Let's get salty part 1

This spring is all about salt!!! In part 1 I relive the saltiness of the emergency department while I was in residency and then get super nerdy about the pathophysiology of hyponatremia. 

Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 Oct;126(10 Suppl 1):S1-42. 

Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E; Hyponatraemia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170(3):G1-47. 

Transcript

SPEAKER_00 0:14

Bonjour mes amis. I'm trying to brush up on my conversational French as my son and I are going to France on vacation at the end of May. The only way I can truly step away from work is to leave the country. I am very excited about it. We fully plan to pretend we are Canadian if anyone asks. Last year I took my son to Chicago over Memorial Day weekend. I used to go there with my mom in the summer and was trying to recapitulate the experience for him. We had dim sum in Chinatown. We went to the Field Museum and Science and Industry, the latter of which now has a different name I can't be bothered to look up. He ate four Chicago hot dogs from a vendor in Grant Park one afternoon. We took photos of ourselves flipping off a certain building, and everything was splendid until our third night there when my son developed pretty significant abdominal pain. I first thought it must be constipation, because it usually is with kids, and adults to be fair, but then I started to get worried because he was curled up on the bed and moaning. And I started to think it might be that other thing that kids get appendicitis. Okay, sometimes it's mesenterogatinitis, which I vaguely remember from my peas rotation in med school, but that presents just like appendicitis, so you can't ignore it either. He said he felt really hot and then had chills, not nauseous at all, no diarrhea, but he wouldn't let me check his abdomen, and I was thinking, I need to see if this kid has an acute abdomen or just ate too many hot dogs. No go. So I ask him if instead he can stand up and jump up and down because up to date says kids with appendicitis can't do that without horrible pain. And he just whimpers. At this point, I should mention it's about midnight and I'm completely exhausted. And then I think to myself, I am just sitting here staring at my child as his appendix is actively rupturing. I am the world's worst mom and a doctor to boot, so I know better. I start looking up emergency departments on my phone and trying to figure out how I'm going to get him there since we have no car, and I'm pretty sure he can't walk even a few feet. So I carefully devise a plan to get a luggage trolley from the lobby and wheel him down on it. I'll have to call an Uber, or maybe I can just wheel him all the way there because the ED is like four blocks away. And then I start to have flashbacks to my experience as a med student and resident in the emergency room. Long lines, bad smells, total chaos. And we're in Chicago, a much bigger city, and I am filled with dread. My child will be withering in the waiting room with a ruptured appendix and promptly just die right there in agony, the end. And at this point he sort of falls asleep, but he's still moaning, so I try to wake him up, but he's sleeping pretty soundly, hopefully not in a coma. Then I lie down too, I'm exhausted, and I fall asleep. And next thing I know, it's morning and he wakes up a bit woozy, but no pain. He finally let me examine his belly, a little ticklish, but otherwise fine there, and then agreed to jump up and down only after I paid him $5, but he did it without any discomfort. And then things were basically okay the rest of the weekend. So appendicite-ish? I can only imagine what our trip to the ED might have been like. The emergency department is a weird and special place that I have never considered working in during my medical journey. I feel strangely attached to it though, because I consumed most of my extracurricular medical education in med school through MRAP, as there was no podcast equivalent for internal medicine. And the emergency management of medical conditions extrapolates to pretty much all settings. Thank you, MRAP, for your discounted membership while I was a trainee. Best hundred bucks a year I ever spent. And I really enjoy the crew in my hospital's ED. Ours is pretty low-key. We mostly don't do trauma, not on purpose anyway. We mostly do do medicine, with some surgery sprinkled in. It's busy, but usually no one is too frazzled, and folks generally are in a good mood. The ED I rotated through in residency was a different animal completely. Whereas my current ED is a bit like an elephant, mostly predictable, fairly calm, pleasant, sometimes goes on the run unexpectedly, but not usually too out of control unless something really catastrophic happens. My ED where I did my rotation in residency was like a rabbit hyena with opposable thumbs and a switchblade. The patients were generally all really pleasant, but a lot of them were in a very bad place in their lives, and there was never a dull moment. My introduction to the service was a guy who managed to get his pants off while in handcuffs and crap down the side of the wall his gurney was parked against. It smelled great, rivaled only by the rotting leg wounds of some poor homeless man on the next cot over that were teeming with maggots. The maggots probably had saved his life. My next patient was in status epilepticus and had bitten off the end of his tongue, blood squirting everywhere. The ED resident was impressive, totally unfazed, and just diligently doing a jaw thrust to keep the airway open while off-handedly requesting anesthesia assistance and more towels. The next night, a patient was wheeled in from an ambulance, actively getting CPR, except I'm pretty sure they tubed his esophagus and not his trachea because fermented dinner was shooting right back out of the tube. Soon thereafter, the paramedics got all cowboy in the field and misplaced a subclavian line, only to dump over a liter of normal saline into the left pleural cavity. My first ever thorough was done to urgently correct that. The most frightening thing I saw was a very large man who turned purple and fell to the ground in the waiting room, pulseless and not breathing. You know, it's surprisingly difficult to get appropriate CPR going on someone very heavy who lands on their stomach between tightly packed rows of chairs. There was a persistent smattering of 20-something-year-old men with meth-induced psychosis strapped to beds and violent restraints. Women apparently have more sense. And there was always a row of heroin ODs on N-title CO2 getting intermittently narcanned. Like a row of neonates in the maternity ward, but with slightly more regret in the aftermath. The ED board that listed the patients, their rooms, and diagnoses was always great reading. Once a male patient was in the emergency psych unit with homicidal ideation, while a female patient with the same last name in the regular unit was listed as no psych unit, husband is in psych unit. There was a pedestrian versus spacecraft with patient last name servant, first name the chosen. I don't think it's a HIPAA violation for me to mention that because I'll go out on a limb and claim none of that information was probably accurate. I once saw a diagnosis of mauling. I have no idea what caused the mauling, but the floor of that room was covered in blood. Nursing staff reassured me he would be fine. I have no idea how that could be true and have since realized that fine is relative. I did have some great moments in the ED where I felt like I really shined. I recognized the cause of a woman's asthma attack as the regodenizen stress test she'd had earlier in the day. The regodenizen triggered it. I was so proud of myself and then very annoyed because I could not convince my attending that this is what had happened. I still stand by it though. I evacuated a 10 centimeter gluteal abscess with a yank hour in a bucket. I sewed someone's ear back onto their head. Probably a plastic surgeon should have done that, but you know, I play the piano, so I'm pretty dexterous. And most importantly, I prevented multitudes of delirious patients from being treated for asymptomatic bacteriuria. So who knows how many cases of C. diff I averted. I had some not so great moments too. Mostly I pissed off the nurses, totally by accident. I tried to hug one of the ED nurses who was clearly not a hugger when we figured out the correct diagnosis for one of our patients. I often ordered labs piecemeal to be a good steward of resources, which meant they might have to draw labs on the same patient more than once. Oops. Sometimes I was too slow and ponderous. Sometimes I argued with the ED chief residents about their diagnoses. But the only unforgivable thing I did was something one of the ED attendings told me to do, and that was tell a woman in her late 20s that she had ovarian cancer based purely on imaging findings. Her parents and boyfriend were there, and they were all sobbing and talking about death because Google has nothing good to say about the prognosis of ovarian cancer, and it turns out, ha! It was just a necrotic fibroid. Now I never tell anyone that they absolutely have cancer until we have a tissue diagnosis. Now I'm always on the other side of the ED, accepting the patients and getting them admitted. I've learned it's best to have a low barrier to entry unless I have a really compelling reason not to take them and the patient themselves doesn't want to stay. I remember being on MICU and getting called about an 80-something-year-old woman with really no past medical history who had syncopized and had been completely abtunded since. Not posturing, but intubated without any sedation. And her labs were stone cold normal. BMP, LFTs, CBC, ESR, CRP, bland urine, normal CT chest, abdomen, pelvis. And I was like, are you sure this isn't a stroke because there is nothing wrong with her body? Like, more healthy than any other patient in their 80s I'd ever taken care of. They said no, they've gotten the CTA of the head and neck, and there's nothing. And it's four in the morning, and I'm completely exhausted. But what I'm hearing in the background in the ED is some guy yelling over and over again, rhythmically, F U, F U, F U, F U. You can guess what the F stands for. And the ED resident sounds more stressed and exhausted than me, so I'm like, you know what? I will admit this patient and get them to where they need to go. So I hang up and start writing admission orders, and about 10 minutes later, I get a call back from the ED resident who says, never mind, it's a massive stroke and going to the neural ICU. The CT was initially misread. Must have been teleradiology. The guy with Tourette's was still going strong. And what does today's topic have to do with the ED? Well, not much. Except, I really wish the ED would start ordering urine studies before giving fluids. Most of the time it doesn't matter, until it does. You'll see what I mean in a moment. But first, a warning. Today, there's going to be a lot of nerding out. Like an obscene amount. The amount of nerding will surpass the amount of swearing by an order of magnitude. By the end, your brain might just simply explode from the massive bolus of science knowledge I'm about to cram in

Sodium, water, ADH, and aldosterone

SPEAKER_00 9:57

there. Today, I am going to talk about hyponatremia. It is a topic near and dear to my heart and so complex that I will need two full episodes to cover it adequately. In this first installment, we will discuss the pathophysiology and diagnosis of hyponatremia. The second installment will be recorded from the underworld where we will discuss the nuances and potential catastrophic complications of management. Okay, raise your hand if you feel like you have a thorough understanding of the hows, whats, and whys of hyponatremia. Besides the one guy who just happened to be stretching, possibly nobody raised their hand. It is a topic that seems to really confuse a lot of physicians, although it's actually so easy. Thinking about the diagnosis involves a lot of really nerdy physiology, but the physiology makes sense and can be reasoned through, although it requires that you use your brain. Burn the algorithm, I say. I feel about algorithms the way Joan Crawford felt about wire hangers. They are better used for beating your children than practicing medicine. Algorithms make you turn off your brain. Please let's not do that. Let's start by talking about sodium and about water. Sodium is super important because it is the main cation in our blood, crucial for osmotic pressure, concentration gradients, voltage gradients, co-transporters, ion pumps, and a good margarita. Our body maintains blood sodium concentrations within a very specific range, 135 to 145. How does it do this? By moving water around. My med students often think that we move sodium around to regulate blood sodium, but moving sodium around just moves volume around without changing the concentration much because water is sodium's minion. Where it goes, water follows. That's why people with heart failure do so poorly if they drink nothing but V8 mixed with soy sauce. True story. When our blood sodium gets too high, we counteract that by increasing the free water in our body to dilute the sodium. If the blood sodium gets too low, we try to decrease the free water to concentrate the sodium back into the normal range. This process is largely regulated by the production and secretion of antidiuretic hormone, or ADH, also known as vasopressin, but I'm just going to call it ADH to simplify. The human body is truly amazing, and the regulation of the secretion of ADH really is something to marvel at. The hypothalamus has sensors that detect the amount of sodium in the blood, located in the organum vasculosum laminae terminalis OVLT and the subformical organ. Although that specifically doesn't matter, I just wanted to show off that I can pronounce them. The sodium sensors are called osmoreceptors because they sense the osmolality of blood in the systemic circulation. For our purposes, blood osmolality is synonymous with the blood sodium concentration. I will just say blood sodium to avoid confusion. When blood sodium levels are high, water is sucked out of the osmoreceptor cells because of the concentration gradient, which then sends signals up to the rest of the brain to increase thirst and triggers the posterior part of the pituitary gland to release ADH into the circulation. ADH primarily acts in the kidneys. Yes, it does also have some vasoconstricting effects, hence why it is sometimes called vasopressin, but its importance as a water regulator is what we care most about right now. Everyone remembers the nephron, right? The adorable functional unit of the kidney, thousands of them comprised of agglomerulus, tubules, and collecting duct. ADH binds to receptors on cells in the late distal tubule and collecting duct to increase insertion of the aquaporens to water channel into the urine side of the membrane. Water then can be passively reabsorbed into the cells and then eventually diffused into the circulation to normalize the sodium concentration of the blood. The half-life of ADH is only about 15 minutes, enabling a state of water reabsorption versus water excretion to be rapidly cycled. As the sodium levels go down, ADH secretion dissipates and normally is shut off completely around a blood level of 135. Now let's talk more about blood volume. The most important hormone in the regulation of blood volume is aldosterone, which is increased with activation of the renin angiotensin aldosterone system or RAS. When blood volume is low, as with dehydration or blood loss, the body doesn't say, hey, I need to increase the water in the blood. It says, hey, I need to increase the sodium in my blood so that its bitch water will come along for the ride. Like I said, where sodium goes, water dutifully follows. Aldosterone also acts on the cells of the late distilled tubule in collecting duct in the kidney. It increases expression of EnaC channels to reabsorb sodium on the urine side, and increases expression of sodium potassium ATP ases to pump out sodium on the interstitial side to maintain a concentration gradient that sodium can follow. And then water passively diffuses out with it. When blood volume is adequate, RAS should not be activated and much of the residual sodium in the urine is excreted unperturbed. So simply stated, ADH regulates blood sodium concentration and aldosterone regulates blood volume. But sometimes it's not so straightforward. Issue number one. RAS responds not to the total volume of fluid in the body, but to the effective circulating blood volume. That is, the volume of blood actually flowing through the vessels. In dehydration and blood loss, the whole body volume is down. But in conditions like heart failure, cirrhosis, and nephrotic syndrome, the whole body often is volume up. It's just that the fluid has fled the vasculature in favor of the cozy interstitium. RAS is blissfully ignorant of the big picture, though. It is a mindless drone that acts only according to blood volume. Whether there is too much fluid or too little fluid overall, RAS can't differentiate. It is myopically focused on what it can see. Issue number two, ADH's perseveration on blood sodium concentration can be overridden. In times of extreme depletion of effective circulating volume, ADH becomes the hero and rides into battle. Remember how ADH secretion is triggered by dehydration of the osmoreceptors in the hypothalamus due to water moving out in high sodium conditions? Well, those same cells can also get dehydrated in a state of general dehydration, as seen when there is very low blood volume, and send the signal for ADH secretion as well. In addition, the posterior pituitary can be signaled by the baroreceptors, stretch receptors in the neck area that sense a drop in blood pressure. ADH secretion because of low blood volume is sort of a nuclear option. When things get dire, blood sodium no longer matters. ADH will sacrifice regulation of sodium to make sure there is enough blood volume to sustain perfusion. Although I want you to think of ADH as regulating sodium, its physiologic effect is to increase reabsorption of water. At this point, the body knows it can't afford to waste a drop. And this response makes sense from an evolutionary perspective because sodium levels aren't as important as making sure there is enough blood volume to perfuse the organs in the

How urine studies reflect ADH and aldosterone activity

SPEAKER_00 16:45

first place. Okay, now that you have a thorough understanding of the physiology of water and sodium regulation, let's discuss how to use this knowledge to determine the etiology of hyponetremia. In most cases, when we have a patient with low sodium, it is nearly always the result of ADH secretion. But if the blood sodium is low, ADH should be turned off, right? I know, weird, huh? Well, sometimes it's not. The question is, is this appropriate secretion in response to severely reduced effective circulating blood volume? Or is it inappropriate, as an SIADH or syndrome of inappropriate antidiuretic hormone? Here, the pituitary has just thrown caution to the wind and the ADH is running amok. There is a third circumstance we'll talk about in a bit that is not related to ADH secretion, but it's much less common, so don't worry about it right now. So how can we tell the difference between these two ADH-driven circumstances? Well, we have to ask ourselves, first, what is ADH doing, and then second, what is aldosterone doing? We can tell what ADH is doing by looking at urinosomes. If ADH is turned off, the aquaporens are hiding and more water is excreted in the urine. So urinosomes are low because the urine is more dilute. We often use a cutoff of about 100 to say it's low. Less than 100 would mean ADH is turned off. If ADH is turned on, aquaporens come out to play, water is reabsorbed out of the urine, and the urine is more concentrated. Urinosomes are then high, or greater than 100 anyway, but usually much higher. Then the question is, what is aldosterone doing? We can tell what aldosterone is doing by looking at urine sodium. If it is low or undetectable, aldosterone is turned on. All the sodium is being reabsorbed out of the urine. If aldosterone is turned off, sodium is spilling into the urine. It will be detectable. A few things about this sometimes confuse people. First, even though we equate blood sodium with blood osomes, urine sodium and urine osomes are not really related. The osmolality of urine is largely dictated by non-sodium solutes. Second, at what urine sodium level can we say for sure that aldosterone is turned on? There is some debate in the literature about this. Because aldosterone has to already be working at full throttle before ADH would jump in in the first place, we typically think of all the sodium being reabsorbed from the urine because there really isn't a circumstance where RAS would be half-assing its job and ADH would still be willing to get involved. ADH is a stickler. However, remember a few episodes when I ragged on the FENA because of all the things that can affect the excretion of sodium into the urine? Well, the workup of hyponatremia is not completely immune to these issues. Patients with CKD, patients with current acute kidney injury, having diuretics on board, especially a thiazide, all may have slightly higher urine sodium despite being volume depleted. So we sometimes use a urine sodium 20 or 30 as a cutoff instead.

Is that ADH appropriate... or not?

SPEAKER_00 19:37

Okay, now say a patient with hyponatremia comes in and you haven't read their medical history or seen them in person, playing the odds, you know right away you are probably looking for one of the two ADH-regulated situations. Both will have high urinosomes because ADH is turned on. So you look at the urine sodium to tell you if it's appropriate or not. If urine sodium is over 30, RAS is turned off because the patient is not volume depleted and they have SiADH. If urine sodium is not detectable, or at least under 30, RAS is already maximally activated and now ADH is pinch hitting, so there must be reduced effective circulating volume. And if that's the case, you need to decide if the patient is total body volume up or down. Physical exam and history should make this obvious. And please differentiate between the two because one is treated with fluids and the other with diuretics. I'll let you figure out which is which. Now for another blow. There are a few circumstances in which urine studies can look like SaADH when there is a different pathology happening, but the list is limited. Really adrenal insufficiency, hypothyroidism, although it's almost never hypothyroidism, and salt wasting, whether renal or cerebral. Salt wasting is also very uncommon. People usually are volume depleted though, whereas folks are usually euvemic with SaADH, adrenal insufficiency, and hypothyroidism. I go ahead and check a TSH and a morning cortisol in patients whose urine studies are suggestive of SAADH, but I don't have a good culprit med or other reason for the diagnosis.

Concentrating and diluting urine and the kidney can't keep up

SPEAKER_00 21:07

Alright, let's touch on the third situation where patients get hyponatremic, but ADH does not play a role. This happens when patients can't dilute their urine enough to get rid of excess free water. Sorry, but this requires a little more nerdiness to explain the physiology. Because the flow of solutes and water in the kidney depends largely on concentration gradients, there is a maximum amount that the urine can be diluted and concentrated. The max concentration, or maximum osomes, depends on the concentration gradient in the loop of Henley. Typically, the max in a very dehydrated state would be up to 12 to 1400 osomes per liter. Absolutely no more water can be sucked out of the urine beyond this. The other important concept here is dietary osomes. We all produce a certain number of waste osomes we have to get rid of in the urine every day. With a Western diet, it's about 600 to 900. So, what is the minimum amount of urine that would have to be made if maximally concentrating but still excreting those 600 900 osms daily? Well, if you can excrete up to 1400 osomes in a liter of urine and you split the difference between 6 and 9, then about 500 cc's. That is why we consider less than 500cc of urine output in 24 hours oliguria suggestive of renal failure, because we know your kidneys can't be excreting everything they need to excrete in less urine than that. Isn't that cool? On the other side of this, kidneys can only dilute the urine to a certain extent as well, because water relies on urine osomes to draw it out. Everything is about concentration gradients in the kidneys. The urine can only be diluted down to 50 osomes per liter, which means if you had about 700 osomes to dump, 700 divided by 50, you couldn't make more than 14 liters of urine per day. So if you drink 18 liters of water, four liters are going to hang around in the bloodstream and dilute the sodium down to scary levels. This is what happens with psychogenic polydipsia, or during hazing rituals, or overwhelmingly stupid YouTube challenges by stupid people doing stupid things, usually 14 to 20-year-old boys who are also doing the hazing. The other way the system can get perturbed is if you take in an incredibly low number of osomes in your diet. If you only have 200 osomes to dump every day, you can only make four liters max of urine. This is what happens with beer potomania, when mostly old men drink beer for breakfast, lunch, and dinner, taking in a fair amount of fluid and very little in the way of food. This also happens with what is referred to in medical textbooks as the tea and toast diet. I suspect this term originated in England because older Americans drink coffee and eat Jimmy Dean's breakfast sandwiches from the gas station and then get scurvy. I had a patient develop scurvy twice because that's what he lived on. What do urine studies look like in this setting? Well, what is ADH doing? It is turned off completely and urine is maximally dilute. So urine osom should be below 100. What is aldosterone doing? Nothing. No volume depletion here. RAS is deactivated and urine sodium is plentiful. So low urinosomes and normal to high urine sodium. This is the only scenario for hyponatremia where that is true. C. Easy peasy. Okay, I would be remiss if I didn't mention that not all hyponatremia is true hyponatremia in the same way that not all patients with red legs have cellulitis. Sometimes it is pseudo-hyponatremia. But this is the most boring part of the topic. So I am relying on you all to have come to me with true hyponatremia in the first place. Don't come to me with hyperglycemia, renal failure, toxic alcohol ingestions, etc. It will be a waste of everyone's time, and I will laugh at you. I will also laugh at you if you come to me with a patient on a thiazide diuretic. I will not laugh if you have a patient with a reset osmostat, which just means that the osmoreceptors regulate ADH secretion in a lower range than normal, sometimes down to a sodium of 125. I'm not going to say any more about that because we can't fix it and it doesn't really cause any harm. So to quickly recap, hyponatremia can be thought about based on what ADH and aldosterone are doing. Urineosomes reflect ADH activity, while urine sodium reflects aldosterone activity. Most hyponatremia happens because ADH is pinch-hitting for aldosterone when the effective circulating blood volume is low. Much of the rest of it happens because ADH is inappropriately secreted as in SiADH, aptly named. ADH is suppressed in hyponatremia where you consume too much free water or beer andor not enough food. But this isn't as common. Don't forget to look for a thizide diuretic and maybe check a morning cortisol. Next time we'll discuss the management and the pitfalls of management of hyponatremia. From the dark side, remember? Slightly less physiology, lots of papers to discuss.