Take your salt game to the next-next level. We brushed off this fan favorite episode and rebooted #48 hyponatremia deconstructed with our Chief of Nephrology, Dr. Joel Topf aka @kidney_boy aka The Salt Whisperer for your CME earning pleasure. Learn the correct steps to diagnose and manage this common and dangerous condition. Topics covered include: true versus false hyponatremia, SIADH, tea and toast hyponatremia, beer potomania, safe rates of sodium correction, IV fluid choice, vaptans and more.
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Serum sodium is used as a marker for serum osmolality, the amount of material per liter dissolved in a fluid (typically 285-295 mmol/L). High serum osmolality draws water from the cellular compartment to the extracellular compartment, which can cause damage to tissues. Conversely, low serum osmolality drives fluid into the intracellular compartment leading to cellular edema and dysfunction.
Hyponatremia can cause anything from moderate symptoms like nausea and vomiting to severe symptoms like coma and death (Spasovski et al 2016). Even asymptomatic hyponatremia can still have clinical implications for older patients, it is associated with increased risk of falls and fractures (Kuo et al 2017).
Not all serum components cause movement of water; urea, ethanol, and other small nonpolar molecules that can freely cross the cell membrane and do not contribute to tonicity, which can be thought of as functional osmolality. Glucose does not contribute to tonicity in normal circumstances due to insulin dependent transport. However, hyperglycemia is an indication that the body cannot effectively manage glucose, turning it into a component of tonicity. While hyperglycemia leads to a measured hyponatremia, the high osmolality caused by hyperglycemia leads to fluid shifts consistent with hypernatremia; water leaving the intracellular space. While serum sodium and tonicity generally agree, this is not always the case. Some individuals have a low sodium yet a high tonicity (Adrogué and Madias 2000 and Rondon-Berrios et al 2017).
The first step in assessing hyponatremia is rechecking the lab to confirm that it is a true measurement. Once you are confident that the measured hyponatremia is real, assess osmolality. Serum osmolality is important because there are different approaches for hyperosmolar-hyponatremia or hypoosmolar-hyponatremia. Hypoosmolar-hyponatremia is most common, which means that the low sodium and osmolarity are concordant.
Low sodium with normal osmolality is likely a lab artifact; increased serum protein or lipids increases the insoluble fraction of a blood sample. This leads to over dilution of the soluble serum component during processing and a falsely reported low serum sodium, when the sample’s actual tonicity is normal. No additional intervention is needed in patients with mild hyponatremia and normal osmolality, but the cause of high protein should be investigated with a drug history (IVIG), lipid panel, and/or serum protein electrophoresis (Spasovski et al 2016).
Low sodium with high osmolality is due to high levels of an additional osmolite, most likely glucose, drawing water into the blood. To understand the sodium concentration in the context of hyperglycemia, correct the level of sodium for hyperglycemia (Hillier and Barrett 1999).
True hyponatremia (hypoosmolar-hyponatremia) is caused by a higher water intake than output, regardless of the cause, this fluid imbalance will lead to sodium dilution and hyponatremia. The first question to ask when a patient is found to have hypoosmolar-hyponatremia is: is this ADH dependent hyponatremia or is this ADH independent hyponatremia? Hyponatremia is often caused by ADH aka antidiuretic hormone aka vasopressin, but think of it as the ADds Hydration hormone. ADH is primarily released in response to hyperosmolality–acting to reduce the amount of fluid excreted by the kidneys, thus retaining free water. Hypotension from volume depletion also increases ADH excretion, which at high levels can cause vasoconstriction. The body’s ability to detect volume is really detecting pressure and stretch, so when there is perfusion failure, the body thinks this is a volume failure leading to ADH mediated water retention. When volume and osmolality are in opposition, the body will retain volume at the expense of osmolality.
To determine the influence of ADH, check the urine osmolality using the urine specific gravity (spec grav if you want to sound cool) of the urine analysis (UA). If the hyponatremia is ADH independent, the spec grav (yes we’re cool) will be 1.005-1.010 [urine osmolality <100-200 mOsm/kg] for dilute urine or isosthenuric urine (a fancy way of saying a urine concentration neither more nor less dilute than protein-free plasma) indicating that the condition is likely caused by tea-and-toast, beer drinkers potomania, or primary polydipsia. If the hyponatremia is ADH dependent the urine will be concentrated, with an osmolality greater than 200-300 mOsm/kg.
Healthy kidneys can produce 18 liters of urine a day or around 0.75 liters an hour. To have hyponatremia secondary only to excessive water intake, as is the case in primary polydipsia, the individual must exceed this threshold. However, water intake does not need to be that extreme to produce hyponatremia via a solute deficit. Dr. Topf reminds us that a bowl of spaghetti is the same as a cup of water to a nephrologist–we are no longer eagerly awaiting an invitation to Dr. Topf’s Sunday night spaghetti dinners–because the carbohydrates are metabolized to water and CO2. Tea-and-toast or beer potomania hyponatremia occur when low solute intake limits the ability of the kidneys to produce urine that maintains electrolyte homeostasis.
Normal solute intake is 10mOsm solute per kg body weight per day, or 600 mOsm/day in a 60 kg individual. This solute is subsequently excreted via urine, which can be concentrated in a range from 50 mmol/L to 1200 mmol/L. So for a person eating a normal diet of 600mOsm, the kidney can produce a max of 12 L urine output if it were completely dilute (50 mmol/L) to a minimum 0.5 L urine if fully concentrated (1200 mmol/L). In tea-and-toast diet or beer potomania, there is too little solute intake. Consider these calculations in the context of a diet that is 100 mOsm/day instead of the expected 600 mOsm/day, now the maximum amount of urine would be 2 L (100mOsm/day 50 mOsm/L = 2 L). It is much easier to exceed this 2 L fluid consumption threshold. The limited urine production of acute kidney failure or end stage renal disease means that even smaller volumes of water ingestion are necessary to cause ADH independent hyponatremia.
While we don’t believe in shortcuts, a good first guess at the cause of hyponatremia, when the urine osmolality is low, is:
Little old lady? Tea-and-toast
Alcoholic? Beer potomania
Water drinking contest? Primary polydipsia
Cr 8? Kidney failure
ADH dependent hyponatremia can either be hypervolemic (ex: heart failure, liver failure, or nephrotic syndrome), hypovolemic (ex: GI losses, renal losses, or bleeding), or euvolemic (SIADH, hypothyroid, or adrenal insufficiency). The urine osmolality in ADH dependent hyponatremia is concentrated compared to serum, typically 300-800 mOsm/kg. While a volume status exam would be a useful way to distinguish between these causes–with jugular venous pressure, orthostatics, peripheral edema, mucous membrane moisture, and skin turgor providing some information–volume status exams are notoriously unreliable (Chung et al 1987). Stuart was kind enough to remind us that axillary moisture is one of the best indicators of volume status, but for some reason, I keep forgetting to check my patients’ armpit sweat (Evidence-Based Physical Exam). History can also be a very useful tool; a diagnosis of heart failure, recent diarrhea, or history of certain medications can provide a clue to the pathology of hyponatremia. SSRI, anti seizure, sulfonylurea, or opioid medications can lead to SIADH mediated hyponatremia (Shepshelovich et al 2017 and Liamis et al 2008).
Urine electrolytes and serum uric acid can provide additional information to distinguish between different etiologies of ADH dependent hyponatremia. In heart failure, cirrhosis, and volume depletion urine sodium will be low. Serum uric acid is increased in heart failure and volume depletion, but reduced in SIADH. (Sterns 2015)
SIADH is a diagnosis of exclusion. Check cortisol to rule out adrenal insufficiency, which presents with hyperkalemia and salt wasting nephropathy (Sterns 2015). Check TSH, which can indicate hypothyroid mediated hyponatremia (Schmitz 2001). Pain (Salaami 2018), surgery (Cornforth 1998), positive pressure ventilation, asthma, medications (Liamis et al 2008), pneumonia (Don et al 2008), and head injury (Dozi et al 1982) can cause transient SIADH (Sterns 2015). SIADH can also be a presenting or late finding for lung cancer, while cancer is not typically the cause of hyponatremia, considering the link between SIADH and neoplastic conditions may lead to life saving early detection (Tai et al 2006).
Treatment of hyponatremia should start with treating the underlying cause: if it is caused by heart failure, treat the heart failure; if it’s caused by hypothyroidism, treat the hypothyroidism; if it’s caused by a medication, stop the medication etc. Normal saline can improve hyponatremia due to hypovolemia, but it worsens hypervolemic-hyponatremia (ex: heart failure); giving a small bolus of fluids and watching the response can differentiate between these conditions and/or alarm unsuspecting doctors.
Dr. Topf’s threshold for hospital admission hyponatremia is < 130 mEq/L.
Mild to moderate hyponatremia from SIADH will typically correct with fluid restriction and salt tabs. Salt tablets can relax fluid restriction by adding solute load. One approach to this pathophysiology is using oral flavored urea-sodium replication with UreNa (yummy?) (Nervo et al 2019). Interestingly, while loop diuretics are often associated with electrolyte abnormalities, administration of loop diuretics can actually speed sodium correction in SIADH (Ellison and Berl 2007).
Sodium correction for severe hyponatremia should be done slowly to avoid the rare but devastating consequence of central pontine myelinolysis (Norenberg et al 1982). Rate of correction for chronic low serum sodium is 5 mEq immediately, 10 mEq over the first day, and 8 mEq per day after that. Aiming for 6 mEq per day gives you a buffer; the guidelines are 0.5 meq/h, so if you aim for 6 mEq, and go a bit too fast, you still stay under the speed limit. Don’t use normal saline for SIADH, for this condition you need to use 3% sodium or you will make it worse. (Spasovski et al 2016)
The “Seal Team 6” of hyponatremia is a “DDAVP clamp” performed in the ICU. This method uses DDAVP, to take kidney autocorrection response out of the picture when trying to correct hyponatremia, so the serum sodium responds in a predictable manner to hypertonic saline.
ADH antagonists (vaptans) are another treatment for select cases of hyponatremia. Tolvaptan is effective, but it is also expensive and associated with liver toxicity (Schrier et al 2006 and Khan et al 2019). More recently the TEMPO 3:4 trial found that tolvaptan slows the progression of autosomal dominant polycystic kidney disease (Torres et al 2012).
More information on the treatment of hyponatremia European Society of Endocrinology Clinical Practice Guidelines is Dr. Topf’s recommended resource.
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Listeners will recall the pathophysiology of hyponatremia and develop a systematized approach to identifying the type and cause of hyponatremia, as well as how to safely manage hyponatremia.
After listening to this episode listeners will…
Dr. Topf has received honoraria from AstraZeneca and Cara Therapeutics. He is joint venture partner in Davita Dialysis centers receiving dividends. The Curbsiders report no relevant financial disclosures.
Topf J, Gorth DJ, Williams PN, Brigham SK, Heublein M, Jyang E, Watto MF. “REBOOT #48 Hyponatremia Deconstructed”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Original air date: July 17, 2017; Updated September 7, 2020.
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