Hyponatremia

Hyponatremia is defined as a serum sodium concentration below 135 mEq/L. Hyponatremia is typically caused by fluid imbalance; common causes are categorized as hypovolemic (e.g., dehydration), euvolemic (e.g., primary polydipsia, SIADH), or hypervolemic (e.g., CHF). Onset can be acute or chronic, and symptoms are predominantly neurological and often nonspecific (e.g., nausea, headache, confusion). The cause of hyponatremia is determined by assessing the patient's volume status and ability to retain sodium. Conditions with very high protein (e.g., multiple myeloma) or glucose levels (e.g., DKA) in the blood can cause falsely low serum sodium levels (pseudohyponatremia). Treatment involves careful correction of the sodium deficit and/or fluid imbalance. A rapid increase in the serum sodium concentration can have damaging osmotic effects (i.e., osmotic demyelination syndrome).

See the section “Core IM podcast 5 pearls on hyponatremia (episode 1: diagnosis)” for their show notes on this topic.

• Eunatremia: a normal concentration of sodium in the blood (i.e., 136–145 mEq/L).
• Hyponatremia: reduced serum sodium concentration (< 135 mEq/L)
• Classification ^[1]
  • Severity ^[2]
    • Mild hyponatremia: 130–135 mEq/L
    • Moderate hyponatremia: 125–129 mEq/L
    • Severe hyponatremia (profound): < 125 mEq/L
  • Disease onset ^[2]
    • Acute hyponatremia: < 48 hours ^[3]
    • Chronic hyponatremia: ≥ 48 hours or duration unknown ^[2]
  • Plasma osmolality (see “Etiology”)

Hyponatremia is classified according to serum osmolality and extracellular volume status. Multiple etiologies may be present. ^[1][2]

Hypotonic hyponatremia ^[1][4]

• Definition: : low measured serum Na⁺ concentration and low serum osmolality (true hyponatremia)
• Serum osmolality: < 280 mOsmol/kg H₂O
• Forms: hypovolemic, euvolemic, hypervolemic
• Causes: extrarenal and renal (see “Causes of hypotonic hyponatremia”)
• Pathophysiology: relative excess of water compared to sodium in the extracellular compartments
  • Dilution: excess body water → dilution of the blood → lower serum sodium concentration
  • Depletion: ↓ body sodium → relative excess body water → lower serum sodium concentration

Thiazide diuretic use and SIADH are the most common causes of hyponatremia in the emergency department. ^[6]

Exercise-associated hyponatremia (EAH) ^[7]

• Definition: serum sodium level < 135 mmol/L that occurs during or up to 24 hours after prolonged, intense physical exercise
• Pathophysiology
  • Ingestion of water or hypotonic beverages in excess of fluid losses
  • ↑ ADH secretion → ↑ solute-free water retention
  • Sodium loss via diaphoresis
• Clinical features
  • Nonspecific symptoms (e.g., dizziness, headache, nausea, vomiting, bloating)
  • Exercise-associated hyponatremic encephalopathy (EAHE): symptoms of cerebral edema (e.g., agitation, confusion, seizures)
• Treatment: fluid restriction PLUS
  • Mild symptoms: oral hypertonic saline
  • Moderate to severe symptoms or EAHE: intravenous hypertonic saline
• Prevention
  • Limit fluid intake according to thirst
  • Education of individuals at risk (e.g., athletes)

Exercise-associated hyponatremia is most commonly associated with marathon running but has also been reported following other exertional activities such as football, cycling, fraternity hazing, and military training. ^[7]

Hypertonic hyponatremia ^[1][4]

• Definition: : low measured serum Na⁺ concentration and high serum osmolality
• Serum osmolality: > 295 mOsmol/kg H₂O
• Causes
  • Hyperglycemia
  • IV mannitol
  • IV radiocontrast use

Isotonic hyponatremia ^[1][4]

• Definition: : low measured serum Na⁺ concentration and normal serum osmolality
• Serum osmolality: 280–295 mOsmol/kg H₂O
• Causes
  • TURP syndrome ^[8]
  • Pseudohyponatremia
    • Asymptomatic laboratory artifact falsely indicating hyponatremia when sodium has not been reduced or diluted
    • Due to very high amounts of protein or lipids in the plasma (e.g., hyperlipidemia, multiple myeloma), which then alter the plasma water concentration
    • Clinical features may include:
      • Pancreatitis
      • Diabetic ketoacidosis
      • Obstructive jaundice ^[9]
      • CRAB criteria in multiple myeloma

Isotonic hyponatremia should always be excluded as a cause of hyponatremia to avoid unnecessarily aggressive treatment.

Clinical features depend on the onset, duration, and severity of hyponatremia. Most patients with chronic hyponatremia are asymptomatic and symptoms typically only occur with serum sodium concentration < 120 mEq/L. ^[4][10]

Severely symptomatic hyponatremia ^[4]

Symptoms usually develop acutely (onset < 48 hours). The severity tends to correlate with the extent of cerebral edema.

• Confusion, stupor, coma
• Seizures
• Ataxia
• Respiratory failure
• Other: malaise; , lethargy, headache, nausea, vomiting

Mild and moderately symptomatic hyponatremia ^[4]

Symptoms usually develop slowly (onset > 48 hours) and are typically nonspecific (patients can also be asymptomatic).

• Forgetfulness
• Gait disturbances
• Muscle weakness
• Malaise
• Headache
• Dizziness
• Fatigue
• Lethargy
• Nausea, vomiting

Depending on the underlying etiology, patients may present with signs of fluid overload, euvolemia, or volume depletion.

Diagnostic approach to hyponatremia ^[1][2][4][8]

• Confirm hyponatremia: Repeat BMP.
• Exclude hyperglycemia: Check serum glucose.
• Check the serum osmolality (S_Osm): first step in the evaluation of confirmed hyponatremia
  • Measured in serum or calculated (see “Hyponatremia formulas” below) ^[1]
  • Interpretation
    • Low serum osmolality; (< 280 mOsmol/kg H₂O): hypotonic hyponatremia (true hyponatremia; most common)
    • High serum osmolality; (> 295 mOsmol/kg H₂O): hypertonic hyponatremia
    • Normal serum osmolality; (280–295 mOsmol/kg H₂O): isotonic hyponatremia or pseudohyponatremia
• Consider additional focused diagnostic evaluation to identify the underlying cause.

Initiate treatment immediately for acute or severely symptomatic hyponatremia.

Serum osmolality measurement is the first step in the evaluation of verified hyponatremia.

Diagnostic evaluation of hyponatremia based on serum osmolality

Hypotonic hyponatremia ^{[2][4][8][11]}

• Initial laboratory studies
  • Serum studies: CBC, BMP; consider uric acid
  • Urine studies
    • Osmolality (U_Osm)
    • Creatinine (U_Creatinine)
    • Sodium (U_Na)
    • Potassium (U_K)
    • Consider also: urea (U_Urea) , uric acid (U_UA)
• Interpretation of urine osmolality (U_Osm): to determine antidiuretic hormone (ADH) activity ; ^[8][11]
  • U_Osm ≤ 100 mOsmol/kg H₂O, and/or urine specific gravity ≤ 1.003: Dilute urine (ADH is suppressed) indicates excess water intake.
  • U_Osm > 100 mOsmol/kg H₂O , and/or urine specific gravity > 1.003: concentrated urine (ADH is appropriately or inappropriately elevated)
• Determination of volume status: to determine if ADH activity is appropriate (i.e., in response to low effective arterial blood volume) or inappropriate (e.g., in SIADH)
  • History: e.g., significant nausea/vomiting or recent hemorrhage might suggest low effective arterial volume due to hypovolemia
  • Clinical assessment of volume status: somewhat limited utility for the distinction between hypovolemia and euvolemia ^[1][2][8]
  • Laboratory studies: See “Laboratory findings that suggest hypovolemia;” should include interpretation of urine sodium (next step)
  • Imaging assessment of volume status: e.g., IVC ultrasound
  • Useful additional tests in patients who are taking diuretics
    • ↓ Fractional excretion of urea (FE_Urea) ^[4][8]
      • FE_Urea < 35%: suggests low effective arterial volume (e.g., in hypovolemia)
      • FE_Urea > 55%: suggests euvolemia (e.g., SIADH)
    • ↓ Fractional excretion of uric acid (FE_UA) ^[8]
      • FE_UA < 12%: suggests low effective arterial volume (e.g., in hypovolemia)
      • FE_UA ≥ 12%: highly suggests euvolemia (e.g., SIADH) ^[2]
• Interpretation of U_Na and/or FE_Na ; : to determine if the cause is renal or extrarenal ; ^[8]
  • Findings ^[1][4][8]
    • U_Na ≥ 20–30 mEq/L and/or FE_Na ≥1%: may suggest renal loss of sodium ^[8]
    • U_Na < 20–30 mEq/L and/or FE_Na < 1%: may suggest extrarenal loss of sodium
  • Urinary sodium excretion is affected by the following: ^[2][12]
    • Effective arterial blood volume (see RAAS and ADH)
    • Dietary sodium intake
    • Renal failure
    • Use of diuretics

In patients taking diuretics, urinary sodium concentrations should be interpreted with caution. An FE_Ua < 12% can provide more diagnostic accuracy than U_Na to differentiate hypovolemia from euvolemia. ^[8]

The distinction between hypovolemia and euvolemia is usually difficult to make on examination alone; examination findings have low sensitivity and specificity. Many authors recommend focusing on urinary sodium rather than clinical features to distinguish between the two. ^[1][2][8]

Additional tests ^[1][2][8]

Consider the following based on clinical suspicion:

• Laboratory studies
  • TSH to evaluate for hypothyroidism (hyponatremia usually only occurs with signs of myxedema or TSH > 50 mIU/mL) ^[1]
  • Serum cortisol and ACTH to evaluate for hypocortisolism and hypoaldosteronism (see “Adrenal insufficiency”)
  • Urine drug screen to evaluate for suspected MDMA use (see “Stimulant intoxication and withdrawal”)
  • BNP to evaluate for CHF (see “Diagnostics” in “CHF”)
  • Urine chloride (U_Cl) may be helpful in rare cases.
• Imaging ^[13]
  • CXR or CT chest: to look for possible pulmonary causes of SIADH
  • CT or MRI head: to identify cerebral edema or suspected CNS etiology

Hypertonic hyponatremia ^[4]

• Check serum glucose and calculate corrected sodium for hyperglycemia.
  • Calculate in all patients with hyponatremia to assess for sodium imbalance due to high glucose levels.
  • Interpretation
    • Low corrected Na⁺: hypotonic hyponatremia likely
    • High corrected Na⁺: hypernatremia likely
    • Normal corrected Na⁺: no hyponatremia
• Identify and treat the underlying cause (see “Etiology”).

Isotonic hyponatremia or pseudohyponatremia ^[8][14][15]

• Confirm or exclude hyponatremia by measuring whole blood sodium (direct potentiometry): Normal Na⁺ concentration confirms the diagnosis of pseudohyponatremia. ^[16]
• Further diagnostic workup of pseudohyponatremia should be guided by clinical suspicion and may include the following: ^[9][16]
  • Lipid panel
  • Total protein concentration

If pseudohyponatremia is suspected, confirm or exclude hyponatremia using whole blood sodium.

Approach

• Management depends on symptom severity, acuity, and the underlying cause.
  • Moderately severe or severely symptomatic hyponatremia: rapid increase in serum sodium with IV hypertonic saline followed by cause-specific treatment for hyponatremia
  • Nonsevere symptoms (usually chronic hyponatremia): slow correction of serum sodium with cause-specific treatment for hyponatremia (e.g., fluid restriction in SIADH).
• Stop all medications that may be causing hyponatremia.
• Avoid sodium overcorrection and minimize the risk of ODS.
  • Carefully monitor sodium levels and urine output (frequency depends on the severity).
  • Follow the recommended sodium correction rates (goals and limits).
  • Provide management of sodium overcorrection if needed.
  • Potassium supplementation also increases sodium levels ^[1][11]

Rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome! Do not exceed hourly or daily maximum correction limits.

Severe or moderately severe symptoms require initial aggressive treatment with IV hypertonic saline to reverse neurological symptoms and prevent brain herniation.

Hypertonic saline (emergency treatment) ^[1][8][11]

Early specialist consultation (intensive care, and/or nephrology) is advised.

• Indications ^[1][8][11]
  • Severe symptoms (e.g., cardiorespiratory distress, somnolence, and/or seizures) ^[8][11]
  • Moderately severe symptoms (e.g., vomiting and/or confusion) ^[11]
  • Suspected or known elevated ICP or intracranial pathology
  • A single hypertonic saline bolus may be considered in acute hyponatremia without severe or moderately severe symptoms. ^[8]
• Regimen
  • Severe symptoms: hypertonic saline bolus (e.g., 3% NaCl ) ^[1]
  • Moderately severe symptoms: Consider hypertonic saline infusion (e.g., 3% NaCl infusion ) ^[1][8]
  • Consider adding desmopressin (off-label) to prevent overcorrection in patients with sodium < 120 mEq/L. ^[11][24]
• Monitoring
  • Serial serum sodium measurement
    • While receiving hypertonic saline bolus: after each bolus (e.g., every 20 minutes) until symptoms resolve and sodium goal is met ^[8]
    • After the initial goal is met: every 4–6 hours during the first 24 hours ^[11]
  • Monitor urine output closely (e.g., every hour). ^[25][26]
• Goal
  • Increase sodium concentration by 4–6 mEq/L within 1–2 hours ^[1][8][11]
  • After sodium concentration has increased by 4–6 mEq/L, consider postponing further correction until the following day. ^[1]
  • For acute hyponatremia: Recommendations vary; consider rapid autocorrection vs. slower correction goals. ^[1][8]
  • See “Recommended sodium correction rates” for daily goals and limits.

Sodium concentration should be increased by 4–6 mEq/L within 1–2 hours for patients with severe or moderately severe symptoms or acute hyponatremia. ^[1]

Cause-specific treatment for hyponatremia ^[1]

• Indications
  • Hyponatremia without severe symptoms: initial therapy
  • Acute and/or severely symptomatic hyponatremia after stabilization and symptom resolution
• Regimens: See “Hypovolemic hyponatremia,” “Euvolemic hyponatremia,” and “Hypervolemic hyponatremia.”
• Trial of volume expansion: Consider if the cause is unclear to differentiate between hypovolemic hypotonic hyponatremia and euvolemic hypotonic hyponatremia.
  • Administer isotonic saline infusion (0.9% NaCl ) and monitor serum sodium. ^[21]
  • ↑ Serum sodium: Hypovolemic hypotonic hyponatremia is likely.
  • ↓ Serum sodium: SIADH is likely. ^[2]
• Monitoring: Monitor patients closely for signs of overcorrection (see “Management of sodium overcorrection”).
  • Monitor urine output (e.g., every hour): > 1 mL/kg/hour should raise concern for overcorrection. ^[1]
  • Measure serum sodium frequently (at least every 4–6 hours until ≥ 125 mEq/L). ^[1]
• Goal: The goal correction rate depends on the risk of ODS; see “Recommended sodium correction rates.” ^[27]

After management of the underlying cause of hyponatremia (e.g., discontinuation of diuretics, glucocorticoids for glucocorticoid deficiency), there is a high risk of rapid autocorrection, which can cause a dangerous increase in sodium concentration.

Urine output > 1 mL/kg/hour should raise concern for sodium overcorrection, which can lead to osmotic damage.

Hypovolemic hyponatremia ^[1]

• Isotonic saline (e.g., 0.9% NaCl IV )
• Consider using hyponatremia formulas to guide the initial correction rate (e.g., calculate the predicted change in sodium concentration and IV fluid rate for correction of hyponatremia). ^[21][23]
• Adjust the infusion rate until the sodium goal is met (see “Recommended sodium correction rates”).

Euvolemic hyponatremia ^[1]

• Fluid restriction (all fluids, not just free water)
  • Usually 500–1000 mL/day
  • Consider < 500 mL/day if the urine-to-serum electrolyte ratio is > 1 (see “Hyponatremia formulas”). ^[21]
• Pharmacological interventions ^[1][8][21]
  • Consider in patients with:
    • High urine osmolality (especially if U_osm is > 500 mOsmol/kg), and/or urine specific gravity > 1.020 ^[1]
    • Euvolemic hyponatremia refractory to fluid restriction
  • Available agents
    • Urea ^[1]
    • Demeclocycline (off-label) ^[1]
    • Vaptans (e.g., conivaptan , tolvaptan ) ^[1][21]
• Management of the underlying cause: see “Hypothyroidism,” “Adrenal insufficiency,” and “SIADH.”

Serum sodium should be monitored every 6–8 hours in patients receiving vaptan therapy to identify overcorrection. ^[1]

Hypervolemic hyponatremia ^[1]

• Fluid restriction with or without loop diuretics (e.g., furosemide )
• Consider vaptans (e.g., conivaptan , tolvaptan ) in hospitalized patients with hyponatremia refractory to fluid restriction. ^[1]
  • Vaptans are unlikely to be effective if creatinine levels are > 3 mg/dL.
  • The use of vaptans is controversial in patients with cirrhosis. ^[1][8]

If hyponatremia persists after diuretic use has been stopped, consider other causes. ^[8]

Management of sodium overcorrection ^[1]

• Initial serum Na⁺ ≥ 120 mEq/L: Management of overcorrection is probably not necessary. ^[1]
• Initial serum Na⁺ < 120 mEq/L: If the increase in sodium exceeds sodium correction limits (e.g., > 8 mEq/L/24 hours in a patient at high risk for ODS), start treatment to lower serum sodium.
  • Discontinue hyponatremia treatment and consider early specialist consult (e.g., nephrology, intensive care).
  • Replace free water losses (e.g., 5% dextrose in water ). ^[1]
  • Consider adding desmopressin (off-label) . ^[1]
  • Consider glucocorticoids, e.g., dexamethasone (off-label) , to prevent ODS. ^[1]
• Monitor urine output and fluid balance closely (typically every hour).
• Check serum sodium frequently (e.g., hourly) until sodium goals and limits are achieved. ^[1]

Disposition

• Severe symptomatic hyponatremia and/or treatment with hypertonic saline: ICU admission
• Acute, symptomatic, or severe hyponatremia and/or risk factors for ODS: inpatient care
• Asymptomatic mild hyponatremia with underlying cause identified and treated: Consider outpatient management with close follow-up.

Patients with serum sodium values < 120 mEq/L typically require intensive care; specialists should be involved early on.

• Repeat BMP to verify hyponatremia.
• Measure serum glucose to exclude hyperglycemia.
• Calculate corrected sodium for hyperglycemia.
• Give emergency treatment with 3% IV NaCl for:
  • Hyponatremia with severe or moderately severe symptoms
  • Known or suspected intracranial pathology or ↑ ICP
  • Acute hyponatremia in certain cases (e.g., sodium decrease of > 10 mEq/L)
• Measure serum sodium after each 3% NaCl bolus.
• Measure or calculate serum osmolality.
• Measure urine osmolality and electrolytes.
• Estimate volume status.
• Consider further diagnostics for hyponatremia based on serum osmolality.
• Initiate cause-specific treatment of hyponatremia.
• Monitor urine output for excessive diuresis.
• Begin management of sodium overcorrection if necessary.

• Edema: sudden decrease in intravascular Na⁺ level → reduced intravascular osmotic pressure → water moving into the interstitium and intracellular space → edema
  • Cerebral edema → elevated intracranial pressure → risk of brain herniation ^[28]
  • Noncardiogenic pulmonary edema
• Bone fractures
• Permanent neurological damage
• Death
• Treatment-associated complications
  • Intracranial hemorrhage
  • Osmotic demyelination syndrome (ODS)

Correcting hyponatremia too rapidly may cause two complications: From low to high, your pons will die (osmotic demyelination syndrome); from high to low, your brain will blow (cerebral edema).

We list the most important complications. The selection is not exhaustive.

• Definition: damage to the myelin sheath of the white matter in the CNS caused by a sudden rise in serum osmolality
  • Central pontine myelinolysis
    • Most common type
    • Affects the central region of the pons
  • Extrapontine myelinolysis: can affect the cerebellum, lateral geniculate body, thalamus, putamen, cortical, and/or subcortical white matter
• Causes
  • Iatrogenic: rapid correction of chronic hyponatremia
    • High-risk factors for ODS: alcohol use disorder, malnutrition, liver disease, hypokalemia, initial sodium concentration ≤ 105 mEq/L ^[1]
  • Rapid changes in other osmotically active solutes (e.g., glucose)
  • Acute severe hypernatremia
• Clinical features ^[29][30]
  • Symptoms first develop several days after the correction of hyponatremia.
  • There can be a wide range of symptoms, depending on the degree and location of demyelination.
  • Central pontine myelinolysis
    • Altered level of consciousness, including coma
    • Locked-in syndrome
    • Impaired cranial nerve function: dysarthria, dysphagia , and diplopia
    • Worsening quadriparesis (initially flaccid, later spastic)
  • Extrapontine myelinolysis: parkinsonism (tremor, rigidity), dystonia, chorea or choreoathetosis, myoclonus, opsoclonus, ataxia, gait disorders
  • Other general symptoms: seizures, encephalopathy, catatonia, mutism, frontal release signs, depression
• Diagnostics: Imaging may only show signs of ODS days to weeks after the onset of symptoms.
  • MRI: imaging technique of choice
    • T2: hyperintense lesion
    • T1: hypointense lesion
    • No contrast enhancement of the lesion
  • CT: easier to conduct in ventilated patients
• Treatment: supportive care (with close monitoring of electrolytes); prevention is key to improving patient outcomes.
• Prognosis: variable; ranging from fatal to residual deficits or a complete recovery
• Prevention
  • Avoid overcorrection of chronic hyponatremia (see “Sodium correction rates for chronic hyponatremia”).
  • Frequent reevaluation of the serum sodium concentration
  • See “Management of sodium overcorrection.” ^[31]

Correcting hyponatremia too rapidly can cause osmotic damage to the axonal myelin sheath in the CNS.

The symptoms and imaging findings of osmotic demyelination syndrome (ODS) first appear several days after the correction of hyponatremia!

AMBOSS has partnered with the popular Core IM podcast to bring you digestible internal medicine content on complex medical topics. In this section, you will find Core IM's 5 clinical pearls on the diagnosis of hyponatremia. Check out their website for the full show notes and listen to our coproduced episode on your favorite podcast platform.

• Pearl 1: general approach
  • Hyponatremia is a significant clinical problem.
    • The most common electrolyte disorder, occurring in up to 30% of hospitalized patients ^[32]
    • May result from:
      • Underlying medical conditions
      • Medications
    • Mild chronic hyponatremia is associated with more frequent falls. ^[33]
  • Understand what each diagnostic test adds vs. rote dependence on algorithms.
  • Patient history and physical examination: may be helpful, but do not ignore other objective data that contradicts them!
    • History
      • Quickly assess for red flags (i.e., confusion, seizures) that require immediate intervention and ICU admission.
      • Ask about dietary history, fluid and alcohol intake, new medications, endocrine ROS, relevant comorbidities.
    • Physical examination
      • Volume status is theoretically helpful, as diagnostic algorithms depend on it, but error-prone. ^[34]
  • Our approach focuses on understanding what each diagnostic test adds rather than rote dependence on algorithms.
    • More helpful given that most cases of hyponatremia in the hospital are multifactorial ^[35]
    • Ask yourself where your patient with hyponatremia is located on a “Cartesian space” with:
      • Anti-diuretic hormone (ADH) secretion relative to effective arterial blood volume (EABV).
  • What if we encounter a patient after intervention and with incomplete labs or urine studies?
    • Still obtain appropriate serum and urine studies to assess:
      • Response to interventions
      • Patient’s current ADH/EABV state
• Pearl 2: serum osmolality
  • Patients with true hyponatremia are expected to have ↓ osmolality.
    • This makes sense because sodium is the most significant contributor to osmolality (see “Hyponatremia formulas”). ^[36]
  • Serum osmolality can be thought of as a quality check to verify the hypothesis that low sodium is accompanied by low osmolality, as it should be.
    • Normal osmolality: Assess if the patient has ↑ triglycerides or paraproteinemia.
    • Such cases are referred to as “pseudohyponatremia.” ^[37]
    • Serum osmolality is not subject to this error.
    • Pseudohyponatremia is not of clinical significance.
    • ↑ Osmolality : Look for extra osmoles, either measured or unmeasured!
      • Measured: severe hyperglycemia, BUN, and, depending on the equation used, ethanol ^[17]
      • Unmeasured: toxic alcohols, iodinated contrast, sucrose ^[38]
  • Serum osmolality assessment prompts a consideration of effective and ineffective osmoles at play.
    • Effective osmoles do not cross the plasma membrane freely → shifts in water movement (impact tonicity)
    • Most of the clinical complications that arise as a result of hyponatremia (and its correction) are driven by the fact that sodium is an effective osmole that impacts tonicity and, therefore, cell size.
    • Ineffective osmoles cross the plasma membrane more readily and, therefore, do not cause shifts in water movement (do not change tonicity).
  • Serum osmolarity is not a serially measured lab! Measure it once, unless you are following clearance of an unmeasured osmole (such as a toxic alcohol) or if there is a significant sodium change that is difficult to contextualize.
• Pearl 3: Urine osmolality (U_Osm) acts as a window into ADH activity.
  • U_Osm is the nearest to a direct measure of ADH activity in clinical practice. ^[2][39]
    • The range of possible urine osmolality in healthy kidneys is broad (50–1200 mOsmol/kg).
      • ADH secretion → resorption of free water in the collecting duct → ↑ U_Osm
      • ADH suppression → ↓ U_Osm
  • If ADH is not active, the result is dilute urine (↓ U_Osm).
    • Low U_Osm on presentation indicates:
      • Too little solute to keep up with normal fluid intake (“tea-toast syndrome”) ^[40]
      • Too much fluid despite normal solute intake (primary polydipsia) ^[41][42]
      • Some combination of low solute and high intake of hypoosmolar fluid (beer potomania) ^[43]
    • Low U_Osm can also occur in the setting of acute illness, in which many patients will push large volumes of hypotonic fluids (i.e., sports drinks) in the setting of GI losses.
  • The story of hyponatremia is often the story of ADH activity. ^[44]
    • ADH activity is reflected by ↑ U_Osm in patients with hyponatremia.
    • If ADH is present: Figure out if this is because of ↓ EABV, ↑ osmolality, or is independent of physiological stimulus (see “Pearl 4”).
  • Remember that renal insufficiency impacts our ability to maximally dilute urine. ^[45]
    • Hyponatremia may develop as a result of acute or chronic renal failure for this reason.
    • Renal insufficiency limits our ability to interpret U_Osm as a direct window into ADH activity. ^[46]
  • Changes in U_Osm (and urine output) can be assessed serially to evaluate treatment response.
    • If urine osmolality gently declines with an intervention (e.g., volume resuscitation): Your intervention has resulted in suppression of ADH (proving the hypothesis).
    • Heads up! If urine output and U_Osm change dramatically in response to an intervention, this may be an early indicator that a patient is correcting too quickly!
• Pearl 4: Urine sodium (U_Na), fractional excretion of sodium (Fe_Na), and fractional excretion of urea (Fe_Urea) reveal RAAS activity.
  • U_Osm acts as a window into ADH activity at a given time; it does not tell us why ADH is activated.
    • Physiological (appropriate) ADH activity can occur in the following circumstances:
      • ↑ Osmolality
      • ↓ Sensed EABV ^[47]
    • ADH activity that is not stimulated by one of the above mechanisms is by definition inappropriate. ^[48]
  • U_Na provides a window into the activity of renin-angiotensin-aldosterone, which is more sensitive than ADH to ↓ EABV states. ^[49]
    • ↓ EABV → RAAS activation → ↓ U_Na
    • SIADH → no RAAS activation → ↑ U_Na
  • In patients with intermediate U_Na , Fe_Na is more sensitive than U_Na for reflecting ↓ EABV. ^[50]
    • ↓ Fe_Na: RAAS is active, ↓ EABV
    • Validated in oliguric patients; less reliable in patients producing large quantities of dilute urine
  • Caveats to U_Na and Fe_Na use ^[2]
    • Use of diuretics (thiazide or loop) increases U_Na, in which case, ↓ Fe_Urea is a reasonable surrogate (↓ Fe_Na PLUS ↓ Fe_Urea is better than either alone). ^[50]
    • CKD impairs Na reabsorption, making U_Na less helpful in this patient group.
    • U_Na will be low in patients with ↓ Na diets (rare in the US).
• Pearl 5: A low serum uric acid can be helpful when considering SIADH (in other words, it points away from hypovolemic states)
  • Theoretically, the lower the serum uric acid level, the less likely it is that the patient's hyponatremia is driven by low-EABV-mediated ADH release.
    • EABV contraction → urinary sodium and uric acid retention
    • EABV expansion → urinary sodium and uric acid wasting
  • Expected characteristics of uric acid in SIADH ^[51]
    • ↓ Serum uric acid ^[52][53]
    • ↑ Urine uric acid
    • ↑ Fractional excretion of uric acid (Fe_UA)
  • Fe_UA may be a more helpful diagnostic test when trying to distinguish between causes of hyponatremia with ↓ EABV and normal or ↑ EABV. ^[20][50]

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