Hyponatremia in Adults

Quick Reference

Critical Alerts

• Severe symptomatic hyponatremia is a medical emergency: Cerebral edema can cause seizures, coma, respiratory arrest, and death [1]
• Treat based on symptoms, not just sodium level: A sodium of 118 mEq/L may be asymptomatic in chronic hyponatremia but life-threatening if acute [2]
• 3% hypertonic saline for severe symptoms: Target acute rise of 4-6 mEq/L to resolve symptoms [1,2]
• Maximum correction 10-12 mEq/L in first 24 hours, 8 mEq/L each subsequent day: Exceeding these limits risks osmotic demyelination syndrome (ODS) [3,4]
• Chronic hyponatremia (> 48 hours) requires slower correction: Brain has adapted by extruding organic osmolytes [5]
• High-risk patients for ODS: Chronic hyponatremia, alcoholism, malnutrition, liver disease, hypokalemia, burns [3,4]
• Monitor sodium every 2-4 hours during active treatment: Essential for safety [1,2]

Severity Classification

Emergency Treatment Algorithm

Overcorrection Management

If sodium rising > 10-12 mEq/L in 24 hours or > 8 mEq/L/day thereafter:

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Definition and Epidemiology

Overview

Hyponatremia is defined as a serum sodium concentration below 135 mEq/L. It is the most common electrolyte disorder encountered in clinical practice, affecting 15-30% of hospitalized patients. [1,6] The condition represents a state of relative excess of body water compared to sodium, leading to hypoosmolality in most cases.

Clinical Significance

Hyponatremia is associated with significant morbidity and mortality:

• Mortality risk increases with severity: Patients with sodium less than 120 mEq/L have mortality rates of 20-25% in acute settings [6]
• Falls and fractures: Chronic mild hyponatremia (130-135 mEq/L) increases fall risk by 67% and fracture risk in elderly patients [7]
• Prolonged hospitalization: Average increase of 2.7 days in hospital length of stay [6]
• Cognitive impairment: Even mild chronic hyponatremia affects attention, gait, and postural stability [7]

Epidemiology

Prevalence:

• Community-dwelling adults: 3-8% [6]
• Hospitalized patients: 15-30% [1,6]
• ICU patients: Up to 35% [6]
• Nursing home residents: 18-22% [7]
• Post-operative patients: 4-8% (higher after neurosurgery) [8]

Age and Gender:

• More common in elderly patients (> 65 years) [7]
• Thiazide-induced hyponatremia more common in elderly women [8]
• Exercise-associated hyponatremia more common in women marathon runners [9]

Mortality:

• In-hospital mortality 4-8% for mild hyponatremia [6]
• In-hospital mortality 15-20% for moderate-severe hyponatremia [6]
• 1-year mortality increased by 2.5-fold in chronic hyponatremia [7]

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Pathophysiology

Water and Sodium Homeostasis

Normal Regulation:

• Plasma osmolality normally maintained at 275-295 mOsm/kg [5]
• Osmoreceptors in hypothalamus detect osmolality changes as small as 1-2% [5]
• Antidiuretic hormone (ADH, vasopressin) released from posterior pituitary when osmolality rises [5]
• ADH acts on V2 receptors in collecting duct, inserting aquaporin-2 water channels [5]
• Thirst mechanism activated at higher osmolality threshold (~295 mOsm/kg) [5]

Hyponatremia Development:

• Hyponatremia develops when water intake exceeds water excretion [1,5]
• Most commonly due to inappropriate ADH secretion or action [1,10]
• Kidneys normally can excrete > 10-15 L/day of dilute urine if ADH is suppressed [5]
• Hyponatremia requires both excess water AND impaired water excretion [1,5]

Cerebral Response to Hyponatremia

Acute Phase (less than 48 hours):

1. Immediate osmotic shift (minutes to hours):

   • Plasma hypoosmolality causes water movement into brain cells [5]
   • Brain edema develops rapidly [5]
   • Increased intracranial pressure (ICP) [5]
   • Risk of cerebral herniation if severe [1,5]

2. Rapid adaptation (first 1-3 hours):

   • Brain extrudes extracellular fluid to interstitial space and CSF [5]
   • Reduces brain volume by ~3% [5]

Chronic Adaptation (> 48 hours):

1. Organic osmolyte extrusion (24-48 hours):

   • Brain cells extrude potassium, sodium, and chloride (first 24h) [5]
   • Then extrude organic osmolytes: glutamine, glutamate, taurine, myo-inositol, phosphocreatine (24-48h) [5]
   • Brain volume returns nearly to normal despite persistent hyponatremia [5]
   • Symptoms improve or resolve [5]

2. Consequence for treatment:

   • Chronic hyponatremia is better tolerated (brain adapted) [1,5]
   • Rapid correction removes adapted state and causes myelin damage [3,4]
   • Brain cells cannot rapidly regain extruded osmolytes [3,5]

Osmotic Demyelination Syndrome (ODS)

Pathogenesis:

• Occurs when hyponatremia corrected too rapidly (> 10-12 mEq/L in 24h) [3,4]
• Adapted brain cells shrink excessively with rapid correction [3]
• Oligodendrocytes in pons are particularly vulnerable [3,4]
• Myelin sheath damage occurs, especially in central pons (central pontine myelinolysis) [3,4]
• Extrapontine sites: basal ganglia, thalamus, cerebellum (extrapontine myelinolysis) [3,4]

Risk Factors for ODS: [3,4]

• Chronic severe hyponatremia (less than 120 mEq/L for > 48h) - highest risk
• Alcoholism and liver disease
• Malnutrition
• Hypokalemia
• Burns
• Chronic diuretic use
• Female gender
• Hypoxia

Clinical Features:

• Timing: Symptoms appear 2-6 days after overcorrection [3,4]
• Pontine: Dysarthria, dysphagia, quadriparesis, pseudobulbar palsy, locked-in syndrome [3,4]
• Extrapontine: Movement disorders, mutism, behavioral changes, seizures [3,4]
• Diagnosis: MRI shows T2 hyperintensity in pons (trident/bat-wing sign) or extrapontine sites [4]
• Prognosis: Variable; may be irreversible, particularly locked-in syndrome [3,4]

Cerebral Edema

Acute Symptomatic Hyponatremia:

• Sodium drop > 10-12 mEq/L in less than 48 hours causes brain edema [1,5]
• Women of childbearing age at highest risk for herniation [9]
• Post-operative hyponatremia particularly dangerous (hypoxia, anesthesia effects) [8]
• Exercise-associated hyponatremia in marathoners (excess hypotonic fluid intake) [9]

Adaptation Failure:

• Children and premenopausal women have less efficient brain adaptation [9]
• Estrogen and progesterone impair Na-K-ATPase activity [9]
• Higher risk of cerebral herniation and death from acute hyponatremia [9]

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Classification and Etiology

Classification by Plasma Osmolality

Step 1: Measure Plasma Osmolality

Isotonic Pseudohyponatremia:

• Occurs with older flame photometry or indirect ion-selective electrodes [1]
• Lipids or proteins occupy plasma volume, reducing measured sodium [1]
• Direct ion-selective electrodes (now standard) eliminate this artifact [1]
• Rare in modern laboratories [1]

Hypertonic Hyponatremia:

• Hyperglycemia: Most common cause [1]
• Glucose > 100 mg/dL draws water from cells, diluting sodium [1]
• Correction factor: Add 1.6 mEq/L to measured sodium for each 100 mg/dL glucose > 100 mg/dL [1]
  • Some recommend 2.4 mEq/L per 100 mg/dL for glucose > 400 mg/dL [1]
• Example: Glucose 500 mg/dL, sodium 128 mEq/L
  • Corrected sodium = 128 + [1.6 × (500-100)/100] = 128 + 6.4 = 134.4 mEq/L (not true hyponatremia)

Classification of Hypotonic Hyponatremia by Volume Status

Step 2: Assess Volume Status (Clinical Examination)

Hypovolemic Hyponatremia

Definition: True sodium deficit with even greater water deficit

Renal Losses (Urine sodium > 40 mEq/L):

• Diuretics: Especially thiazides [8]
  • Thiazides impair diluting segment (distal convoluted tubule) [8]
  • Loop diuretics less commonly cause hyponatremia [8]
  • Elderly women on low-dose thiazides at highest risk [8]
• Osmotic diuresis: Glucose (DKA recovery), urea, mannitol
• Salt-wasting nephropathy: Medullary cystic disease, reflux nephropathy, post-obstruction
• Cerebral salt wasting (CSW): After SAH, TBI, neurosurgery [11]
• Mineralocorticoid deficiency: Addison's disease, hypoaldosteronism
• Bicarbonaturia: Renal tubular acidosis, vomiting with volume depletion

Extrarenal Losses (Urine sodium less than 20-25 mEq/L):

• Gastrointestinal: Vomiting, diarrhea, nasogastric suction, enterocutaneous fistula, tube drainage
• Third-spacing: Pancreatitis, peritonitis, bowel obstruction, burns
• Skin losses: Severe burns, cystic fibrosis (sweat losses)

Clinical Features:

• Dry mucous membranes, decreased skin turgor [1]
• Tachycardia, orthostatic hypotension [1]
• Flat neck veins, reduced JVP [1]
• Oliguria, elevated BUN/creatinine ratio (> 20:1) [1]

Euvolemic Hyponatremia

Definition: Normal total body sodium, excess total body water

Syndrome of Inappropriate Antidiuresis (SIAD/SIADH):

Most common cause of euvolemic hyponatremia [10,12]

Diagnostic Criteria (all required): [10,12]

1. Hypotonic hyponatremia (less than 275 mOsm/kg)
2. Urine osmolality > 100 mOsm/kg (typically > 300 mOsm/kg)
3. Urine sodium > 40 mEq/L (on normal salt/water intake)
4. Euvolemia on clinical examination
5. Normal thyroid, adrenal, and renal function
6. No recent diuretic use

Causes of SIAD: [10,12]

Pathophysiology Types: [12]

• Type A: Classic SIADH - osmotically inappropriate ADH release
• Type B: ADH levels undetectable but renal response as if ADH present (ADH receptor activation mutation)
• Type C: Partial ADH escape - some suppressibility
• Type D: Low ADH but increased sensitivity

Other Euvolemic Causes:

• Primary polydipsia (psychogenic polydipsia):

  • Psychiatric illness, medications (thioridazine), hypothalamic lesions [13]
  • Urine osmolality typically less than 100 mOsm/kg (maximally dilute) [13]
  • Urine sodium less than 20-25 mEq/L [13]
  • Water intake exceeds 10-15 L/day [13]

• Beer potomania:

  • Low solute intake (less than 200 mOsm/day) with high beer consumption [14]
  • Beer provides water and calories but minimal solute [14]
  • Impaired ability to excrete free water (need solute for urine dilution) [14]
  • Urine osmolality less than 100 mOsm/kg, urine sodium less than 25 mEq/L [14]
  • Also "tea and toast" diet in elderly [14]

• Hypothyroidism:

  • Severe hypothyroidism (TSH typically > 50-75 mIU/L) [1]
  • Reduced cardiac output → non-osmotic ADH release [1]
  • Reduced GFR [1]

• Adrenal insufficiency (glucocorticoid deficiency):

  • Primary adrenal insufficiency (Addison's) also has aldosterone deficiency → volume depletion [1]
  • Isolated glucocorticoid deficiency (secondary/tertiary adrenal insufficiency) presents as euvolemic [1]
  • Cortisol deficiency → non-osmotic ADH release [1]
  • Cannot suppress ADH appropriately [1]

• Exercise-associated hyponatremia (EAH):

  • Endurance athletes (marathon, triathlon, ultra-distance) [9]
  • Excessive hypotonic fluid intake during exercise [9]
  • Non-osmotic ADH release (pain, nausea, stress) [9]
  • Premenopausal women at highest risk [9]

• Reset osmostat:

  • Osmotic threshold for ADH release and thirst lowered [15]
  • Sodium maintained at lower level (typically 125-132 mEq/L) [15]
  • Normal response to water loading and deprivation (at new set point) [15]
  • "Causes: Malnutrition, chronic illness, pregnancy (physiologic) [15]"

Hypervolemic Hyponatremia

Definition: Excess total body sodium AND even greater excess total body water (dilutional)

Pathophysiology: [1,16]

• Effective arterial blood volume depletion (despite total volume overload)
• Baroreceptor-mediated non-osmotic ADH release
• Activation of RAAS (renin-angiotensin-aldosterone system)
• Increased proximal sodium and water reabsorption
• Impaired distal water excretion

Causes:

• Congestive heart failure (CHF):

  • Reduced cardiac output → baroreceptor activation [16]
  • ADH and RAAS activation [16]
  • Degree of hyponatremia correlates with severity and prognosis [16]
  • Urine sodium less than 25 mEq/L, urine osmolality > 400 mOsm/kg [16]

• Cirrhosis with ascites:

  • Splanchnic vasodilation → reduced effective arterial volume [17]
  • Portal hypertension and low oncotic pressure → ascites [17]
  • Severe activation of ADH and RAAS [17]
  • Hyponatremia (less than 135 mEq/L) present in 30-50% of cirrhotics [17]
  • Urine sodium less than 25 mEq/L, urine osmolality > 400 mOsm/kg [17]
  • Strong predictor of mortality (MELD-Na score) [17]

• Nephrotic syndrome:

  • Severe proteinuria (> 3.5 g/day) and hypoalbuminemia [1]
  • Reduced oncotic pressure → edema [1]
  • Effective arterial volume depletion → ADH/RAAS activation [1]
  • Urine sodium variable (may be high if kidneys losing salt) [1]

• Advanced chronic kidney disease:

  • GFR less than 15-20 mL/min/1.73m² [1]
  • Reduced solute delivery to diluting segment [1]
  • Impaired free water excretion [1]

Clinical Features:

• Peripheral edema (legs, sacrum) [1]
• Ascites [1,17]
• Pulmonary edema (rales, dyspnea) [1]
• Elevated JVP [1]
• Hepatomegaly (in heart failure) [1]
• Weight gain [1]

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Clinical Presentation

Symptoms by Severity and Acuity

Asymptomatic (often sodium 130-135 mEq/L, chronic):

• Many patients have no symptoms [1]
• May have subtle findings: mild fatigue, nausea, difficulty concentrating [7]

Mild-Moderate Symptoms (sodium 120-130 mEq/L):

• Nausea (without vomiting) [1,5]
• Headache [1,5]
• Lethargy, fatigue [1,5]
• Confusion, disorientation [1,5]
• Muscle cramps [1]
• Weakness [1]
• Anorexia [1]

Severe Symptoms (sodium less than 120 mEq/L, or acute drop):

• Vomiting [1,5]
• Cardiorespiratory distress (Cheyne-Stokes respiration, hypoxia, hypercapnia) [1,5]
• Somnolence, stupor [1,5]
• Seizures (generalized tonic-clonic) [1,5]
• Coma [1,5]
• Respiratory arrest [1,5]
• Brainstem herniation [1,5]
• Death [1,5]

Factors Determining Symptom Severity

Rate of Sodium Decline:

• Acute (less than 48 hours): More symptomatic for same sodium level [1,5]
  • Brain has not adapted [5]
  • Sodium drop of 10-12 mEq/L can cause seizures or coma [1]
• Chronic (> 48 hours): Better tolerated [1,5]
  • Brain has adapted by extruding osmolytes [5]
  • Sodium of 115 mEq/L may be minimally symptomatic [1]

Absolute Sodium Level:

• less than 120 mEq/L: Higher risk of severe symptoms [1]
• less than 110-115 mEq/L: Very high risk of seizures, coma, death [1]

Patient Age and Sex:

• Premenopausal women: Higher risk of cerebral edema and herniation [9]
• Postmenopausal women and men: Better adapt to acute hyponatremia [9]
• Elderly: Higher risk of falls, gait disturbance even with mild chronic hyponatremia [7]

Underlying Conditions:

• CNS pathology (brain tumor, stroke): Lower threshold for symptoms [1]
• Hepatic encephalopathy: Hyponatremia worsens encephalopathy [17]
• Hypoxia, acidosis: Worsen cerebral edema [1]

Physical Examination Findings

Neurological:

• Mental status: Alert, confused, lethargic, stuporous, comatose [1]
• GCS (Glasgow Coma Scale): Quantify level of consciousness [1]
• Seizure activity: Generalized tonic-clonic most common [1]
• Focal deficits: May occur with herniation [1]
• Abnormal posturing: Decerebrate or decorticate (severe) [1]
• Gait ataxia: Broad-based gait, postural instability (chronic mild hyponatremia) [7]
• Reflexes: May be hyperreflexic or hyporeflexic [1]

Volume Status Assessment:

Specific Examination Clues:

• Cushingoid features: Exogenous steroids (if stopped → adrenal insufficiency) [1]
• Hyperpigmentation: Primary adrenal insufficiency [1]
• Thyroid goiter/myxedema: Hypothyroidism [1]
• Spider angiomata, palmar erythema, jaundice, asterixis: Liver disease [17]
• Signs of malignancy: Cachexia, lymphadenopathy (SIAD from malignancy) [10]
• Surgical scars: Recent surgery (postoperative hyponatremia) [8]

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Red Flags - Immediate Recognition

Life-Threatening Presentations

High-Risk Scenarios for Osmotic Demyelination Syndrome

Identify before correcting to avoid overcorrection: [3,4]

• Chronic severe hyponatremia (less than 120 mEq/L for > 48 hours)
• Alcoholism (active or history)
• Liver disease (cirrhosis, alcoholic hepatitis)
• Malnutrition (anorexia, starvation, poverty)
• Hypokalemia (K less than 3.0 mEq/L)
• Burns
• Advanced age with multiple comorbidities

Management in High-Risk Patients:

• Slower correction targets: 4-6 mEq/L in first 24 hours [3,4]
• Monitor sodium Q2-4h [3,4]
• Correct hypokalemia simultaneously (potassium rises sodium) [3,4]
• Have D5W and desmopressin ready to reverse overcorrection [3,4]

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Diagnostic Approach

Initial Evaluation

History:

Timeline (critical for management):

• When did symptoms start? [1]
• Any recent sodium levels? [1]
• Chronic vs. acute (less than 48h vs. > 48h)? [1]
• If unknown, assume chronic (safer) [1]

Medications: [1,8,10]

• Diuretics (thiazides, loop diuretics)
• SSRIs, SNRIs, tricyclic antidepressants
• Antiepileptics (carbamazepine, oxcarbazepine, valproate)
• Chemotherapy (cyclophosphamide, vincristine, cisplatin)
• NSAIDs
• Proton pump inhibitors
• Opiates, tramadol
• Recreational drugs (MDMA/ecstasy)

Fluid Intake:

• Excessive water intake (polydipsia)? [13]
• Beer consumption (beer potomania)? [14]
• Sports drinks during exercise (EAH)? [9]
• IV fluids (postoperative)? [8]

Symptoms to Elicit:

• Nausea, vomiting, diarrhea (GI losses)
• Headache, confusion, seizures (CNS symptoms)
• Weakness, fatigue (adrenal, thyroid)
• Chest pain, dyspnea (heart failure)
• Abdominal distension (ascites)

Medical History:

• Heart failure [16]
• Cirrhosis [17]
• Chronic kidney disease [1]
• Thyroid disease [1]
• Adrenal insufficiency [1]
• Malignancy (especially lung) [10]
• CNS disease (meningitis, SAH, stroke) [10,11]
• Psychiatric illness [13]
• Recent surgery [8]
• Recent endurance exercise [9]

Diagnostic Algorithm

Step 1: Confirm True Hyponatremia

Measure Serum Osmolality:

If Hypertonic (Hyperglycemia):

• Corrected Na = Measured Na + [1.6 × (Glucose - 100) / 100] [1]
• If corrected sodium is normal, no true hyponatremia [1]

Calculated Osmolality:

• Plasma Osm = (2 × Na) + (Glucose/18) + (BUN/2.8) [normal: 280-295 mOsm/kg]
• Osmolal gap = Measured Osm - Calculated Osm [normal less than 10]
• Elevated gap suggests unmeasured osmoles (mannitol, ethanol, methanol, ethylene glycol, contrast)

Step 2: Assess Volume Status

Clinical examination (see table above): Hypovolemic, Euvolemic, or Hypervolemic

Step 3: Urine Studies

Essential Tests:

• Urine sodium (spot sample acceptable) [1,2]
• Urine osmolality (spot sample acceptable) [1,2]

Urine Sodium Interpretation:

• less than 25-30 mEq/L: Avid renal sodium retention (volume depletion or effective volume depletion) [1]

• 40 mEq/L: Renal sodium wasting OR appropriate response to volume overload OR SIAD [1]

• 25-40 mEq/L: Intermediate zone, consider clinical context and repeat [1]

Urine Osmolality Interpretation:

• less than 100 mOsm/kg: ADH suppressed, appropriate dilute urine (polydipsia, beer potomania, reset osmostat) [1,13,14]
• 100-300 mOsm/kg: Partial ADH suppression or low solute intake [1]

• 300 mOsm/kg: ADH present (appropriate or inappropriate) [1]

• 400 mOsm/kg: Avid ADH effect (volume depletion or SIAD) [1]

Fractional Excretion of Uric Acid (FEUa):

• May help distinguish SIAD from volume depletion [12]
• FEUa = (Urine uric acid × Plasma Cr) / (Plasma uric acid × Urine Cr) × 100
• FEUa > 12% suggests SIAD (ADH causes uric acid excretion) [12]
• FEUa less than 12% suggests volume depletion [12]
• Limited utility; clinical assessment usually sufficient [12]

Step 4: Additional Laboratory Tests

Step 5: Imaging and Special Tests (if indicated)

Diagnosing SIAD/SIADH

Essential Criteria (all must be met): [10,12]

1. Hypotonic hyponatremia: Plasma osmolality less than 275 mOsm/kg
2. Urine osmolality > 100 mOsm/kg: Typically > 300 mOsm/kg (concentrated urine despite hypo-osmolality)
3. Urine sodium > 40 mEq/L: On normal diet (not restricted)
4. Euvolemia: No edema, no signs of volume depletion
5. Normal renal, thyroid, adrenal function:
   • Creatinine less than 1.5 mg/dL or GFR > 60
   • TSH normal
   • Cortisol normal (or excluded clinically)
6. No recent diuretic use: Must be off diuretics > 48 hours

Supportive Findings: [12]

• Low serum uric acid (less than 4 mg/dL) - 75% sensitive
• Low BUN (less than 10 mg/dL)
• High FEUa (> 12%)
• Improvement with fluid restriction

Identify Underlying Cause: [10,12]

• Malignancy (especially small cell lung cancer, pancreatic, bladder)
• CNS disorder (meningitis, SAH, stroke, head trauma)
• Pulmonary disease (pneumonia, TB, aspergillosis)
• Medications (SSRIs, carbamazepine, chemotherapy)
• Postoperative state
• Idiopathic (diagnosis of exclusion)

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Treatment

General Principles

1. Treat Based on Symptoms, Not Sodium Number: [1,2]

• Severe symptoms (seizures, coma): Medical emergency requiring immediate 3% saline [1]
• Moderate symptoms (confusion, vomiting): Urgent treatment with 3% saline [1]
• Mild/no symptoms: Treat underlying cause; slow correction acceptable [1]

2. Determine Acuity: [1,2]

• Acute (less than 48 hours): May correct faster initially, but still limit total correction [1]
• Chronic or unknown duration: Assume chronic; slower correction mandatory [1,2]

3. Correction Rate Limits: [1,2,3,4]

• First 24 hours: Maximum 10-12 mEq/L (some recommend 8-10 mEq/L) [2]
• Subsequent days: Maximum 8 mEq/L per 24 hours [2]
• High-risk patients for ODS: Target 4-6 mEq/L in first 24 hours [3,4]

4. Frequent Monitoring: [1,2]

• Sodium Q2h during active treatment (hypertonic saline)
• Sodium Q4-6h once stable
• Stop hypertonic saline once symptoms resolve OR safe correction achieved [1]

5. Treat Underlying Cause: [1]

• Fluid restriction for SIAD
• IV saline for volume depletion
• Treat heart failure, cirrhosis
• Stop offending medications
• Hormone replacement for hypothyroidism or adrenal insufficiency

Severe Symptomatic Hyponatremia

Indications for Emergent Treatment: [1,2]

• Seizures
• Coma or severely decreased level of consciousness (GCS ≤8)
• Respiratory distress or respiratory arrest
• Cardiopulmonary instability

3% Hypertonic Saline Bolus Protocol: [1,2]

Mechanism:

• 3% saline = 513 mEq/L sodium (hypertonic) [1]
• Rapidly increases plasma osmolality [1]
• Reduces cerebral edema [1]
• Small rises (4-6 mEq/L) sufficient to reverse herniation and stop seizures [1]

Airway Management:

• Intubate if GCS ≤8 or unable to protect airway [1]
• Seizures: Benzodiazepines (lorazepam 2-4 mg IV) plus hypertonic saline [1]
• Do NOT delay hypertonic saline for intubation if patient seizing [1]

Moderate Symptomatic Hyponatremia

Indications: [1,2]

• Confusion, disorientation
• Nausea with vomiting
• Headache with altered mental status
• Gait instability

3% Hypertonic Saline Infusion Protocol: [1,2]

Calculation Tools:

Adrogue-Madias Formula (estimates sodium rise per liter of infusate): [1]

ΔNa = (Infusate Na - Serum Na) / (Total Body Water + 1)

Total Body Water (TBW):
- Men: 0.6 × weight (kg)
- Women: 0.5 × weight (kg)
- Elderly/cirrhosis: 0.45-0.5 × weight (kg)

3% Saline: 513 mEq/L sodium

Example:

• 70 kg woman, serum Na 118 mEq/L
• TBW = 0.5 × 70 = 35 L
• ΔNa per liter 3% saline = (513 - 118) / (35 + 1) = 395 / 36 = 10.97 ≈ 11 mEq/L
• To raise Na by 6 mEq/L: Need ~550 mL of 3% saline
• Infuse over 3-6 hours (goal 1-2 mEq/L/hr)

Limitations of Formula: [1]

• Estimates only; actual rise may vary
• Does not account for ongoing losses or intake
• Monitor actual sodium levels; do not rely on calculation alone

Chronic Asymptomatic or Mildly Symptomatic Hyponatremia

Goal: Gradual correction while treating underlying cause [1,2]

General Approach:

• Correct slowly: 4-8 mEq/L in first 24 hours [1,2]
• Treat underlying etiology [1]
• Avoid hypertonic saline unless symptomatic [1]

Treatment by Cause:

Hypovolemic Hyponatremia

Renal Losses (Urine Na > 40 mEq/L):

Extrarenal Losses (Urine Na less than 25 mEq/L):

Monitoring:

• Volume repletion can cause rapid sodium rise (ADH suppression) [8]
• Check sodium Q4-6h initially [8]
• If rising > 1 mEq/L/hr, slow IV fluids or switch to D5W [8]
• Risk of overcorrection especially with thiazide diuretics [8]

Euvolemic Hyponatremia - SIAD/SIADH

First-Line: Fluid Restriction [1,10,12]

Calculation of Free Water Clearance:

Electrolyte-Free Water Clearance = Urine Volume × [1 - (Urine Na + Urine K) / Plasma Na]

If negative → gaining free water (restrict further)
If positive → excreting free water (restriction working)

Second-Line: Salt Intake with Fluid Restriction [10,12]

• Increase dietary sodium to 3-6 g/day (sodium chloride tablets 1-2 g TID)
• Increases solute load, improves free water excretion
• Combine with fluid restriction
• Useful for mild SIAD

Third-Line: Urea [18]

Fourth-Line: Vasopressin Receptor Antagonists (Vaptans) [19]

Tolvaptan Considerations: [19]

• Indications: Symptomatic or severe SIAD refractory to fluid restriction
• Initiate in hospital: Risk of rapid overcorrection
• Starting dose: 15 mg PO once daily in morning
• Monitor sodium Q4-6h for first 24h: May rise rapidly (6-12 mEq/L in 24h)
• Black box warning: Hepatotoxicity with prolonged use (> 30 days); avoid in liver disease
• Cost: Very expensive
• Response: Aquaresis (clear urine output) within hours; sodium rises over 24-48h
• Hypokalemia: Monitor K; replace as needed

Overcorrection Risk with Vaptans:

• Higher risk if baseline sodium less than 120 mEq/L [19]
• Monitor closely; may need to stop drug and give desmopressin + D5W [19]

Fifth-Line: Demeclocycline [10]

Treat Underlying Cause of SIAD: [10,12]

• Malignancy: Chemotherapy, radiation, surgery
• Infection: Antibiotics for pneumonia, meningitis
• CNS disorder: Treat SAH, meningitis, mass
• Medications: Stop offending drug (SSRI, carbamazepine, etc.)
• Idiopathic: Chronic fluid restriction or urea

Euvolemic Hyponatremia - Other Causes

Primary Polydipsia: [13]

• Treatment: Restrict water intake to less than 1-1.5 L/day
• Psychiatric meds: Adjust if contributing (thioridazine)
• Behavioral therapy: For psychogenic polydipsia
• Monitoring: Outpatient follow-up; rarely needs admission
• Challenge: Compliance difficult in psychiatric patients

Beer Potomania: [14]

• Treatment: Stop beer; normal diet with adequate solute
• Risk: Very rapid correction when solute intake restored (risk of ODS) [14]
• Prevention: Monitor sodium Q4-6h; give desmopressin + D5W if rising too fast [14]
• Nutrition: Thiamine supplementation (alcoholism)

Hypothyroidism: [1]

• Treatment: Levothyroxine 1.6 mcg/kg/day PO (lower initial dose in elderly or cardiac disease)
• Onset: Gradual sodium normalization over weeks
• Monitoring: TSH, free T4, sodium

Adrenal Insufficiency (Glucocorticoid Deficiency): [1]

• Acute: Hydrocortisone 100 mg IV q8h
• Chronic: Hydrocortisone 15-25 mg/day PO (divided BID-TID) OR prednisone 5-7.5 mg/day
• Primary adrenal insufficiency: Also needs fludrocortisone 0.05-0.2 mg/day PO
• Monitoring: Sodium normalizes within 24-72 hours with cortisol replacement

Exercise-Associated Hyponatremia: [9]

• Acute symptomatic: 3% saline bolus (same as other severe hyponatremia)
• Prevention: Education for athletes
  • Drink to thirst, not on schedule
  • Avoid overhydration during endurance events
  • Avoid NSAIDs during exercise (impair water excretion)
• Return to sport: After full recovery and education

Hypervolemic Hyponatremia

Heart Failure: [16]

Cirrhosis with Ascites: [17]

Prognostic Significance:

• Hyponatremia in cirrhosis predicts mortality [17]
• MELD-Na score incorporates sodium for transplant prioritization [17]

Nephrotic Syndrome:

• Treat underlying glomerulopathy (steroids, immunosuppression)
• IV albumin if severe hypoalbuminemia (less than 2 g/dL)
• Loop diuretics with albumin co-administration
• Fluid and sodium restriction

Advanced CKD:

• Fluid restriction
• Avoid salt-wasting
• Optimize kidney disease management
• May need dialysis if refractory and symptomatic

Overcorrection and Re-Lowering Protocol

Recognize Overcorrection: [3,4]

Monitor sodium Q2-4h during treatment. Overcorrection defined as:

• 10-12 mEq/L rise in first 24 hours

• 8 mEq/L rise in any subsequent 24-hour period

• 18-20 mEq/L rise in first 48 hours

Immediate Actions to Prevent ODS: [3,4]

Example:

• Baseline Na: 112 mEq/L
• After 24 h: 126 mEq/L (rise of 14 mEq/L - overcorrection!)
• Target: Re-lower to 120-122 mEq/L (8-10 mEq/L rise from baseline)
• Give DDAVP 2-4 mcg IV + D5W 300 mL/hr
• Check Na Q2h; stop when Na = 120-122 mEq/L

Monitoring for ODS: [4]

• Even with re-lowering, risk of ODS remains [4]
• MRI brain if any neurologic symptoms develop 2-6 days post-correction [4]
• MRI findings: T2/FLAIR hyperintensity in pons (central pontine myelinolysis) or extrapontine sites [4]

Special Populations

Post-Operative Hyponatremia: [8]

• Common causes: Excess hypotonic IV fluids, SIAD (stress, pain, nausea), ADH release from surgery/anesthesia
• High risk: Premenopausal women, neurosurgery, prolonged surgery
• Prevention: Isotonic fluids (0.9% saline or lactated Ringer's) instead of hypotonic fluids
• Treatment: As above; may be acute (less than 48h) → faster initial correction acceptable but limit total

Thiazide-Induced Hyponatremia: [8]

• Onset: Typically within 2 weeks of starting thiazide (can be years later)
• Risk factors: Elderly women, low body weight, low baseline sodium
• Mechanism: Impaired diluting ability; continued water intake
• Treatment: Stop thiazide; IV 0.9% saline cautiously; monitor Q4-6h (can correct rapidly)
• Risk: Rapid overcorrection when thiazide effect wears off and volume replete
• Prevention: May need desmopressin + D5W if rising > 1 mEq/L/hr

Exercise-Associated Hyponatremia (EAH): [9]

• Risk factors: Prolonged exercise (> 4 hours), excessive hypotonic fluid intake, NSAIDs, premenopausal women
• Presentation: Symptoms during or within 24h of event completion
• Treatment: Symptomatic → 3% saline bolus; asymptomatic → restrict fluids, monitor
• Do NOT give hypotonic fluids: Worsens hyponatremia
• Prevention education: Drink to thirst, avoid overhydration, avoid NSAIDs

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Monitoring and Follow-Up

Acute Phase Monitoring

During Active Treatment (3% Saline or Rapid Correction):

Once Stable (Sodium Rising Appropriately):

Chronic Phase Monitoring

Outpatient Management:

Monitoring for Osmotic Demyelination Syndrome

High-Risk Patients (chronic severe hyponatremia, alcoholism, malnutrition):

• Clinical vigilance: Days 2-6 post-correction [4]
• Symptoms to watch: Dysarthria, dysphagia, weakness, movement disorders, behavior changes, decreased level of consciousness [4]
• MRI brain: If any concerning symptoms develop [4]
  • T2/FLAIR hyperintensity in pons or extrapontine sites [4]
  • May be normal in first 2 weeks; repeat if suspicion high [4]
• Management of ODS: Supportive care; no proven reversal therapy; may consider re-lowering sodium but efficacy unclear once ODS developed [4]

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Disposition and Care Settings

ICU Admission Criteria

Absolute Indications:

• Seizures
• Coma or GCS ≤8
• Respiratory distress or intubation
• Requiring 3% saline boluses
• Sodium less than 110 mEq/L (even if asymptomatic)
• Hemodynamic instability

Relative Indications:

• Sodium 110-115 mEq/L with symptoms
• High risk for ODS (chronic severe hyponatremia, alcoholism, malnutrition)
• Requiring 3% saline continuous infusion
• Acute hyponatremia less than 48 hours
• Recent overcorrection requiring re-lowering

Hospital Ward Admission Criteria

• Sodium less than 120-125 mEq/L
• Symptomatic hyponatremia (mild-moderate symptoms)
• New diagnosis requiring workup
• Requiring IV isotonic saline
• Requiring close monitoring (Q4-6h sodium checks)
• Unable to comply with outpatient fluid restriction
• Complicated social situation

Outpatient Management Criteria

Safe for Discharge:

• Sodium > 125 mEq/L
• Asymptomatic or minimal symptoms
• Chronic stable hyponatremia (known from prior labs)
• Underlying cause identified and treatment initiated
• Patient can comply with fluid restriction or medication
• Reliable follow-up available within 1 week
• No high-risk features

Discharge Instructions:

• Fluid restriction instructions (measure daily intake)
• Medication compliance (stop offending drugs, start hormone replacement)
• Follow-up lab work (sodium check in 3-7 days)
• Return precautions (confusion, seizures, worsening symptoms)
• Dietary sodium counseling (if SIAD)

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Patient Education

Explaining Hyponatremia (Layperson Language)

What is Hyponatremia? "Your blood sodium level is too low. Sodium is an important salt that helps your body regulate water balance. When sodium is too low, extra water moves into your cells, including brain cells. This can cause the symptoms you are experiencing, such as confusion, nausea, or headache."

Why is it Dangerous? "If sodium drops too low or too quickly, your brain can swell, which can be very dangerous and even life-threatening. That's why we are treating this carefully and monitoring you closely."

Treatment Explanation: "We are giving you fluids (or restricting fluids, depending on the cause) to slowly bring your sodium back to normal. It's very important to correct this slowly because correcting too fast can damage the brain in a different way. We are checking your blood sodium levels frequently to make sure we are correcting at a safe rate."

Chronic Hyponatremia: "Your sodium has been low for a while, so your brain has adapted to the low level. We need to bring it up very slowly over several days to avoid causing harm."

Specific Instructions by Cause

SIAD/SIADH:

• "Your body is holding onto too much water. You need to restrict your fluid intake to less than 1 to 1.5 liters (about 4-6 cups) per day."
• "This includes all fluids: water, coffee, tea, juice, soup, ice cream."
• "Measure your fluids with a measuring cup each day."
• "You may also need to increase your salt intake by adding salt to food or taking salt tablets."
• "We need to find out why your body is holding onto water. This may require some tests to look for lung infections, cancer, or other causes."

Heart Failure or Cirrhosis:

• "Your heart (or liver) is not working well, causing fluid to build up in your body. Even though you have extra fluid, your sodium is diluted."
• "You need to restrict both fluids (1-1.5 liters per day) and salt (2 grams per day)."
• "Weigh yourself daily at the same time. Call your doctor if you gain more than 2-3 pounds in a day or 5 pounds in a week."
• "Take your diuretics (water pills) as prescribed."

Diuretic-Induced:

• "Your water pill (diuretic) caused your sodium to drop. We are stopping this medication."
• "Your sodium may come back up quickly once the medication is out of your system. We will monitor closely."
• "Drink fluids normally; don't restrict unless told otherwise."

Hypothyroidism or Adrenal Insufficiency:

• "Your thyroid (or adrenal gland) is not making enough hormone. This is causing your sodium to be low."
• "You will need to take hormone replacement medication every day for the rest of your life."
• "Your sodium will gradually return to normal over the next few weeks as the hormone levels improve."
• "Never stop these medications without talking to your doctor."

Prevention Counseling

For Patients at Risk:

• Elderly on thiazides: Monitor sodium within 1-2 weeks of starting diuretic; avoid hypovolemia; consider potassium-sparing diuretic instead
• Endurance athletes: Education on fluid intake
  • Drink to thirst, not on schedule
  • Avoid excessive water intake before and during events
  • Use sports drinks with electrolytes (but don't overconsume)
  • Avoid NSAIDs during prolonged exercise
• Patients on SSRIs: Monitor sodium, especially in first few months; higher risk in elderly
• Postoperative patients: Isotonic fluids; avoid hypotonic fluids

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Prognosis and Outcomes

Acute Hyponatremia

Untreated Severe Symptomatic Hyponatremia:

• Mortality 50% or higher without treatment [1]
• Risk of cerebral herniation and death [1]
• Permanent neurologic damage if prolonged cerebral edema [1]

With Appropriate Treatment:

• Mortality 5-10% (depends on underlying cause) [1]
• Most patients recover fully if corrected appropriately [1]
• Prognosis depends more on underlying condition (e.g., malignancy, CNS infection) than hyponatremia itself [1]

Chronic Hyponatremia

Morbidity: [7]

• Increased fall risk: 67% higher in elderly with sodium less than 135 mEq/L [7]
• Increased fracture risk: Hip and other fragility fractures [7]
• Cognitive impairment: Attention, gait, postural stability affected even with mild hyponatremia (130-135 mEq/L) [7]
• Osteoporosis: Associated with chronic hyponatremia [7]

Mortality: [6,7]

• In-hospital mortality 2.5-fold higher with hyponatremia [6]
• 1-year mortality increased with chronic hyponatremia [7]
• May be marker of underlying disease severity rather than direct cause [6]

Improvement with Correction:

• Gait and attention improve with sodium correction [7]
• Fall risk reduces [7]
• Quality of life may improve [7]

Osmotic Demyelination Syndrome

Prognosis: [3,4]

• Variable outcomes: Some recover, some have permanent deficits, some develop locked-in syndrome [4]
• Severe cases: Quadriparesis, dysarthria, dysphagia may be permanent [4]
• Mortality: 25-50% in severe cases [4]
• No proven effective treatment once ODS develops [4]
• Prevention is critical [4]

Condition-Specific Prognosis

SIAD:

• Depends on underlying cause [10]
• Malignancy-associated SIAD: Prognosis determined by cancer [10]
• Idiopathic SIAD: Chronic condition; good prognosis with fluid restriction [10]
• Medication-induced: Resolves after stopping drug (days to weeks) [10]

Heart Failure:

• Hyponatremia is strong negative prognostic marker [16]
• Sodium less than 135 mEq/L predicts increased mortality and readmission [16]
• Marker of disease severity and neurohormonal activation [16]

Cirrhosis:

• Hyponatremia predicts mortality independent of MELD score [17]
• Sodium less than 130 mEq/L: 1-year mortality ~30% [17]
• Sodium less than 125 mEq/L: 1-year mortality > 50% [17]
• Indication for liver transplant evaluation [17]

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Quality Metrics and Performance Indicators

Process Measures

Outcome Measures

Documentation Requirements

Essential Documentation:

• Sodium level and trend (include prior values if available)
• Symptom severity and timeline
• Volume status assessment
• Plasma osmolality
• Urine sodium and osmolality
• Underlying etiology identified
• Treatment plan (hypertonic saline dose and rate, fluid restriction, etc.)
• Target correction rate
• Monitoring plan (frequency of sodium checks)
• High-risk features for ODS documented

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Key Clinical Pearls

Diagnostic Pearls

1. Confirm hypotonic hyponatremia first: Measure plasma osmolality to rule out pseudohyponatremia and hypertonic hyponatremia [1]

2. Correct sodium for hyperglycemia: Add 1.6 mEq/L for each 100 mg/dL glucose > 100 mg/dL (or 2.4 for glucose > 400) [1]

3. Volume status is key: Clinical exam (JVP, edema, orthostatics, mucous membranes) guides diagnosis [1]

4. SIAD diagnosis requires euvolemia: If edema or hypovolemia present, not SIAD [10,12]

5. Urine sodium > 40 mEq/L + euvolemia = SIAD (assuming normal diet, no diuretics, normal thyroid/adrenal/renal function) [10,12]

6. Urine osmolality less than 100 mOsm/kg = ADH suppressed: Think polydipsia or beer potomania [13,14]

7. Low uric acid (less than 4 mg/dL) supports SIAD: ADH causes uric acid excretion [12]

8. Always assess chronicity: Acute (less than 48h) vs. chronic (> 48h) determines correction rate safety [1,2]

9. If duration unknown, assume chronic: Safer to correct slowly [1,2]

10. Post-op hyponatremia is often acute: High risk, especially premenopausal women [8,9]

Treatment Pearls

1. Treat symptoms, not sodium number: Severe symptoms require 3% saline regardless of sodium level [1,2]

2. 3% saline bolus for emergencies: 100 mL over 10 min; target 4-6 mEq/L rise to stop symptoms [1,2]

3. Limit correction to 10-12 mEq/L in first 24h, 8 mEq/L each day thereafter: Prevent ODS [3,4]

4. High-risk for ODS: chronic + severe + alcoholism/malnutrition/liver disease/hypokalemia: Aim for 4-6 mEq/L in first 24h [3,4]

5. Monitor sodium Q2h during active treatment: Essential to avoid overcorrection [1,2]

6. Stop hypertonic saline when symptoms resolve: Don't need to reach specific number [1]

7. Overcorrection protocol: DDAVP + D5W: Bring sodium back down into safe range [3,4]

8. Fluid restriction is first-line for SIAD: 500-1000 mL/day; works if urine osmolality less than 500 mOsm/kg [10,12]

9. Volume depletion can cause rapid correction: Monitor Q4-6h when giving IV saline for hypovolemic hyponatremia, especially with thiazides [8]

10. Correct hypokalemia simultaneously: Potassium correction raises sodium; low K increases ODS risk [3,4]

11. Vaptans risk rapid overcorrection: Monitor very closely; reserve for refractory SIAD [19]

12. Don't use vaptans in cirrhosis: Hepatotoxicity risk, no mortality benefit [17,19]

13. Beer potomania: high ODS risk when diet normalized: Solute intake → rapid ADH suppression → rapid correction [14]

14. Adrenal insufficiency: give hydrocortisone, not just saline: Cortisol deficiency is the problem [1]

15. Heart failure/cirrhosis: restrict fluids AND sodium: Avoid hypertonic saline (worsens volume overload) [16,17]

Disposition Pearls

1. ICU for severe symptoms: Seizures, coma, respiratory distress, requiring 3% saline boluses [1]

2. ICU for sodium less than 110 mEq/L: Even if asymptomatic; very high risk [1]

3. Admit for sodium less than 120-125 mEq/L: Requires close monitoring [1]

4. High-risk for ODS needs ICU: Close monitoring for re-lowering protocol if needed [3,4]

5. Outpatient for chronic stable mild hyponatremia: If > 125 mEq/L, asymptomatic, known cause, reliable follow-up [1]

6. Follow-up sodium check in 3-7 days: For all discharged patients [1]

Safety Pearls

1. Hyponatremia + seizures = 3% saline bolus, not just benzos: Treat the cause [1]

2. Premenopausal women at highest risk for herniation: Acute hyponatremia + estrogen impairs adaptation [9]

3. Post-op hyponatremia in young women is deadly: High index of suspicion; aggressive treatment [8,9]

4. Never delay hypertonic saline for intubation if seizing: Give bolus first, then secure airway [1]

5. Don't give hypotonic fluids in exercise-associated hyponatremia: Worsens hyponatremia; give 3% saline if symptomatic [9]

6. Watch for rapid correction when treating volume depletion: ADH suppression → aquaresis → overcorrection [8]

7. Thiazide-induced hyponatremia corrects rapidly: Stop thiazide, cautious IV saline, monitor Q4-6h [8]

8. Re-lowering sodium may prevent ODS: DDAVP + D5W if overcorrecting [3,4]

9. MRI brain if symptoms develop days 2-6 post-correction: ODS [4]

10. No proven treatment for ODS once developed: Prevention is everything [3,4]

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References

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2. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-S42. doi:10.1016/j.amjmed.2013.07.006

3. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3):282-299. doi:10.1016/j.semnephrol.2009.03.002

4. Lambeck J, Hieber M, Dreßing A, Niesen WD. Central Pontine Myelinolysis and Osmotic Demyelination Syndrome. Dtsch Arztebl Int. 2019;116(35-36):600-606. doi:10.3238/arztebl.2019.0600

5. Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120(8):653-658. doi:10.1016/j.amjmed.2006.09.031

6. Corona G, Giuliani C, Parenti G, et al. The Economic Burden of Hyponatremia: Systematic Review and Meta-Analysis. Am J Med. 2016;129(8):823-835.e4. doi:10.1016/j.amjmed.2016.03.007

7. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e1-8. doi:10.1016/j.amjmed.2005.09.026

8. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52(1):144-153. doi:10.1053/j.ajkd.2008.03.004

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11. Yee AH, Burns JD, Wijdicks EF. Cerebral salt wasting: pathophysiology, diagnosis, and treatment. Neurosurg Clin N Am. 2010;21(2):339-352. doi:10.1016/j.nec.2009.10.011

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13. Goldman MB. The assessment and treatment of water imbalance in patients with psychosis. Clin Schizophr Relat Psychoses. 2010;4(2):115-123. doi:10.3371/CSRP.4.2.4

14. Hilden T, Svendsen TL. Electrolyte disturbances in beer drinkers. A specific "hypo-osmolality syndrome". Lancet. 1975;2(7928):245-246. doi:10.1016/s0140-6736(75)90353-7

15. DeFronzo RA, Goldberg M, Agus ZS. Normal diluting capacity in hyponatremic patients. Reset osmostat or a variant of the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med. 1976;84(5):538-542. doi:10.7326/0003-4819-84-5-538

16. Gheorghiade M, Abraham WT, Albert NM, et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J. 2007;28(8):980-988. doi:10.1093/eurheartj/ehl542

17. Ginès P, Solà E, Angeli P, et al. Hepatorenal syndrome. Nat Rev Dis Primers. 2018;4(1):23. doi:10.1038/s41572-018-0022-7

18. Wendt RE, Fenves AZ, Geisler BP. Use of Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone: A Systematic Review. JAMA Netw Open. 2023;6(10):e2340313. doi:10.1001/jamanetworkopen.2023.40313

19. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099-2112. doi:10.1056/NEJMoa065181

20. Hoorn EJ, Zietse R. Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines. J Am Soc Nephrol. 2017;28(5):1340-1349. doi:10.1681/ASN.2016101139