. Pederson (Guest): I don't think so. What's important is the doctor is matching the treatments to your needs, to your symptoms. It can be a helpful way to talk about it, or to classify these, but it's not critical that your doctor is diagnosing you with a subtype of POTS. And let me use my own daughter as an example. She takes a variety of medications, like many of our listeners probably. And she takes Clonidine, that was the one that went into the brain to shut down the sympathetic nervous system for hyperadrenergic POTS. But she also takes pyridostigmine - that's the one that increased the parasympathetic nervous system that I mentioned under neuropathic POTS. And she also took for many years, although she no longer does, Fludrocortisone, which was for hypovolemic POTS. So even my own daughter I think probably fits in at least two or maybe all three of these categories. So don't worry if you feel like that's the case for you. If you're going through and saying, "Oh my gosh, I'm taking medications from each subtype," that's OK. That's OK. What we need is for you to be as functional as you can. And work with your doctor. Don't be afraid to experiment or let him or her experiment with these medications to figure out what helps you the best.

51:11 Jill (Host): Excellent advice, as always. Dr. Pederson, thank you so much. You are such a great teacher and we love learning about POTS from you.

51:21 Dr. Pederson (Guest): I love coming and doing these shows. Thanks, Jill.

51:24 Jill (Host): Hey patients. we hope you enjoyed this episode, We've got more coming next week, but until then, thank you for listening. Remember, you're not alone. And please join us again soon.

51:37 Announcer: As a reminder, anything you hear on this podcast is not medical advice. Consult your healthcare team about what's right for you. This show is a production of standing up to pots which is a 501(c)(3) nonprofit organ. You can send us feedback or make a tax-deductible donation at www.standinguptopots.org. You can also engage with us on social media at the handle @standinguptopots. If you like what you heard today, please consider subscribing to our podcast and sharing it with your friends and family. You can find us wherever you get your podcasts or at www.thepotscastcom. Thanks for listening. © 2022 Standing Up to POTS. All rights reserved. [Transcriber’s note: If you would like a copy of this transcript or the transcript for any other episode of the POTScast, please send an email to volunteer@standinguptopots.org]