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Hyponatremia represents the most common electrolyte abnormality encountered in both inpatient and outpatient settings and reflects a complex disturbance involving total body water and total body sodium balance. The condition develops when total body water exceeds total body solute, most often due to impaired renal free water excretion or excess antidiuretic hormone activity. Clinicians classify hyponatremia as hypovolemic, euvolemic, or hypervolemic, and may further characterize it by serum tonicity to account for additional osmoles such as glucose or alcohol. Serum sodium levels below 135 mEq/L generally define the disorder, though clinical context influences interpretation. The physiologic regulation of sodium and water depends on kidney function, cardiac output, antidiuretic hormone, natriuretic peptides, and the distribution of intracellular and extracellular fluids. Disruption in any of these systems contributes to the broad diagnostic spectrum. Accurate assessment of volume status, understanding of osmotic gradients, and awareness of underlying endocrine and renal mechanisms are essential for appropriate diagnosis and management. The learning activity equips participants with a structured understanding of when to consider hyponatremia in the differential diagnosis, how sodium transport mechanisms influence clinical presentation, and which laboratory and clinical assessments guide accurate classification. Instruction emphasizes evidence-based treatment strategies, including emerging therapeutic options that support the safe correction of serum sodium. Participants strengthen their ability to interpret laboratory values, apply physiologic principles, and tailor interventions to individual patient profiles. Collaboration with an interprofessional team—including clinicians, nurses, pharmacists, nephrologists, and dietitians—enhances patient safety by supporting coordinated monitoring, preventing overly rapid correction, and ensuring comprehensive evaluation of contributing conditions. Engagement in this activity promotes more effective, consistent, and patient-centered management of hyponatremia, ultimately improving clinical outcomes. Objectives: Assess hemodynamic status, urine studies, and biochemical markers to determine dilutional versus depletional states accurately.

The learning activity equips participants with a structured understanding of when to consider hyponatremia in the differential diagnosis, how sodium transport mechanisms influence clinical presentation, and which laboratory and clinical assessments guide accurate classification. Instruction emphasizes evidence-based treatment strategies, including emerging therapeutic options that support the safe correction of serum sodium. Participants strengthen their ability to interpret laboratory values, apply physiologic principles, and tailor interventions to individual patient profiles. Collaboration with an interprofessional team—including clinicians, nurses, pharmacists, nephrologists, and dietitians—enhances patient safety by supporting coordinated monitoring, preventing overly rapid correction, and ensuring comprehensive evaluation of contributing conditions. Engagement in this activity promotes more effective, consistent, and patient-centered management of hyponatremia, ultimately improving clinical outcomes. Objectives: Assess hemodynamic status, urine studies, and biochemical markers to determine dilutional versus depletional states accurately. Implement guideline-supported strategies, including fluid restriction, salt supplementation, vaptans, or hypertonic saline. Differentiate hypotonic hyponatremia from isotonic or hypertonic presentations influenced by osmoles such as glucose, mannitol, or lipids. Communicate the importance of enhancing care coordination among the interprofessional team to ensure proper evaluation and management of hyponatremia. Access free multiple choice questions on this topic.

A crucial development that enabled animals to migrate from an aquatic to a terrestrial environment is the regulation and conservation of water and salt during periods of excess and scarcity. Hyponatremia is the most common electrolyte abnormality found in hospitalized individuals. This condition is usually defined as a serum sodium concentration of less than 135 mEq/L, but may vary slightly depending on the laboratory's set values.[1] An excess of total body water usually causes hyponatremia relative to total body sodium content. Sodium and water balance depend on a complex interplay between volume status, antidiuretic hormone, kidney function, cardiac function, natriuretic peptides, and other hormones. Hyponatremia represents an imbalance in this ratio, in which total body water exceeds total body solutes. Total body water comprises 2 main compartments: extracellular fluid (ECF), which accounts for one-third, and intracellular fluid (ICF), which accounts for the remaining two-thirds. Sodium is the primary solute of ECF, and potassium is the primary solute of ICF. Hyponatremia can be classified as follows: Mild is 130–135 mEq/L. Moderate is 125–130 mEq/L. Severe is <125 mEq/L.[2] Patients with hyponatremia are classified into 3 main categories: hypovolemic, euvolemic, and hypervolemic. In addition, patients can be categorized by tonicity as hypotonic, eutonic, or hypertonic. Tonicity is defined as the amount of effective osmoles that cannot cross the cellular membrane from the extracellular to the intracellular space and therefore influence the movement of water across cell membranes. This differs from serum osmolality, which includes all solutes and is defined as 2 x [Na] + [glucose]/18 + [blood urea nitrogen]/2.8. Osmolality is dependent on the properties of the solution and independent of movement across a membrane. Tonicity excludes urea, which freely crosses the cellular membrane and can also be considered a measurement of effective osmoles. Tonicity is defined as 2 x [Na] + [glucose]/18. In normoglycemia, glucose can be excluded as its contribution to tonicity is minimal (5–10 mOsm/kg). Normal tonicity is 285 to 295 mOsm/kg; hypertonicity is more than 295 mOsm; hypotonicity is less than 285 mOsm/kg.[3][4]

Osmolality is dependent on the properties of the solution and independent of movement across a membrane. Tonicity excludes urea, which freely crosses the cellular membrane and can also be considered a measurement of effective osmoles. Tonicity is defined as 2 x [Na] + [glucose]/18. In normoglycemia, glucose can be excluded as its contribution to tonicity is minimal (5–10 mOsm/kg). Normal tonicity is 285 to 295 mOsm/kg; hypertonicity is more than 295 mOsm; hypotonicity is less than 285 mOsm/kg.[3][4] Most hyponatremic individuals will have hypotonic hyponatremia. Exceptions include those with hyperglycemia, those who received mannitol or immunoglobulins, and those with pseudohyponatremia. Understanding and treating hyponatremia is important as even mild hyponatremia has been shown to cause increased morbidity and mortality, particularly in older adults.[5][6]

The etiology of hyponatremia can be classified according to extracellular fluid volume status. As mentioned earlier, sodium (Na) is the primary solute of extracellular fluid (ECF). Based on ECF volume, a patient can be classified as being hypovolemic, euvolemic, or hypervolemic.[7] To understand the movement of sodium and water in the kidney, it is essential to understand the roles of the different nephron segments. Under normal physiologic conditions, the kidney filters free water, and about 70% and 20% is reabsorbed in the proximal tubule and thin descending loop of Henle, respectively. Both of these segments express aquaporin-1, a water channel located on the apical and basolateral tubular membranes. In the proximal tubule, water can also diffuse paracellularly, accounting for about 30% of this segment's water transport.[8] The thin descending loop of Henle is permeable to water but impermeable to solutes, allowing urine concentration mediated by the countercurrent multiplier. On the other hand, the ascending loop of Henle and the distal convoluted tubule are impermeable to water and are also known as the diluting segments. The Na+/potassium (K+)/chloride 2 (2Cl-) channel, located on the apical side of the thick ascending loop of Henle, is essential to creating the medullary gradient via active transport. Therefore, the descending loop of Henle helps concentrate urine, while the ascending loop helps dilute it.[9] The more distal segments are where active regulation of water absorption occurs. The primary regulator is through arginine vasopressin (AVP), also known as antidiuretic hormone. The distal convoluted tubule begins after the macula densa part of the nephron. This segment absorbs about 5% to 10% of filtered Na. Absorption of Na in this segment is primarily mediated through the NaCl cotransporter (also the site of action for thiazide-like diuretics). The distal convoluted tubule can be divided into early and late segments (ie, DCT1 and DCT2).

The more distal segments are where active regulation of water absorption occurs. The primary regulator is through arginine vasopressin (AVP), also known as antidiuretic hormone. The distal convoluted tubule begins after the macula densa part of the nephron. This segment absorbs about 5% to 10% of filtered Na. Absorption of Na in this segment is primarily mediated through the NaCl cotransporter (also the site of action for thiazide-like diuretics). The distal convoluted tubule can be divided into early and late segments (ie, DCT1 and DCT2). In addition to the NaCl co-transporter, the latter segment of the collecting tubule (DCT2) contains epithelial sodium channels (ENaC), which help create a negative transmural potential difference in the tubular lumen. This is the site of action for potassium-sparing diuretics (eg, amiloride and triamterene). They can be used in conjunction with thiazide-type diuretics for additional diuresis. Mineralocorticoid receptors for aldosterone are present throughout the distal convoluted tubule, but the latter segment is more sensitive to aldosterone. This is the site of action for mineralocorticoid receptor antagonists (ie, finerenone, spironolactone, eplerenone). Several distal convoluted tubules converge to form the collecting ducts.[10][11] The collecting duct is impermeable to water in the absence of external factors, which is how the body regulates water absorption and serum osmolality. AVP is the major hormone regulating Na and water reabsorption. AVP binds to V1 and V2 receptors; V1 receptors mediate the vasoconstrictive effects of AVP, and V2 receptors cause aquaporin-2 water channels to translocate to the apical collecting duct tubular membrane. Aquaporin-3 and aquaporin-4 are constitutively expressed in the basolateral membrane, allowing water to be reabsorbed in the collecting duct of the nephron as it is transported from urine to the interstitium.[8][9] In addition, the connecting tubule and the outer cortical and medullary parts of the collecting duct are impermeable to water; in the presence of AVP, the inner medullary collecting duct becomes permeable to urea by the UTA1 and UTA3 channels.[9] Other hormones affecting the collecting duct include renin and endothelin.[12]

Aquaporin-3 and aquaporin-4 are constitutively expressed in the basolateral membrane, allowing water to be reabsorbed in the collecting duct of the nephron as it is transported from urine to the interstitium.[8][9] In addition, the connecting tubule and the outer cortical and medullary parts of the collecting duct are impermeable to water; in the presence of AVP, the inner medullary collecting duct becomes permeable to urea by the UTA1 and UTA3 channels.[9] Other hormones affecting the collecting duct include renin and endothelin.[12] Physiological stimuli that trigger vasopressin release, along with increased fluid intake, can lead to hyponatremia. Stimuli for vasopressin release include loss of intravascular volume (hypovolemic hyponatremia), loss of effective intravascular volume (hypervolemic hyponatremia), drugs, and symptoms of inappropriate antidiuretic hormone (SIADH). Please see StatPearls' companion reference, "Symptom of Inappropriate Diuretic Hormone."[13]. Causes of Hypovolemic Hyponatremia (TBW decreases less than a decrease in total body sodium) Gastrointestinal fluid loss (diarrhea or vomiting) Third spacing of fluids (pancreatitis, hypoalbuminemia, small bowel obstruction) This creates relative intravascular depletion. Diuretics Osmotic diuresis (glucose, mannitol) Salt-wasting nephropathies Cerebral salt-wasting syndrome (urinary salt wasting, possibly caused by increased brain natriuretic peptide). For further information, please see StatPearls companion reference, "Cerebral Salt Wasting." [14][15] Mineralocorticoid deficiency Causes of Hypervolemic Hyponatremia (TBW increases greater than an increase in total body sodium) Renal causes (acute renal failure, chronic renal failure, nephrotic syndrome) Extrarenal causes (congestive heart failure, cirrhosis) Iatrogenic [16][17] Causes of Euvolemic Hyponatremia (TBW increase with stable total body sodium) Nonosmotic, pathologic vasopressin release may occur in the setting of normal volume status, as with euvolemic hyponatremia. Causes of euvolemic hyponatremia include the following: Drugs (mentioned below) Syndrome of inappropriate antidiuretic hormone (SIADH) Addison disease Hypothyroidism High fluid intake in conditions like primary polydipsia or potomania, caused by a low intake of solutes, with relatively high fluid intake Medical testing related to excessive fluids, such as a colonoscopy or cardiac catheterization [18][19][20]

Drugs (mentioned below) Syndrome of inappropriate antidiuretic hormone (SIADH) Addison disease Hypothyroidism High fluid intake in conditions like primary polydipsia or potomania, caused by a low intake of solutes, with relatively high fluid intake Medical testing related to excessive fluids, such as a colonoscopy or cardiac catheterization [18][19][20] Iatrogenic [13][18][19][20] Many drugs cause hyponatremia, and the most common include: Vasopressin analogs such as desmopressin and oxytocin Medications that stimulate vasopressin release or potentiate the effects of vasopressin, such as selective serotonin-reuptake inhibitors and other antidepressants, morphine, and other opioids Medications that impair urinary dilution, such as thiazide diuretics Medications that cause hyponatremia, such as carbamazepine or its analogs, vincristine, nicotine, antipsychotics, chlorpropamide, cyclophosphamide, nonsteroidal anti-inflammatory drugs Illicit drugs, such as methylenedioxymethamphetamine (MDMA or ecstasy).[18]

Hyponatremia is the most common electrolyte disorder, with a prevalence of 20% to 35% among hospitalized patients. The incidence of hyponatremia is high among critical patients in the intensive care unit and also in postoperative individuals. This is more common in older adults due to multiple comorbidities, multiple medications, and a lack of access to food and drinks.[21] In the community, an estimate is that 5% of the population has this condition.[6][21] Results from a study found that 2% to 10% of patients presenting to the emergency department had hyponatremia.[22]

Thirst stimulation, antidiuretic hormone (ADH) secretion, and handling of filtered sodium by the kidneys maintain serum sodium and osmolality. To maintain normal osmolality, water intake should be equal to water excretion, and this depends on the ability of the kidney to excrete urine of varying osmolality. There are also insensible losses through the skin and respiratory tract, which can total up to 1000 mL per day. The imbalance of water intake and excretion causes hyponatremia or hypernatremia. The kidneys filter about 180 L of water daily and usually excrete between 1 and 2 L of urine daily, depending on fluid intake. The minimal osmolarity that urine can be diluted to is 50 to 100 mOsm, and the maximal concentration that urine can reach is 1200 mOsm.[8] Patients with normal renal function can secrete up to 20 liters of water per day.[23][24] Results from one study found that the most common causes of hyponatremia are SIADH, diuretics, polydipsia, adrenal insufficiency, and heart and liver failure.[7] Water intake is regulated by the thirst mechanism, where osmoreceptors in the hypothalamus trigger thirst when body osmolality reaches about 295 mOsm/kg. Some of the sensory pathways mediating thirst involve the tongue acid-sensing receptor cells, the hypothalamic median preoptic nucleus, the subfornical organ, and the organum vasculosum.[8][25][26] Water excretion is tightly regulated by AVP (ADH), which is synthesized by the hypothalamic magnocellular neurons and stored in the posterior pituitary gland. Changes in tonicity can enhance or suppress AVP secretion. Baroreceptors in the carotid sinus and renal arteries can also stimulate AVP secretion, but they are less sensitive than the osmoreceptors. Baroreceptors trigger AVP secretion in response to decreased adequate circulating volume, nausea, pain, stress, and certain drugs.[27] Increased AVP secretion promotes water reabsorption in the kidney, whereas decreased AVP secretion has the opposite effect. Baroreceptors in the carotid sinus and renal arteries can also stimulate AVP secretion, but they are less sensitive than the osmoreceptors. Baroreceptors trigger AVP secretion in response to decreased effective circulating volume, nausea, pain, stress, and certain drugs.[27] In patients with normal renal function, urine can be diluted to a minimum of 50 mOsm/kg; a dilution below 100 mOsm/kg suggests AVP suppression.

Baroreceptors in the carotid sinus and renal arteries can also stimulate AVP secretion, but they are less sensitive than the osmoreceptors. Baroreceptors trigger AVP secretion in response to decreased effective circulating volume, nausea, pain, stress, and certain drugs.[27] In patients with normal renal function, urine can be diluted to a minimum of 50 mOsm/kg; a dilution below 100 mOsm/kg suggests AVP suppression. Urine sodium levels less than 20 mmol/L suggest decreased renal perfusion, while urine sodium levels greater than 40 mmol/L suggest SIADH.[28] The differentiation between acute and chronic hyponatremia is usually 48 hours. This is important in correcting hyponatremia, as rapid correction of chronic hyponatremia is associated with osmotic demyelination.[7] Hypertonic Hyponatremia Serum osmolality: Greater than 295 mOsm/kg Hyperglycemia Exogenous osmoles Mannitol Maltose Radiocontrast Sucrose [7][29][30] Isotonic Hyponatremia Serum osmolality: Between 275 mOsm/kg and 295 mOsm/kg Pseudo-hyponatremia is a laboratory artifact. This is usually caused by hypertriglyceridemia, lipoprotein X (from cholestasis, genetic, or liver disease), or hyperproteinemia (monoclonal gammopathy, intravenous immunoglobulin [IVIG]). The large amount of protein decreases the aqueous portion of plasma, and indirect ion-selective electrodes assume a normal plasma volume; therefore, the measured sodium concentration will be low. Two-thirds of clinical labs still use indirect ion-selective electrode technology; hence, the problem persists. However, IVIG can also contain maltose, dextrose, or sucrose, which can cause hypertonicity as above.[30][31] Transurethral prostate resection syndrome occurs when hypotonic fluids—such as glycine, sorbitol, mannitol, and urea—are used for irrigation. In addition, glycine can cause toxicity by metabolizing to ammonia, causing further impairment. The degree of hyponatremia depends on the volume of fluid administered and the duration of the procedure. Isotonic fluids are increasingly used.[32][33] Hypotonic Hyponatremia Serum osmolality: Less than 275 mOsm/kg Hypotonic hyponatremia represents an excess of free water. Two mechanisms can cause this excess free water:

Transurethral prostate resection syndrome occurs when hypotonic fluids—such as glycine, sorbitol, mannitol, and urea—are used for irrigation. In addition, glycine can cause toxicity by metabolizing to ammonia, causing further impairment. The degree of hyponatremia depends on the volume of fluid administered and the duration of the procedure. Isotonic fluids are increasingly used.[32][33] Hypotonic Hyponatremia Serum osmolality: Less than 275 mOsm/kg Hypotonic hyponatremia represents an excess of free water. Two mechanisms can cause this excess free water: This occurs when a patient drinks a large volume of free water (usually more than 18 L/day or greater than 750 mL/h) that overwhelms the kidney's capacity to excrete it. Examples of this are psychogenic polydipsia, marathon runners, water drinking competitions, and drugs similar to MDMA (ecstasy). Decreased free water excretion results from the kidneys' inability to excrete it. There are 3 main mechanisms involved in the inability of the kidneys to excrete water: High ADH activity Decreased effective arterial blood volume (EABV): ADH is released when there is a reduction of 15% or more of the EABV. This occurs with hypovolemia (eg, vomiting, diarrhea), decreased cardiac output (eg, heart failure), or vasodilation (eg, cirrhosis). SIADH ADH is secreted autonomously. Four general causes of this are brain disorders, lung disorders, drugs (eg, selective serotonin reuptake inhibitors), and miscellaneous (eg, nausea and pain). Cortisol deficiency: Cortisol inhibits ADH release. When cortisol is decreased, ADH is released in large amounts. Adrenal insufficiency is the cause of this mechanism.[34] Low glomerular filtration rate (GFR): A low GFR can impair the kidney's ability to excrete water. Typical examples are acute kidney injury, chronic kidney disease, and end-stage renal disease. Low solute intake Patients on a regular diet consume 600–900 mOsm of solute per day. Solutes are defined as substances that are freely filtered by the glomeruli but have relative or absolute difficulty in being reabsorbed by the tubules compared to water. The primary solutes are urea (produced by protein metabolism) and electrolytes (eg, salt). Carbohydrates do not contribute to solute load. In steady-state conditions, solute intake is equal to urine solute load. Therefore, it is expected that these patients also excrete 600–900 mOsm of solute in the urine.

Patients on a regular diet consume 600–900 mOsm of solute per day. Solutes are defined as substances that are freely filtered by the glomeruli but have relative or absolute difficulty in being reabsorbed by the tubules compared to water. The primary solutes are urea (produced by protein metabolism) and electrolytes (eg, salt). Carbohydrates do not contribute to solute load. In steady-state conditions, solute intake is equal to urine solute load. Therefore, it is expected that these patients also excrete 600–900 mOsm of solute in the urine. Urine volume, and hence water excretion, is dependent on the urine solute load. The more solute one needs to excrete, the larger the urine volume one needs to produce. The less solute one needs to excrete, the smaller the urine volume one needs to produce. Patients who eat a low amount of solute per day (eg, 200 mOsm/day) on steady-state conditions will still excrete a low amount of solute in the urine, resulting in a smaller urine volume. This reduced urine volume limits the kidneys' capacity to excrete water. Typical examples of this are beer potomania and the tea-and-toast diet. Much rarer causes of potomania are ingestion of diet sodas or soy-based drinks, as these are both low-solute beverages. Carbohydrates do not contribute to osmolarity.[35][2] Alcohol itself can also be associated with  SIADH, hypovolemia, malnutrition, and liver cirrhosis. Beer is particularly associated with this condition because, in addition to its higher volume intake compared to other forms of alcohol, it is high in carbohydrates. Therefore, beer intake prevents protein catabolism, reducing the urine urea and osmolality.[23][36] Beer potomania has traditionally been associated with low urine osmolality and low urine sodium. However, one study's results found a wide range in urine osmolality and urine sodium levels.[37] Patients with this condition are at very high risk of too rapid correction of sodium. They should be closely monitored in an intensive care setting with frequent sodium and neurologic checks.[38]

Therefore, beer intake prevents protein catabolism, reducing the urine urea and osmolality.[23][36] Beer potomania has traditionally been associated with low urine osmolality and low urine sodium. However, one study's results found a wide range in urine osmolality and urine sodium levels.[37] Patients with this condition are at very high risk of too rapid correction of sodium. They should be closely monitored in an intensive care setting with frequent sodium and neurologic checks.[38] Case reports have described hyponatremia related to bowel preparation for colonoscopies in the setting of rapid fluid intake without solute intake. A similar situation arises in patients who participate in extreme exercise such as marathons. Both situations also involve nonosmotic AVP release.[39][40] In exercise-induced hyponatremia, increased water intake, solute loss through sweating, and sympathetic stimulation of AVP can lead to hyponatremia. For more information, please see StatPearls companion review, "Exercise-Associated Hyponatremia." SIADH This is a condition in which inappropriate secretion of ADH, despite normal or increased plasma volume, impairs kidney water excretion, leading to hyponatremia. SIADH is a diagnosis of exclusion, as there is no single test to confirm the diagnosis. Patients are usually hyponatremic and euvolemic.[41][42] Causes of SIADH include the following: Any central nervous system disorder Ectopic production of ADH (most commonly small cell carcinoma of the lung) Drugs (carbamazepine, oxcarbazepine, chlorpropamide, and multiple other drugs) HIV Pulmonary diseases (pneumonia, tuberculosis) Postoperative patients (pain medicated) Reset osmostat occurs when AVP is released at a lower Na threshold, leading to chronic hyponatremia. Unlike typical SIADH, the nephron has normal diluting capacity. This can occur in physiologic states such as pregnancy, advanced age, severe illness, malignancy, cerebral hemorrhage, and other conditions. SIADH is evaluated by a water loading test.[43][44] Treatment of SIADH, aside from resetting the osmostat, includes fluid restriction and vasopressin 2–receptor inhibitors.[34][45]

A detailed history, including a history of pulmonary and neurologic disorders, all prescribed and over-the-counter medications, use of drugs or alcohol, exercise and eating habits, and urinary symptoms (polyuria, oliguria), or excessive thirst, is significant. Symptoms depend upon the degree and chronicity of hyponatremia and do not necessarily correlate with the absolute plasma sodium level. Patients with mild-to-moderate hyponatremia (greater than 125 mEq/L) or a gradual decrease in sodium (>48 hours) generally have minimal symptoms. Patients with severe hyponatremia (<125 mEq/L) or with a rapid reduction in sodium levels may exhibit a wide range of symptoms.[46] A detailed history, including a history of pulmonary and neurologic disorders, all prescribed and over-the-counter medications, use of drugs or alcohol, exercise and eating habits, and urinary symptoms (polyuria, oliguria), or excessive thirst, is significant. The physical exam starts with vital signs and assessment of volume status. Patients will demonstrate different physical signs depending on the cause of the hyponatremia. For example, patients with liver cirrhosis may have ascites and anasarca.[5] Symptoms The symptoms of hyponatremia are variable, but often correlate with the degree of the condition. Mild: Na 130–134 mEq/L fatigue weakness neurologic symptoms Cognitive dysfunction, including attention and memory problems (dysfunction seems to correlate directly with hyponatremia levels). Cerebral edema is a common finding in hyponatremia. An unexplained headache could be a sign of cerebral edema. Some of the osmolytes lost due to hyponatremia are neurotransmitters, further worsening the dysfunction. Gait abnormalities are also prevalent.[6][47][48] falls bone fractures Osteoporosis is directly associated with hyponatremia. V1 and V2 receptors can be found on osteoclasts and osteoblasts and may increase osteoclast activity relative to osteoblasts. Moderate: Na 125–129 mEq/L Increased fatigue and drowsiness Generally worsening neurologic symptoms, including decreased alertness, memory, attention, and increased gait abnormalities Increased nausea and vomiting Muscle cramps Nausea and vomiting [49][50] Severe: Na <125 mEq/L Somnolence Confusion and disorientation Decreased consciousness Muscle weakness Falls Seizures Nausea/vomiting Cardiorespiratory distress Some institutions use Na <120 mEq/L or 125 mEq/L with symptoms as the definition for severe hyponatremia [6][22]

The following steps may be performed during the evaluation of a patient with suspected hyponatremia. As noted above, clinical volume status is the most critical part of the clinical exam, although it may not be sensitive in patients with multiple comorbid conditions: Step 1: Plasma Osmolality (normal values 275 mOsm to 295 mOsm/kg) This can help differentiate between hypertonic, isotonic, and hypotonic hyponatremia.[7][51] Of note, this step is not always necessary when the patient has a clinically apparent cause of hypervolemia or hypovolemia. Most hyponatremic individuals are hypotonic. The difference between osmolarity and osmolality is that osmolality is osmoles/Kg H2O, while osmolarity is osmoles/L H2O. The density of water is 1 Kg/L, so these values are usually similar in physiology, but osmolarity can be temperature-dependent. Serum osmolarity, again, is 2[Na] + [BUN]/2.8 + [glucose]/18; a high osmolar gap >10 should raise the suspicion for unmeasured osmoles (eg, alcohols, sugars, pseudohyponatremia).[51][52][53] Pseudonatremia can be ruled out by serum glucose and lipids. If the patient is hypotonic, then go to step 2. Step 2: Urine Osmolality Urine osmolality <100 mOsm/kg usually indicates primary polydipsia, reset osmostat, or potomania. As noted above, reset osmostat is a diagnosis of exclusion.[43] Urine osmolality >100 mOsm/kg usually indicates a high AVP state. This is generally due to low effective arterial blood volume (eg, heart/liver failure), hypovolemia (eg, diarrhea, vomiting, drugs), or SIADH.[28] Step 3: Urine Sodium Concentration  [7] Urine Na <30 mEq/L suggests low intravascular volume. Hypervolemic states may indicate heart/liver failure or nephrotic syndrome. Hypovolemic states may indicate diarrhea, vomiting, third spacing, or decreased intake of salt or water. Urine Na levels >30 mEq/L can be related to diuretics, which must always be considered (and are sometimes sold as weight-loss "supplements"). Hypovolemic states may reflect renal salt wasting, cerebral salt wasting, or primary adrenal insufficiency. Primary adrenal insufficiency will cause hypovolemia due to loss of glucocorticoid and mineralocorticoid activity. Euvolemic states may include SIADH, secondary adrenal insufficiency, or hypothyroidism (rare). In secondary adrenal insufficiency, mineralocorticoid activity is preserved through the renin-angiotensin-aldosterone system.[7][48]

Urine Na levels >30 mEq/L can be related to diuretics, which must always be considered (and are sometimes sold as weight-loss "supplements"). Hypovolemic states may reflect renal salt wasting, cerebral salt wasting, or primary adrenal insufficiency. Primary adrenal insufficiency will cause hypovolemia due to loss of glucocorticoid and mineralocorticoid activity. Euvolemic states may include SIADH, secondary adrenal insufficiency, or hypothyroidism (rare). In secondary adrenal insufficiency, mineralocorticoid activity is preserved through the renin-angiotensin-aldosterone system.[7][48] Other considerations: If a patient is on diuretics, thereby making urine Na levels unreliable, fractional excretion of urea or uric acid is often used. Fractional excretion of urea greater than 55% or fractional excretion of uric acid greater than 10% indicates concentrated urine.[28] Thyroid studies: Low thyroid hormone levels can cause low cardiac output and elevated AVP, but this is usually associated with very abnormal thyroid function, and other symptoms typically present first.[54] Other tests that might help in differentiating the causes include the following: Serum adrenocorticotropic hormone should be measured, and corticotropin-releasing hormone can be measured if secondary adrenal insufficiency is suspected. Liver function tests are used to evaluate for cirrhosis and albuminemia. Serum protein electrophoresis can be conducted if paraproteinemia is suspected. Conduct a chest x-ray or computed tomography (CT) scan of the chest to evaluate for malignancy. Conduct a CT scan of the head to evaluate for central nervous system causes.

Treating hyponatremia depends on the degree of hyponatremia, its duration, the severity of symptoms, and volume status. Traditionally, it was thought that hyponatremia should be corrected at a maximum level of 10 to 12 mEq/L daily.[7] More recent guidelines in the United States and Europe recommend treating severely symptomatic hyponatremia with a bolus of hypertonic saline to reverse hyponatremic encephalopathy by increasing the serum Na level by 4 mEq/L to 6 mEq/L within 1 to 2 hours, but by no more than 10 mEq/L (correction limit) within the first 24 hours. Regardless of the initial Na level, increasing it by 6 mEq should decrease severe neurologic symptoms. This treatment approach exceeds the correction limit in about 4.5% to 28% of people. The main concern in rapid overcorrection is osmotic demyelination syndrome (ODS), a rare complication that can cause Parkinsonian symptoms, quadraparesis, or death.[6][55] However, patients with neurological symptoms and signs from hyponatremia also need to be treated promptly to prevent permanent neurological damage and cerebral herniation.[56] A recent review of 16 studies of severely hyponatremic individuals found that slower rates of correction lead to higher mortality. Correction rates of 8 to 10 mEq/L or higher over 24 hours were associated with lower mortality and shorter length of stay than slow correction rates of less than 8 mEq/L over 24 hours. This was dose-dependent—ie, the lower the correction rate, the higher the mortality. The review did not find a significant increase in ODS with more rapid correction.[57] A key feature of treatment is determining the acuity of the hyponatremia development. Acute hyponatremia (<48 hours) causes cerebral edema, as cells have less time to adapt to a hypotonic environment. Chronic hyponatremia (>48 hours) allows cells to adapt by expelling other osmoles, and rapid correction increases the risk of ODS. Serum Na changes in hypovolemic hyponatremia may be challenging to predict due to water diuresis after correcting the hypovolemia. If it is unclear whether the hyponatremia is chronic or acute, and no concerning neurologic symptoms are present, slower correction goals should be followed.[55] Treatment should be based on clinical presentation and laboratory values.[7] No single set of guidelines for sodium correction exists, but general principles are as follows:

A key feature of treatment is determining the acuity of the hyponatremia development. Acute hyponatremia (<48 hours) causes cerebral edema, as cells have less time to adapt to a hypotonic environment. Chronic hyponatremia (>48 hours) allows cells to adapt by expelling other osmoles, and rapid correction increases the risk of ODS. Serum Na changes in hypovolemic hyponatremia may be challenging to predict due to water diuresis after correcting the hypovolemia. If it is unclear whether the hyponatremia is chronic or acute, and no concerning neurologic symptoms are present, slower correction goals should be followed.[55] Treatment should be based on clinical presentation and laboratory values.[7] No single set of guidelines for sodium correction exists, but general principles are as follows: Acute Symptomatic Hyponatremia Severely symptomatic hyponatremia: For patients with severe symptoms (eg, seizures, obtundation, delirium), 3% sodium chloride can be administered as 100 mL intravenous (IV) boluses over 10 minutes as needed, with a goal correction rate of 4 to 6 mEq/L in the first 4 hours of treatment. The United States Expert Panel Recommendations do not set an upper limit for sodium correction, whereas the European Clinical Practice Guidelines set an upper limit of 10 mEq/L. Results from multiple studies have shown that bolus treatment is associated with fewer complications than hypertonic saline infusion.[48] Mild to moderately symptomatic hyponatremia: For patients with milder symptoms (eg, fatigue, somnolence, nausea, weakness), 3% sodium chloride can be administered by a slow infusion using the sodium deficit formula to calculate the rate of infusion, but the deficit should be recalculated frequently along with frequent sodium monitoring, some suggest hourly or every 4 to 6 hours depending on the clinical scenario. The equation used to calculate the sodium deficit is Sodium deficit (mEq/L) = total body water (TBW) x (desired sodium level - current sodium level). TBW is weight (in Kg) x 0.6 for men/children and 0.5 for women/older patients. Chronic Asymptomatic Hyponatremia Hypovolemic hyponatremia is usually treated with isotonic fluid administration, treating nausea/vomiting, and withholding diuretics. Hypervolemic hyponatremia is usually treated by addressing the underlying condition, restricting salt and fluids, and administering loop diuretics.

TBW is weight (in Kg) x 0.6 for men/children and 0.5 for women/older patients. Chronic Asymptomatic Hyponatremia Hypovolemic hyponatremia is usually treated with isotonic fluid administration, treating nausea/vomiting, and withholding diuretics. Hypervolemic hyponatremia is usually treated by addressing the underlying condition, restricting salt and fluids, and administering loop diuretics. Euvolemic hyponatremia is usually treated with fluid restriction to <1 L/day.[58] Patients with chronic hyponatremia are at much higher risk of ODS than those with acute hyponatremia. Risk factors for ODS: Hypokalemia, liver disease, malnutrition, and alcohol use. Desmopressin or free water can be given if the rate of correction is too rapid to avoid ODS.[58] For further information, please see StatPearls' companion reference, "Central Pontine Myelinolysis." Vasopressin Receptor Agonists (Vaptans) Selective vasopressin-2 receptor antagonists have been widely used for hypervolemic and euvolemic hyponatremia (especially congestive heart failure and SIADH). They block AVP's effects on the renal collecting duct, increasing water excretion without affecting sodium excretion, thereby increasing serum sodium levels. The SALT 1 and SALT 2 trials found tolvaptan to treat SIADH and hypervolemic hyponatremia (excluding cirrhosis) effectively. However, the tested dose of 15 mg is considered by many to be too high, as overcorrection was observed at doses as low as 3.75 mg. Patients with severe hyponatremia require intensive inpatient monitoring with vaptan use.[48][59] Conivaptan is a dual vasopressin 1 and 2 antagonist, and is Food and Drug Administration-approved for inpatient treatment of euvolemic and hypovolemic hyponatremia. While the United States' guidelines recommendations suggest treating SIADH with vaptans if fluid restriction is ineffective, European guidelines do not recommend their use. Vaptans have a risk of rapid correction, but higher rates of ODS have not been noted.[48][59][60] Results from several trials have also shown that vaptans are effective in improving neurocognition in patients with mild and moderate hyponatremia.[9][61] Urea

Conivaptan is a dual vasopressin 1 and 2 antagonist, and is Food and Drug Administration-approved for inpatient treatment of euvolemic and hypovolemic hyponatremia. While the United States' guidelines recommendations suggest treating SIADH with vaptans if fluid restriction is ineffective, European guidelines do not recommend their use. Vaptans have a risk of rapid correction, but higher rates of ODS have not been noted.[48][59][60] Results from several trials have also shown that vaptans are effective in improving neurocognition in patients with mild and moderate hyponatremia.[9][61] Urea Urea has been used as an inexpensive method to increase solute intake, increase urine volume, and induce osmotic diuresis. Spot urine samples can identify patients with low urine osmolality and urine output, and these patients may benefit from oral solute administration rather than free water restriction. Results from several randomized controlled trials have found that oral urea is a safe and effective treatment.[62][63][64] While oral urea has been used in Europe and Australia for many years, it was only recently approved in the United States under the name Ur-Na. This form of urea comes in a powdered form, mixed with water or juice, and is considered a food-like supplement; therefore, it does not require a prescription. Doses range from 15 to 60 g/day, and because of its bitter taste, it is recommended to mix it with a sweet-tasting liquid. Although blood urea nitrogen levels may increase, this is an expected effect of urea metabolism and does not reflect decreased kidney function. In addition, urine sodium loss has been shown to decrease with oral urea administration, further potentiating its effects on hyponatremia. Some studies' results showed that oral urea is as effective as vaptans without the adverse effects of severe thirst or sodium overcorrection. In addition, there is a significant cost benefit: one dose of urea costs about $4, while one dose of tolvaptan costs about $400. Urea should not be used in cases of hypovolemic hyponatremia, drug-related SIADH, or adrenal insufficiency. Urea is also contraindicated in liver cirrhosis as it may cause hyperammonemia.[48][60][64]

In addition, there is a significant cost benefit: one dose of urea costs about $4, while one dose of tolvaptan costs about $400. Urea should not be used in cases of hypovolemic hyponatremia, drug-related SIADH, or adrenal insufficiency. Urea is also contraindicated in liver cirrhosis as it may cause hyperammonemia.[48][60][64] Results from some studies have also shown that 90 g/day of protein supplementation can induce osmotic diuresis. Unlike sodium, urea has minimal tubular reabsorption, further making this an effective treatment. Although the adverse effects of urea appear minimal and the risk of overly rapid correction appears low, no randomized controlled trials have been conducted to date.[55] Sodium Chloride Tablets Sodium chloride tablets have also been prescribed to increase solute intake and promote diuresis; however, their efficacy has proven to be limited. These tablets are prescribed in conjunction with fluid restriction and diuretics, resulting in frequent non-compliance due to excessive thirst. Oral urea allows for more liberal fluid intake (1.5–1.8 L) and likely improves patient compliance. In addition, a large quantity of sodium chloride tablets may be required to achieve the same solute load, as these tablets are about 60% chloride and 40% sodium due to their molecular weights. Comparatively, one 600 mg tablet of sodium chloride provides 21 mOsm, while 15 grams of urea provides 250 mOsm of solute.[55][64] Sodium-Glucose Cotransporter 2 Inhibitors Sodium-glucose cotransporter (SGLT2) inhibitors are oral medications approved for the treatment of type 2 diabetes, chronic heart failure, and chronic kidney disease. SGLT2 inhibitors inhibit glucose reabsorption in the early proximal tubule via the SGLT2 receptor, which accounts for about 90% of tubular glucose reabsorption. The SGLT1 receptor reabsorbs the rest of the urine glucose in the more distal segments of the proximal tubule.

Sodium-glucose cotransporter (SGLT2) inhibitors are oral medications approved for the treatment of type 2 diabetes, chronic heart failure, and chronic kidney disease. SGLT2 inhibitors inhibit glucose reabsorption in the early proximal tubule via the SGLT2 receptor, which accounts for about 90% of tubular glucose reabsorption. The SGLT1 receptor reabsorbs the rest of the urine glucose in the more distal segments of the proximal tubule. As implied by the name, sodium, chloride, and water are also reabsorbed along with water. When these molecules remain in the urine, fluid and NaCl are sensed by the macula densa, triggering tubuloglomerular feedback and reducing glomerular capillary pressure and the hyperfiltration associated with diabetic nephropathy; this will also reduce the glomerular filtration rate (GFR) and intraglomerular pressure. Reduced NaCl reabsorption also reduces oxygen consumption in the proximal tubule. The increased glucose, sodium, and chloride also cause osmotic diuresis. This class of medication is particularly effective in SIADH, which can often be identified by an elevated fractional excretion of urea (except for reset osmostat).[60] However, this class of medication is contraindicated in patients with type 1 diabetes due to the risk of diabetic ketoacidosis and should not be used when GFR is less than 30 mL/min. Other risks include an increased risk of genital infections from glucosuria, Fournier gangrene, volume depletion, and it is not recommended in pregnancy. Results from the CANVAS trial showed that canagliflozin may be associated with a higher risk of foot amputation. Patients with heavy alcohol use or on a ketogenic diet may also be predisposed to diabetic ketoacidosis.[65]

However, this class of medication is contraindicated in patients with type 1 diabetes due to the risk of diabetic ketoacidosis and should not be used when GFR is less than 30 mL/min. Other risks include an increased risk of genital infections from glucosuria, Fournier gangrene, volume depletion, and it is not recommended in pregnancy. Results from the CANVAS trial showed that canagliflozin may be associated with a higher risk of foot amputation. Patients with heavy alcohol use or on a ketogenic diet may also be predisposed to diabetic ketoacidosis.[65] Multiple studies' results have shown inhibitors to be renoprotective, both in patients with diabetes and those without.[65] Results from some studies have shown a decrease in estimated GFR of up to 30% after treatment initiation, but this decrease has been renoprotective through the mechanisms described above. In addition to nephroprotective effects, initial studies show a neuroprotective effect on cognition and gait, not only in patients with hyponatremia but also in those with normal sodium levels.[55][60] SGLT2 inhibitors likely improve compliance compared with fluid restriction, which is often unsuccessful, especially in patients with high serum osmolality (>500 mOsm/L). This class of medications is also not cost-prohibitive (~$4 per pill), especially when compared to vaptans.[60][66]

True hyponatremia is associated with hypo-osmolality. Conditions causing hyperosmolar hyponatremia and iso-osmolar hyponatremia (pseudo-hyponatremia) should first be differentiated and include the following: Hyperglycemia Mannitol administration Hyperlipidemia Hyperproteinemia [67] Differential Diagnosis for Hypo-Osmolar Hyponatremia Gastroenteritis Diuretic use Congestive heart failure Liver failure Psychogenic polydipsia Renal causes SIADH Adrenal crisis Hypothyroidism

The prognosis in patients with hyponatremia depends on the severity of hyponatremia and the underlying condition causing it. The prognosis is poor in patients with severe hyponatremia, acute hyponatremia, and older adults.[68] Patients with euvolemic hyponatremia had a better prognosis than those with other types.[17] Chronic hyponatremia is also associated with increased morbidity and mortality. Some complications, particularly among older individuals, are chronic osteoporosis and neuromuscular and cognitive impairment.[5]

If left untreated or inadequately treated, patients with hyponatremia can develop rhabdomyolysis, altered mental status, seizures, and even coma. Rapid correction of chronic hyponatremia can lead to osmotic demyelination syndrome. Osmotic demyelination syndrome, formerly known as central pontine myelinolysis, is a complication of rapid correction of sodium in patients with chronic hyponatremia.[69] In patients with hyponatremia, the brain adapts to a fall in serum sodium levels without developing cerebral edema within about 48 hours. As a result, patients with chronic hyponatremia are mostly asymptomatic. Once the brain adapts to low serum sodium, rapid correction of sodium levels can lead to osmotic demyelination syndrome. Clinical manifestations are typically delayed by a few days and comprise several irreversible neurological symptoms, including seizures, disorientation, and even coma. "Locked-in" syndrome occurs in severely affected patients. These patients are awake but unable to move and can communicate only with their eyes.[70] Hyponatremia is strongly associated with osteoporosis, likely due to increased osteoclast activity. Normalization of sodium levels has been associated with decreased osteoclast activity.[71]

Consulting a nephrologist in a patient with severe hyponatremia, a rapid decrease in sodium, or persistent hyponatremia is imperative. Cardiology and gastroenterology consultations might be necessary for patients with congestive heart failure and hepatic failure, respectively.

Patients with hyponatremia should be followed closely at discharge by both the primary care and nephrology clinicians. Follow-up labs are ordered as needed, and patients who require fluid restriction should be appropriately educated.[72]

Pearls and other issues concerning hyponatremia include the following: This condition is the most common electrolyte abnormality seen in healthcare settings. Hyponatremia can range from asymptomatic conditions to life-threatening conditions. Hyponatremia can occur with hypovolemic, hypervolemic, or euvolemic states. Common causes include diuretics, vomiting, diarrhea, congestive heart failure, renal and liver disease. The degree and duration of hyponatremia, along with symptom severity, determine the management algorithm and the rate of sodium correction. Hyponatremia should not be corrected at a rate risking osmotic demyelination syndrome; however, 3% sodium boluses may be necessary to avoid severe neurologic symptoms such as obtundation or cerebral herniation. Newer drugs such as urea and SGLT2 inhibitors are newer agents that can be used, as well as traditional methods such as hypertonic saline, fluid restriction, salt tablets, and vaptans.

Patients with acute or chronic hyponatremia are at high risk of complications. Early identification and care for patients with hyponatremia are imperative in reducing morbidity and mortality. Caring for patients with hyponatremia necessitates a collaborative approach among healthcare professionals to ensure patient-centered care and improve overall outcomes. Nephrologists, cardiologists, emergency medicine and critical care clinicians, nurses, pharmacists, and other health professionals involved in the care of these patients should possess the essential clinical skills and knowledge to diagnose and manage hyponatremia accurately. This includes expertise in recognizing the varied clinical presentations, understanding which appropriate laboratory tests should be ordered, and evaluating them, which is crucial to understanding the etiologies of patients' hyponatremia. A strategic approach is equally crucial, involving evidence-based strategies to optimize treatment plans and minimize adverse effects. Ethical considerations must guide decision-making, ensuring informed consent and respecting patient autonomy in treatment choices. Each healthcare professional must be aware of their responsibilities and contribute their unique expertise to the patient's care plan, fostering a multidisciplinary approach. Effective interprofessional communication is paramount, allowing seamless information exchange and collaborative decision-making among the team members. Care coordination plays a pivotal role in ensuring that the patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient safety. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance in the management of hyponatremia.