Hyponatremia

The Hyponatremia Walk-Through... Na physiology explained!(15 minutes + scenarios) You admit a patient who's a 55 F with unknown past medical history who comes in after a seizure. Na is 108. The seizure breaks with Ativan. Labs are drawn immediately and 1L of normal saline is given. She's admitted to the MICU It's up to you to figure out why this patient is hyponatremic.... we'll circle back to this. First, is hyponatremia a problem with sodium regulation or a problem with water regulation? [[Na problem ->H2O problem]] [[H2O problem]] TODO: Add figures

Hyponatremia (or more accurately, hypotonicity) causes symptoms by tissue swelling! Here's how it happens: -the serum is hypotonic (mostly Na). -the intracellular space is eu-tonic -water moves through the semipermeable membrane to the higher tonicity compartment (=osmosis) This swelling of all the cells causes symptoms. Imagine you have a low serum sodium concentration because you have some other solute that can't passive cross a semipermeable membrane, like glucose or mannitol. Thus, overall serum tonicity is high but the sodium concentration is low. In this case, would you expect symptoms similar to hyponatremia or hypernatremia? [[Hypernatremia ]] [[Hyponatremia ->Hypernatremia ]]

Hypernatremia! Why? The way that Na abnormalities cause symptoms is by an imabalance of tonicity between the intracellular and extracellular/serum compartments, leading to either swelling or contraction of the intracellular space. If the serum tonicity is increased, then symptoms are related to intracellular contraction - regardless of what the solute is (Na, Mannitol, Glucose). So, what's the reason people check serum osmolarity in hyponatremia workups? [[To confirm hyponatremia is real, meaning hypoosmolar->Hypoosmolar]] [[To quantify how severe hyponatremia is->Hypoosmolar]] [[To rule out psychogenic polydipsia->Hypoosmolar]]

We want to confirm that this is 'real' hyponatremia - meaning that symptoms are caused by hypotonic serum. If it is not 'real' hyponatremia (meaning, the osmolarity of the serum is unchanged or increased), then management is fixing whatever the other solute is (and looking for complications, like hypovolemia, that are normally associated with hypernatremia). Point 1: Serum osmolarity confirms that the symptoms are due to hypotonic serum, which is what we expect in hyponatremia As mentioned earlier... hyponatremia is a problem with too much water. What is the hormone that controls free water balance? [[Aldosterone->ADH]] [[ADH]] [[Natriuretic Peptides->ADH]]

It's a water problem - too much water! To explain this maximally, we need a brief review osmosis and how semipermeable membranes (e.g. cell membranes) work. If interested see the note below How does hyponatremia cause symptoms? [[Tissue Swelling]] [[Changed resting membrane potential in neurons->Tissue Swelling]] [[Increased Vagal Tone->Tissue Swelling]] Note, Mechanism: 1. Cations and Anions can't pass through the cell wall 2. H2O can freely diffuse 3. Therefore, by osmosis fluid equilibrates so that tonicity is equal on either side. 4. If there are more particles on 1 side of the membrane, it will cause there to be more water on that side but the concentration of particles will equalize. This means that retention or loss of Na causes changes in volume on either side of the membranes (intracellular or extracellular/serum). Problems with water retention or loss will lead to dilution or concentration of both sides of the membrane. Thus, hyponatremia is caused by too much free water.

ADH is the primary hormone that controls water retention or excretion. Does more ADH lead to more or less free water in the body? [[More H2O in the body]] [[Less H2O in the body->More H2O in the body]]

More H2O ADH = ADds Hydration to the body. Thus: [[More ADH = Lower Serum Na]] [[More ADH = Higher Serum Na->More ADH = Lower Serum Na]]

More ADH = Adds Hydration to serum = dilutes serum Na (lowers the serum concentration). Hypothetical: If the body (kidneys, pituitary) is functioning correctly and the serum Na is low.. should ADH be present, or suppressed? [[High ADH->Low ADH]] [[Low ADH]]

ADH should be suppressed! The body is already retaining too much water. ADH ADds Hydration to the serum by reabsorbing free water from the collecting ducts. When ADH is present, more water is reabsorbed. Thus, if ADH is not supprssed, that's a problem (and likely the cause of hyponatremia). Next step: When ADH is present (=abnormal)... would you expect concentrated or dilute urine? [[Concentrated Urine]] [[Dilute Urine->Concentrated Urine]]

Concentrated Urine! Like reducing a sauce (boiling off the water), you're left with a more concentrated solution if you remove the water. If ADH is present, water is reabsorbed to the body and the urine will be concentrated. If ADH is not present, the urine will be dilute. What is the best way to measure urine concentration? [[Urine Specific Gravity->Urine Osmolarity]] [[Urine Osmolarity]] [[Urine Sodium->Urine Osmolarity]] [[Urine Anion Gap->Urine Osmolarity]]

Urine Osmolarity (though spec grav can be used sometimes too, see below)! Because we're interested primarily in how much water has been removed. Key Point: If the body is responding appropriately to hyponatremia, ADH should be suppressed and urine osm should be low. If urine osm is high, it suggests that ADH is active, which it should not be. If ADH is present (concentrated urine), we need to explain why it is there. If ADH is not present (dilute urine), we need to explain why the serum Na is still low despite an appropriate response. Which do you want to discuss first? [[ADH is present, let's figure out why]] [[ADH is not present. Why's the sodium low?]] *Of note, the specific gravity = mass of one milliliter of solution grams can be used to approximate the urine osmolarity, especially if the urine is not filled with especially heavy particles such as glucose or contrast. 1.000 sg = osm 0 1.005 = 175 1.010 = 350 1.15 = 525 1.020 = 700 1.025 = 875 1.030 - 1050

Let's say we have a patient who has real hyponatremia (low serum osm), and that ADH is present when it shouldn't be (concntrated urine). To explore why ADH might be present, let's consider a hypothetical scenario: You've just been shot in the leg, and are losing massive amounts of blood. Sorry. Your body is doing everything it can to hold on to volume, so that blood flow can continue to deliver O2 to vital organs. What hormone does the body use to hold on to volume? [[ADH ->Aldosterone]] [[Aldosterone]] [[Natriuretic Peptides-->Aldosterone]]

If ADH is suppressed, that means that the body is responding appropriately.. but can't keep up. Let's explore why. What's the most dilute urine the (healthy) body can make? [[0 mmol/L->50 mmol/L]] [[50 mmol/L]] [[200 mmol/L->50 mmol/L]] [[500 mmol/L->50 mmol/L]]

Aldosterone! Remember: ADH = water retention = controls tonicity Aldosterone = Na retention = controls volume (because H2O follows Na - fluids will equilibrate to equal concentration on either side of a semi-permeable membrane via osmosis) If you are bleeding out, you expect that your aldosterone would be high and you would be holding on to all the sodium = volume that you can. Let's say you're bleeding out really fast... So fast that even with maximum aldosterone action you're still losing volume. Your body has a choice - which seems better to you? [[Use ADH to absorb water at the expense of lowering tonicity to temporarily increase blood volume->Use ADH]] [[Continue with maximum aldosterone and lose more volume, but maintain the serum tonicity->Use ADH]]

In extreme hypovolemia, you've evolved to sacrifice serum tonicity to maintain volume. Why? We can survive with a sodium of 130.. 120.. maybe even 110 on occasion. If you lose blood volume even for a moment, you're in cardiovascular collapse and will die. Thus, when faced with the extreme choice of: 'defend volume' or 'defend tonicity', the body is evolved to defend volume. To summarize: in extreme hypovolemia, the body will use ADH to sacrifice serum tonicity in order to temporarily maintain volume by reabsorbing free water. Though technically due to actions at other receptors... you can think of this scenario as your body using ADH as an endogenous vasopressor of last resort. After all, ADH's other name is... [[Octreotide->Vasopressin]] [[Vasopressin]] [[Oxytocin->Vasopressin]]

Vasopressin! Thus, your body can use ADH as an endogenous vasopressor if you can't maintain enough blood volume despite maximum aldosterone action to hold on to sodium. If aldosterone is not maxed out, your body won't use ADH as a pressor (because it's better to use aldosterone/Na first and not sacrifice serum tonicity if we don't have to). What lab would tell us if aldosterone is active? [[Low Urine Anion Gap->Urine Sodium]] [[High Urine Sodium->Urine Sodium]] [[High Urine Anion Gap->Urine Sodium]] [[Low Blood Pressure->Urine Sodium]] [[Low Urine Sodium->Urine Sodium]]

Urine Sodium is the key! Remember, Sodium is how the body controls volume. If due to blood loss you're losing blood volume, then your body wants to retain sodium. Aldosterone will be used to cause reabsorbtion of sodium from the distal convoluted tubule to the serum, resulting in a low urine sodium. So... where does the body figure out if it needs to hold on to volume? [[The Macula Densa in the Kidney->Kidney]] [[The atria of the heart->Kidney]] [[The pituitary gland->Kidney]]

All of the above! ADH is there and it's shouldn't be (meaning, the body is not using it like a pressor), which is creatively termed SIADH. SIADH can be caused by a variety of things (lung disease, intracranial processes, pain) or endocrinopathies (hypothyroidism, adrenal insufficiency). Thus, arriving at a diagnosis of SIADH should prompt an evaluation for all of these things. And, of course, there could be sodium in the urine because the patient is taking a diuretic.. which works by causing the kidneys to excrete sodium. So make sure they're not taking a diuretic. Got it? [[Yes, let's talk about hyponatremia with an appropriate, suppressed ADH->ADH is not present. Why's the sodium low?]] [[Yes, let's do some practice scenarios]] [[No, let's walk through hyponatremia with ADH present->ADH is present, let's figure out why]]

The afferent limb of the RAAS system starts at the Macula Densa in the kidney. The Macula Densa senses sodium delivery to the distal convoluted tubule. If it's low, it tells the juxtaglomerular apparatus to secrete Renin...blah blah blah.. eventually you get more aldosterone. Less sodium to macula densa = more aldosterone = more sodium reabsorption = less sodium in the urine. If, despite this, the sodium delivery continues to drop.. it might get so bad that the body decides to use ADH to maintain volume (as sensed by the macula densa) at the expense of tonicity. So.. is there anything else besides profound hypovolemia that might 'trick' the kidney causing a profoundly decreased sodium delivery to the macula densa? [[Heart failure with congestion lowering renal perfusion pressure.. aka cardiorenal physiology->Hypervolemic]] [[Abdominal compartment syndrome reducing renal perfusion->Hypervolemic]] [[Cirrhosis leading to preferential flow through the splanchnic circulation... aka hepatorenal physiology->Hypervolemic]] [[All of the above->Hypervolemic]]

All of the above can! Cardiorenal, Hepatorenal, Abdominal compartment syndrome... and all of these are misinterpreted by the kidney as PROFOUND hypovolemia. However, it's a vicious cycle... because the retention of sodium makes them WORSE, not better (as in the case of hypovolemia). The kidney's fluid retention feedback loops do not respond correctly to a failing heart, liver, etc. Based on the things we've talked about (serum osm, urine osm, and urine sodium)... how can you tell those etiologies apart from profound hypovolemia? [[Urine osm is different->exam]] [[Urine sodium is different->exam]] [[Serum osm is different->exam]] [[You can't, do an exam->exam]]

Exam is the only way! You have to assess the patient's volume status, which can be tricky! Especially if you're trying to decide between euvolemia and hypovolemia.. or hypevolemia and euvolemia. Good new! You're just trying to tell: are they in profound hypovolemia, florid heart failure, cirrhosis, or abdominal compartment syndrome - which generally aren't subtle! Unlike the classic categorization of hyponatremia that relies on initial classification by volume status - the ONLY time you need to assess volume status is in the case of: real hyponatremia (low serum osm), ADH is inappropriately present (concentrated urine), and the body is maximally reabsobing sodium (low urine Na). Switching gears: if urine is concentrated (high osms, ADH is present) but urine sodium IS NOT LOW... how do you explain that? [[ADH is there... inappropriately? ->SIADH]] [[Adrenal Insufficiency, Hypothyroidism, or other zerbras ->SIADH]] [[Syndrome of Inappropriate Diuretic Use ->SIADH]]

It's about 50 mmol/L. (Conversely, a health kidney can make urine as concentrated as 1200 mmol/L) Every day, the body produces about 10 mmol/kg/day of solute (metabolic waste), assuming a normal diet. So, a 60 Kg person makes 600 mmol of waste per day that the kidney needs to excrete. What's the maximal amount of urine you can make? -Maximal urine volume = GFR * 60 minutes * 24 hours = [[172.8L->12L]] -Maximal urine volume = daily solute load / minimum urine concentration = [[12L]]

Maximal urine volume = daily solute load / minimum urine concentration = 12L (Maximal urine volume = GFR * 60 minutes * 24 hours = 172.8L is the amount of blood that is filtered through the glomerulus in a day, but you can't urinate ALL of that out - which would require pumps working against a huge concentration gradient... thus much of it must be reabsorbed.) What would happen if you drank 15L of water in a day? -You'd make 12L of maximally dilute urine, then the remaining 3L would remain in the body leading to dilution of the solutes in the body = hypotonicity and [[Hyponatremia]] -You'd make 12L of maximally diluate urine, then the body wouldn't not absorb any more [[no change in sodium ->Hyponatremia]] -[[You can't drink that much->Hyponatremia]]

You'd make 12L of maximally dilute urine, then the remaining 3L of "electrolyte free water" (also sometimes called just free water) would dilute the serum, leading to hypotonic, hyponatremic serum. This is the simplest way to get hyponatremia despite a functionally responding kidney (=no ADH, maximally diluate urine): drinking so much water the kidney can't keep up! This is how psychogenic polydypsia causes hyponatremia. How else can you get hyponatremia despite a suppressed ADH? Consider: What happens if you eat half as much total solute every day? -Waste production stays the same, maximally dilute urine stays the same, so [[no change->decreased]] in the amount of water you can drink before sodium drops. -Waste production stays the same, maximally dilute urine becomes more dilute, so you can handle [[more->decreased]] water before sodium drops. -Waste production drops, maiximally dilute urine stays the same, so you can only drink a [[decreased]] amount of water before sodium drops

Ethanol (C2H5OH) -> CO2 and H2O. What are carbohydrates metabolized to? [[CO2 + H2O]] [[Na, NH4, and CO2->CO2 + H2O]] [[Uric acid and H2O->CO2 + H2O]]

Yes! Carbohydrates are also all carbon, oxygen, and hydrogen. How is CO2 excreted? [[Lungs]] [[Bowels->Lungs]] [[Kidneys->Lungs]]

Mostly Lungs! As ventilation eliminates most carbon-dioxide (a smaller amount can be converted to bicarbonate that is excreted in the kidney). Thus, just water remains. So, as far as the kidneys are concerned, beer (EtOH and Carbohydrates) is just water! If you get most of your calories from beer, you are not taking in solutes, and you can overwhelm the kidneys ability to excrete free water. This is 'beer potomania'. Lastly, what happens in chronic kidney disease that is almost end-stage. Imagine, you drink 2.5L of water, but you can only make 2L of urine because the GFR is so low? Hyponatremia with [[Appropriate ADH response]] Hyponatremia with [[Inappropriate ADH response->Appropriate ADH response]] Hypernatremia with [[Inappropriate ADH response->Appropriate ADH response]]

Total solutes in has to equal total solutes out (or else you'd be wasting away!), so your solute waste production goes down if you eat less. Thus, if the most dilute urine you can make (50 mmol/L) is the same, then half as much waste production (5 mmol / kg / day) in a 60kg person leads to half (6L of H2O) before the remaining free water is retained and dilutes the serum! If you eat 1/4 as much solute (for long enough to reach steady state) as an average person.. then how much water can you drink per day before your serum sodium drops? [[24L->3L]] [[12L->3L]] [[6L->3L]] [[3L]]

1/4 as much solute = can drink 1/4 as much water as normal (12L -> 3L). If you drink more than 3L, serum sodium and tonicity drops. This is 'tea and toast' hyponatremia: Serum sodium and tonicity is low, ADH is appropriately suppressed, but water intake overwhelms the ability of the kidney to excrete it! Let's talk about another mechanism... What is Ethanol metabolized in to? [[CO2 and H2O]] [[Na, NH4, and CO2->CO2 and H2O]] [[Uric acid and H2O->CO2 and H2O]]

You get hyponatremia with an appropriate (suppressed) ADH response! Because the body is trying to respond appropriately to excess free water, but because the kidneys can't filter quick enough to excrete that free water - so serum sodium will drop. So, to review. There are several ways you can get a low serum sodium despite an appropriate (suppressed ADH, maximally dilute urine) response: 1. You drink huge amounts of free water (Psychogenic polydypsia) 2. You do not take in much solute (Tea and Toast) 3. Your intake is entirely digested to H2O and CO2, then the CO2 is breathed off (Beer Potomania) 4. Your kidneys don't filter fast enough, so can't keep up with even relatively normal amounts of water intake. Or, more commonly, some combination of the above factors! Got it? [[Yes, let's review causes of hyponetremia with non-suppressed ADH->ADH is present, let's figure out why]] [[Yes, let's do some practice scenarios]] [[No, let's walk through it 1 more time->ADH is not present. Why's the sodium low?]]

Key: Low serum osmolarity = below 270 ADH suppressed = urine osms below 100 Aldosterone active = urine sodium below 20 Question 1: Serum Osm 450 Urine Osm 330 Urine Na 70 Which of the following is the cause? It's DKA! Since the serum osms is high (not low) this is NOT real hyponatremia - in fact, you would expect symptoms more typical of hypernatremia (thirst, osmotic diuresis). Of the options, the only clinical scenario that involves another solute is DKA (glucose). [[Question 2]]

Key: Low serum osmolarity = below 270 ADH suppressed = urine osms below 100 Aldosterone active = urine sodium below 20 Question 2: Serum Osm 250 Urine Osm 70 Urine Na 20 Which of the following is the cause? [[Beer Potomania-->Beer Potomania!]] [[DKA-->Beer Potomania!]] [[CHF-->Beer Potomania!]] [[SIADH-->Beer Potomania!]] [[Profound hypovolemia-->Beer Potomania!]]

Key: Low serum osmolarity = below 270 ADH suppressed = urine osms below 100 Aldosterone active = urine sodium below 20 Question 2: Serum Osm 250 Urine Osm 70 Urine Na 20 This is Beer Potomania! -Serum osms are low, so this is REAL hyponatremia (excess free water). -ADH is suppressed so the body is making dilute urine. This means the body is responding appropriately, but can't keep up. -The only clinical scenario of the options that involves the body have an appropriate response to excess free water is beer potomania - though psychogenic polydypsia, tea and toast, and CKD would all cause identical laboratories. We don't need to use the urine sodium because we are not worried that the body is using ADH like a vasopressor. [[Question 3]]

Key: Low serum osmolarity = below 270 ADH suppressed = urine osms below 100 Aldosterone active = urine sodium below 20 Question 3: Serum Osm 250 Urine Osm 500 Urine Na 10 Which of the following is the cause? [[Need more info]] [[Hypovolemia->Need more info]] [[Cirrhosis->Need more info]] [[SIADH->Need more info]] [[CKD->Need more info]]

Key: Low serum osmolarity = below 270 ADH suppressed = urine osms below 100 Aldosterone active = urine sodium below 20 Question 3: Serum Osm 250 Urine Osm 500 Urine Na 10 We need more info! We've gone down this algorithm: Serum Osm 250 = real hyponatremia Urine Osm 500 = ADH is present Urine Na 10 = the kidney is trying to hold on to volume due to decreased Na to the macula densa... thus we need to figure out why! In this case, a volume exam could differentiate between hypovolemia, heart failure, cirrhosis, etc. [[Question 4]]

Low serum osmolarity = below 270 ADH suppressed = urine osms below 100 Aldosterone active = urine sodium below 20 Question 4: We return to our initial scenario! "You admit a patient who's a 55 F with unknown past medical history who comes in after a seizure. Na is 108. The seizure breaks with Ativan. Labs are drawn immediately and normal saline is given." She's admitted to you in the MICU. You astutely fire off 'hyponatremia labs' off her admission blood draw and first urine sample: Serum Osm 220 Urine Osm - Pending Urine Na - Pending Upon arrival to the MICU, a blood gas is repeated and shows her Na is now 106. Going DOWN! How is this possible? If the urine is [[more concentrated than the serum->more concentrated than the normal saline]], the serum sodium drops If the urine is [[more concentrated than the normal saline]], the sodium drops If the [[Urine sodium level is higher than the normal saline sodium->more concentrated than the normal saline]] level, the serum sodium drops

If the Urine is more concentrated than the normal saline, then free water in > free water out, and the serum will get more dilute! Whoops.... Labs return... Key: Low serum osmolarity = below 270 ADH suppressed = urine osms below 100 Aldosterone active = urine sodium below 20 Serum Osm 220 Urine Osm - 500 Urine Na - 100 What's going on? [[Hypovolemia->Syndrome of Inappropriate ADH]] [[Hypervolemia->Syndrome of Inappropriate ADH]] [[Syndrome of Inappropriate ADH]]

Syndrome of Inappropriate ADH: Hyponatremia is real (low urine osms) ADH is present (concentrated urine) ADH is not being used as a pressor (Urine sodium not below 20) Note: this could theoretically be due to a thiazide diuretic, but you'd usually not have the Na drop after normal saline. It would be appropriate to screen for Adrenal, Thyroid, and causes of SIADH at this point. What are the options to treat this? [[Free water restriction->All 3 of the above]] [[Loop Diuretic->All 3 of the above]] [[Extra solute intake->All 3 of the above]] [[All 3 of the above]]

Believe it or not, all 3 of the above work! Why? Recall: when reasoning causes of hyponatremia with a suppressed (=appropriate) ADH... Maximal urine volume = daily solute load / minimum urine concentration When extra ADH is present, the minimum concentration of the urine is increased... in this case, the minimum urine concentration is (presumably) 500. If this person has an average diet (10 mmol/kg) and weighs 50 kg (to make the math easy).. what's the maximum amount of urine they can make? [[10L->1L]] [[1L]] [[100 mL->1L]]

500 mmol of solute / 500 mmol/L of urine concentration = 1 L of urine Thus, if they take in more than 1L of free water in 24h, they will retain the rest and the sodium concentration will drop. (Similarly, if you give normal saline = 308 mmolL.. the kidney excretes 500 mmol/L concentration and keeps the rest of the free water = why the serum sodium drops). Unfortunately, it's essentially impossible to restrict free water intake to less than 1L per day... What would happen if you doubled the solute intake? (to 20 mmol/kg/day) [[Halve the amount of free water they can drink in a day->Double the amount of free water they can drink in a day]] [[Double the amount of free water they can drink in a day]] [[Square the amount of free water they can drink in a day->Double the amount of free water they can drink in a day]]

You'd double it! 20 mmol/kg/day * 50 kg = 1000 mmol/d 1000 mmol / 500 mmol/L = 2L of free water that is allowable! (Note... that this doesn't have to be sodium, but can be any solute!) 2L is, unfortunately, still pretty hard to maintain. How does the furosemide play in to this? Furosemide makes (to a very rough approximation), urine that is eutonic to barely hypotonic when compared with the serum. Thus... if you increase the urine output, you can help further lower the urine Na as long as... [[Urine osm greater than Serum osm]] [[Urine na greater than serum osm ->Urine osm greater than Serum osm]] [[Urine osm less than serum osm->Urine osm greater than Serum osm]] [[urine na less than serum osm->Urine osm greater than Serum osm]]

Urine osm greater than Serum osm! This is because, if you make more urine that is closer to the serum osm.. you are decreasing the 'minimum concentration' of urine (independent of ADH), and thus allowing for more urine to be produced with the same solute intake! The last treatment is the most obvious.... you could use an inhibitor at the vasopressin receptors (-vaptans), but they are expensive and have liver related side effects.. and are boring physiologically so we'll leave them off. The End! Thanks for completing!