Hyponatremia

Epidemiology

Hyponatremia is One of the Most Common Electrolyte Disturbances Encountered in Clinical Practice (Am J Med, 2006) [MEDLINE]

Inpatient

  • Study of Incidence of Hyponatremia (Clin Chim Acta, 2003) [MEDLINE]: n >300,000 sodium samples measured in >120,000 patients (from acute care hospital, ambulatory hospital, and community-based clinics in Singapore)
    • Incidence of Hyponatremia (Serum Sodium <136 mEq/L) in Acute Care Hospital Setting: 42.6%
    • Incidence of Hyponatremia (Serum Sodium <126 mEq/L) in Acute Care Hospital Setting: 6.2%
    • Incidence of Hyponatremia (Serum Sodium <116 mEq/L) in Acute Care Hospital Setting: 1.2%

Outpatient

  • Study of Incidence of Hyponatremia (Clin Chim Acta, 2003) [MEDLINE]: n >300,000 sodium samples measured in >120,000 patients (from acute care hospital, ambulatory hospital, and community-based clinics in Singapore)
    • Incidence of Hyponatremia (Serum Sodium <136 mEq/L) in Ambulatory Hospital Care Setting: 21%
    • Incidence of Hyponatremia (Serum Sodium <136 mEq/L) in Community Care Ambulatory Setting: 7.2%

Etiology

Pseudohyponatremia

General Comments

  • Pseudohyponatremia Due to Either Hyperproteinemia or Hypertriglyceridemia are Considered Isotonic Hyponatremia (Since the Sodium Concentration in Plasma Water and Interstitial Fluid are Normal)
  • Patients with Pseudohyponatremia are Asymptomatic

Hyperproteinemia (Severe, Total Protein Usually >10 g/dL) (see Hyperproteinemia)

  • Epidemiology
  • Mechanism
    • Pseudohyponatremia Occurs Due to a Laboratory Artifact When Using Flame Photometry or Indirect Potentiometry (Which Measure Sodium Concentration Per Volume of Plasma)
      • Note that the Laboratory Artifact Does Not Occur When Using Direct Potentiometry (Which Directly Measure the Sodium Concentration in the Water Phase of Plasma)
      • Note that the Sodium Concentration Will Be Assayed as Normal by Direct Sodium-Selective Electrodes Used by Blood Gas Analyzers and Some Point-of-Care Devices
      • Hyperproteinemia Increases the Mass of the Nonaqueous Protein Component of Serum and a Concomitant Decrease in the Proportion of the Water Component
      • Sodium Concentration is Usually Reported by the Laboratory as mEq/L of Plasma or Serum
      • Normal Plasma or Serum is 93% Water and 7% Fats/Proteins
        • However, in the Setting of Significant Hypertriglyceridemia/Hyperproteinemia, the Plasma or Serum Water Fraction May Fall to <80%
      • Sodium is Restricted to the Serum Water Component (Although the Sodium Concentration in the Water Phase is Not Affected, the Sodium Concentration Per Unit of Plasma is Decreased)
        • The Sodium Concentration in Plasma Water is What is Physiologically Important
    • Numerical Impact of Hyperproteinemia on the Serum Sodium Concentration
      • A 1 g/dL Increase in Plasma Protein Will Decrease the Serum Sodium by Approximately 0.7 mEq/L (Nephrol Dial Transplant, 2015) [MEDLINE]
  • Diagnosis
    • Hyponatremia (When Assessed by Autoanalyzer Which Uses Flame Photometry or Indirect Potentiometry)
    • Normonatremia (When Assessed by Sodium-Selective Electrode)
    • Normal Serum Osmolality (see Serum Osmolality)
      • Serum Osmolality Measurements are Not Affected by this Laboratory Artifact (Am J Med, 1989) [MEDLINE] (NEJM, 2003) [MEDLINE]

Hypertriglyceridemia (Severe) (see Hypertriglyceridemia)

  • Epidemiology
    • Severe Hypertriglyceridemia May Occur in Uncontrolled Diabetes Mellitus (see Diabetes Mellitus)
    • Severe Hypertriglyceridemia May Occur Due to Other Etiologies
      • In Patients with Acute Pancreatitis, the Presence of Pseudohyponatremia at Presentation Increases the Probability that the Pancreatitis is Due to the Hypertriglyceridemia (Pancreas, 2019) [MEDLINE]
  • Mechanism
    • Pseudohyponatremia Occurs Due to a Laboratory Artifact When Using Flame Photometry or Indirect Potentiometry (Which Measure Sodium Concentration Per Volume of Plasma)
      • Note that the Laboratory Artifact Does Not Occur When Using Direct Potentiometry (Which Directly Measure the Sodium Concentration in the Water Phase of Plasma)
      • Note that the Sodium Concentration Will Be Assayed as Normal by Direct Sodium-Selective Electrodes Used by Blood Gas Analyzers and Some Point-of-Care Devices
      • Hypertriglyceridemia Increases the Mass of the Nonaqueous Lipid Component of Serum and a Concomitant Decrease in the Proportion of the Water Component
      • Sodium Concentration is Usually Reported by the Laboratory as mEq/L of Plasma or Serum
      • Normal Plasma or Serum is 93% Water and 7% Fats/Proteins
        • However, in the Setting of Significant Hypertriglyceridemia/Hyperproteinemia, the Plasma or Serum Water Fraction May Fall to <80%
      • Sodium is Restricted to the Serum Water Component (Although the Sodium Concentration in the Water Phase is Not Affected, the Sodium Concentration Per Unit of Plasma is Decreased)
        • The Sodium Concentration in Plasma Water is What is Physiologically Important
    • Numerical Impact of Hypertriglyceridemia on the Serum Sodium Concentration
      • A 886 mg/dL (10 mmol/L) Increase in Plasma Triglycerides Will Decrease the Serum Sodium Concentration by Approximately 1 mEq/L (Clin Chem, 2006) [MEDLINE]
  • Diagnosis
    • Hyponatremia (as Assessed by Autoanalyzer Which Uses Flame Photometry or Indirect Potentiometry)
    • Normonatremia (as Assessed by Sodium-Selective Electrode)
    • Normal Serum Osmolality (see Serum Osmolality)
      • Serum Osmolality Measurements are Not Affected by this Laboratory Artifact (Am J Med, 1989) [MEDLINE] (NEJM, 2003) [MEDLINE]

Obstructive Jaundice/Cholestasis (see Hyperbilirubinemia)

  • Mechanism
    • Severe Elevation of Total Serum Cholesterol and Elevated Lipoprotein X
      • The Lowest Reported Total Serum Cholesterol Resulting in Pseudohyponatremia was 977 mg/dL (with Corresponding Serum Sodium of 129 mmol/L) (J Clin Lipidol, 2015) [MEDLINE]
      • The Highest Reported Total Serum Cholesterol was 4091 mg/dL (with Corresponding Serum Sodium of 101 mmol/L) (J Clin Lipidol, 2015) [MEDLINE]
      • Lipoprotein X is an Insoluble Compound Which Forms When There is a Reflux of Unesterified Cholesterol and Phospholipids into the Circulation
      • Lipoprotein X Does Not Accumulate in Other Hyperlipidemic States with Severely Elevated Total Serum Cholesterol (Such as Homozygous Familial Hypercholesterolemia)
      • In Contrast to Hypertriglyceridemia, Elevated Lipoprotein X Does Not Cause the Serum to Appear Lipemic
  • Diagnosis

Hypertonic Hyponatremia

Hyperglycemia (see Hyperglycemia)

  • Mechanism
    • Glucose is an Osmotically Active Solute (and an “Effective Osmole”), Which Increases Serum Tonicity and Causes Water to Be Pulled Out of Cells, Expanding the Extracellular Water Space and Resulting in Dilution of the Serum Sodium and Hypertonic Hyponatremia
      • The Development of Hyponatremia is at Least Partially Countered by Free Water Loss Resulting from the Associated Glycosuria-Induced Osmotic Diuresis
    • Hypertonic Hyponatremia Due to Hyperglycemia Does Not Increase the Risk of Cerebral Edema, Because Water Moves Out of Cells
      • However, the Rapid Correction of Hyperglycemia without a Commensurate Increase in Serum Sodium May Result in a Precipitous Decrease in Effective Osmolality and Cause Cerebral Edema (Particularly in Children and Young Adults with Diabetic Ketoacidosis) (J Pediatr, 2007) [MEDLINE]
        • Therefore, One Should Monitor Effective Serum Osmolality During the Treatment of Severe Hyperglycemia/Diabetic Ketoacidosis, Targeting a Gradual Decrease in Effective Serum Osmolality
  • Diagnosis
    • Increased Serum Osmolality (see Elevated Serum Osmolal Gap)
    • Correction of Serum Sodium Concentration for Hyperglycemia
      • Correct the Serum Sodium Concentration Upward by Approximately 2 mEq/L for Each 100 mg/dL (5.5 mmol/L) Increase in the Serum Glucose
        • Studies of Experimentally-Induced Hyperglycemia Suggest that the Previously Utilized 1.6/100 Ratio Applies Only When the Serum Glucose is <400 mg/dL (with Serum Glucose >400 mg/dL, a 4/100 Ratio was Instead Observed) (Am J Med, 1999) [MEDLINE]

Intravenous Immunoglobulin (IVIG) Use in the Setting of Renal Failure (see Intravenous Immunoglobulin)

  • Mechanism
    • Intravenous Immunoglobulin Parenteral Solutions are Suspended in Hypertonic Mannitol, Maltose, or Sucrose
      • Mannitol/Maltose/Sucrose are “Effective Osmoles” (Solutes Which Do Not Move Freely Across Cell Membranes and Obligate Water to Move with Them)
    • Mannitol/Maltose/Sucrose are Osmotically-Active Solutes, Which Cause Water to Be Pulled Out of Cells, Resulting in Dilution of the Serum Sodium (and Hypertonic Hyponatremia) (Ann Intern Med, 1993) [MEDLINE] (South Med J, 2000) [MEDLINE] (Nephron Clin Pract, 2007) [MEDLINE]
    • Use of Intravenous Immunoglobulin in the Presence of Renal Failure
      • If Renal Failure is Present (Preventing Renal Excretion of These Substances), Mannitol/Maltose/Sucrose are Undesirably Retained in the Blood, Increasing Serum Tonicity and Resulting in Water Movement Out of Cells into the Serum (Resulting in Hyponatremia)
      • Hyponatremia May Be Severe and Prolonged (Especially in Cases with Concomitant Intravenous Immunoglobulin-Associated Renal Failure, Which Impairs Water Excretion)
    • Some Investigators Have Suggested that the Intravenous Immunoglobulin-Associated Decrease in Serum Sodium is Actually Pseudohyponatremia Caused by Hyperproteinemia and Hyperviscosity (Am J Hematol, 2003) [MEDLINE]
      • However, Pseudohyponatremia Has Not Been Supported by Studies Measuring the Serum Sodium Using a Sodium-Selective Electrode (Ann Intern Med, 1993) [MEDLINE] (South Med J, 2000) [MEDLINE] (Nephron Clin Pract, 2007) [MEDLINE]
      • Additionally, the Observed Increase in Serum Protein After Intravenous Immunoglobulin is Insufficient to Result in a Significant Decrease in the Serum Sodium
  • Diagnosis
    • Elevated Serum Osmolal Gap >10 mOsmol/kg Indicates that the Mannitol/Maltose/Sucrose Has Been Retained (see Elevated Serum Osmolal Gap)

Intravenous Mannitol Use in the Setting of Renal Failure (see Mannitol)

  • Clinical Uses of Intravenous Mannitol
    • Intravenous Mannitol Used to Treat Increased Intracranial Pressure
  • Administration
    • 20% Mannitol Solution (20 g Mannitol/100 mL) is Hyperosmotic (with 1098 mOsmol/L
    • Typical Intravenous Dose: 50 g (of 20% solution) infused over 30-60 min
  • Mechanism
    • Mannitol is an Osmotically-Active Solute (it is an “Effective Osmole”, Similar to Hyperglycemia), Which Causes Water to Be Pulled Out of Cells, Resulting in Dilution of the Serum Sodium (and Hypertonic Hyponatremia)
      • As Mannitol is Subsequently Excreted in the Urine (Similar to Hyperglycemia), it Acts as an Osmotic Diuretic Promoting Urinary Water Loss and Consequently Increases the Serum Sodium
    • Use of Mannitol in the Presence of Renal Failure
      • If Renal Failure is Present, Mannitol Can Be Undesirably Retained in the Extracellular Space, Causing Hypertonicity, Which Pulls Water Out of Cells, Resulting in Hyponatremia
      • Therefore, If Hyponatremia Occurs After Mannitol Treatment, Serum Osmolality Should Be Monitored
  • Diagnosis

Isotonic Hyponatremia

Procedural Use of Glycine/Sorbitol/Mannitol-Containing Irrigation Solutions (see Glycine and Sorbitol, and Mannitol)

  • Etiology
    • Intravesical Glycine/Sorbitol/Mannitol Irrigant Used During Transurethral Resection of the Prostate (TURP) or Transurethral Resection of the Bladder Tumors (“Transurethral Resection Syndrome”) (see Transurethral Resection of the Prostate)
      • Transurethral Resection Syndrome Occurs in 2% of TURP Cases (J Urol, 2002) [MEDLINE] (J Endourol, 2008) [MEDLINE]
    • Glycine/Sorbitol/Mannitol Irrigation During Hysteroscopy (for Submucosal Leiomyoma Resection, etc) (see Hysteroscopy)
    • Glycine/Sorbitol/Mannitol Irrigation During Percutaneous Nephrolithotomy (Removal of Kidney Stones)
    • Glycine/Sorbitol/Mannitol Irrigation During Laparoscopy (see Laparoscopy)
  • Mechanism
    • Previously Used Electrosurgery Devices were Monopolar and Could Not Be Used with Conductive (Electrolyte-Containing) Irrigation Solutions
      • Bipolar Devices are Now More Commonly Used (These are Compatible with Conductive (Electrolyte-Containing) Irrigation Solutions Such as Normal Saline, Lactated Ringers)
        • However, with These Newer-Generation Devices, the Large Volumes of Saline Irrigant Used May Exhibit Other Adverse Effects (Expansion of the Extracellular Fluid Volume with Fluid Overload/Pulmonary Edema, Hyperchloremia, etc) (Acta Anaesthesiol Scand, 2017) [MEDLINE]
    • The Following are the Most Commonly Used Non-Conductive (Non-Electrolyte) Solutions Used During These Procedures
      • 1.5% Glycine (see Glycine): hypoosmotic (200 mOsmol/kg)
      • 3% Sorbitol (see Sorbitol): hypoosmotic (165 mOsmol/kg
      • 5% Mannitol (see Mannitol): isoosmotic (275 mOsmol/kg)
    • Inadvertent Systemic Absorption of Sodium-Free Glycine/Sorbitol/Mannitol-Containing Solution from the Urinary Bladder/Uterus/Peritoneal Space During the Procedure with Distribution to the Extracellular Space
      • Fluid Absorption into the Vascular Space (Intravasation, Presumably Through Opened Vessels) Occurs When the Fluid Pressure Exceeds the Venous Pressure (at Approximately 10 mm Hg) (Br J Anaesth, 2006) [MEDLINE]
      • Fluid Can Also Be Absorbed Via Inadvertent Surgical Perforation of a Viscus (in Which Case the Serum Sodium May Instead Nadir 1-2 hrs Postoperatively and the Degree of Decrease in the Serum Sodium is Generally Less than that Observed with Intravasation) (Scand J Urol Nephrol, 1993) [MEDLINE]
      • Mannitol/Glycine/Sorbitol are “Effective Osmoles” (Solutes Which Do Not Move Freely Across Cell Membranes and Obligate Water to Move with Them)
    • Glycine (see Glycine)
      • If a Large Volume of Glycine Solution is Absorbed, the Serum Osmolality will Decrease Slightly, But the Serum Sodium Will Decrease Significantly
      • Glycine Enters Cells Over Several Hours (Pulling Water into the Cells with it) and, by 4 hrs Later, Glycine is Almost Equally Distributed Between the Intracellular and Extracellular Compartments (with a Gradual Increase in the Serum Sodium Back Toward Baseline)
      • Glycine is Also Metabolized into Ammonia, Serine, and/or Glyoxylate with the Development of Neurologic Symptoms
    • Sorbitol (see Sorbitol)
      • Sorbitol Solutions Which are Not Renally Excreted Will Be Slowly Hepatically Metabolized to Glucose and Fructose, Then to Carbon Dioxide and Water (with Only 5-10% Being Excreted Unchanged in the Urine), Resulting in a Delayed Onset of Hyponatremia
    • Mannitol (see Mannitol)
      • Mannitol Does Not Enter Cells and is Not Metabolized (it is Excreted Entirely in the Urine, Causing an Osmotic Diuresis)
  • Diagnosis
    • Marked Hyponatremia: Na <110 mEq/L
    • Initial Serum Osmolality (see Serum Osmolality)
      • Since Glycine and Sorbitol Solutions are Hypoosmotic, the Initial Serum Osmolality Will Be Decreased
      • However, Since Mannitol 5% Solution is Isoosmotic, the Initial Serum Osmolality Will Be Relatively Unchanged
    • Elevated Serum Osmolal Gap >10 mOsmol/kg (Indicating that the Glycine/Sorbitol/Mannitol Has Been Retained) (see Elevated Serum Osmolal Gap)
      • The Osmolal Gap Can Exceed 30-60 mOsmol/kg Immediately Postoperatively
      • The Serum Osmolal Gap Will Gradually Disappear Over Time (Due to Glycine Entering Cells, the Metabolism of Glycine/Sorbitol, and the Urinary Excretion of Glycine/Sorbitol/Mannitol)
    • Urine Osmolality (see Urine Osmolality)
      • While One Might Expect the Urine Osmolality to Be Maximally Dilute (<100 mOsmol/kg) to Facilitate Water Excretion in this Clinical Scenario, Factors Such as Postoperative Stress-Related Antidiuretic Hormone Release Can Counter This (by Impairing Water Excretion and Slowing the Correction of the Hyponatremia), Mannitol Causes an Osmotic Diuresis, and Glycine Can Directly Stimulate Antidiuretic Hormone Release (Am J Kidney Dis, 1997) [MEDLINE]
  • Clinical
    • In the Case of Glycine Use, Neurologic Symptoms (Due to Hyponatremia, Glycine Toxicity, and Accumulation of Ammonia/Serine/Glyoxylate, Which are Glycine Metabolites) May Occur (see Glycine)

Cardioplegia with Histidine-Tryptophan-Ketoglutarate (HTK) Solution

  • Etiology
    • Histidine-Tryptophan-Ketoglutarate (HTK) Solution is Widely Used to Induce Electromechanical Cardiac Arrest During Cardiac Surgery
  • Mechanism
    • Histidine-Tryptophan-Ketoglutarate (HTK) Solution is Slightly Hypertonic (with 310 mOsmol/L) and a Low Sodium
      • In One Study, HTK (Median Amount of 2L), Resulted in a Decreased Serum Sodium of 15 mmol/L within 30-60 min (with the Hyponatremia Resolving Spontaneously by the End of Surgery) (J Cardiothorac Surg, 2012) [MEDLINE]
  • Diagnosis
    • Normal Serum Osmolal Gap

Hypotonic Hyponatremia

Disorders with Normal Antidiuretic Hormone (ADH) Levels

  • Decreased Sodium Intake
    • Associated Conditions
      • Beer Potomania (Am J Kidney Dis, 2007) [MEDLINE]
        • Beer Contains Little or No Sodium/Potassium/Protein to Generate Solutes for Excretion
        • Alcohol and Carbohydrate in Beer Suppresses Endogenous Protein Degradation and Consequent Urea Excretion
      • Tea and Toast Diet
  • Psychogenic (Primary) Polydipsia (see Polydipsia)
    • Epidemiology
      • Primary Polydipsia is Most Commonly Observed in Patients with Psychiatric Illness (Psychosis)
    • Mechanism
      • Compulsive Water Intake May Involve Hyperactivity of the Hypothalamic Thirst Center, Neuroleptic Drugs, and/or Resetting of the Hypothalamic Osmostat
      • High-Volume Water Intake Overtasks the Renal Diluting Mechanism

Disorders with Impaired Urine Dilution, But Normal Suppression of Antidiuretic Hormone (ADH)

  • Advanced Renal Failure
    • Associated Conditions
    • Diagnosis
      • Increased Serum Osmolality (see Serum Osmolality)
        • Moderate-Severe Renal Failure May Have a Serum Osmolality Which is Higher Than Predicted by Their Serum Sodium Concentration, Due to the Presence of Urea in Extracellular Fluid
        • However, Since Urea is an “Ineffective Osmole” (It Can Freely Cross Cell Membranes and Does Not Obligate Water Movement Out of Cells), the Effective Serum Osmolality (Measured Osmolality Minus the Contribution of Urea) is Low
    • Mechanism
      • Ability of the Kidney to Excrete Free Water (Free Water Excretion/GFR) is Generally Preserved in Mild-Moderate Renal Failure: therefore, normonatremia is usually present
      • However, in Advanced Renal Failure (GFR <15 mL/min), the Minimum Urine Osmolality Can Increase to as High as 200-250 mOsm/kg, Despite Appropriate Suppression of Antidiuretic Hormone Secretion: this results in an impaired ability to excrete free water
  • Diuretics
    • Bumetanide (Bumex) (see Bumetanide): less common cause of hyponatremia than thiazides
    • Chlorothiazide (see Chlorothiazide): thiazides are the most common class of diuretics associated with hyponatremia
    • Furosemide (Lasix) (see Furosemide): less common cause of hyponatremia than thiazides
    • Hydrochlorothiazide (HCTZ) (see Hydrochlorothiazide)
      • Epidemiology
        • Thiazides are the Most Common Class of Diuretics Associated with Hyponatremia
        • Thiazide-Associated Hyponatremia Typically Begins Soon After Starting the Medication, But Can Occur Later in Some Cases
      • Risk Factors
        • Hypokalemia (see Hypokalemia)
        • Indapamide Administration (see Indapamide): indapamide is a thiazide-like diuretic
        • Institutionalized Elderly Patient
        • Low Body Weight
      • Mechanism
        • Probably Mediated Via Hypovolemia-Stimulated Antidiuretic Hormone Release and Interference with Urinary Dilution in the Cortical Diluting Segment
      • Diagnosis
        • Low Serum Uric Acid (see Serum Uric Acid): common
        • Low Blood Urea Nitrogen (BUN) (see Blood Urea Nitrogen): common
        • FE Uric Acid >12% Has Been Reported in a Small Study to Diagnose SIADH (Over Thiazide-Associated Hyponatremia) with a 100% Positive Predictive Value, While an FE Uric Acid <8% Excluded SIADH with a 100% Negative Predictive Value (J Clin Endocrinol Metab, 2008) [MEDLINE]
        • However, Other Larger Studies Have Not Supported These Findings (Cureus, 2020) [MEDLINE]
      • Clinical
        • Euvolemia: common
      • Treatment
        • Trial of Discontinuation of Thiazide: hyponatremia should improve (but some patients may remain mildly hyponatremic for a week or more after discontinuation of the thiazide)
    • Spironolactone (Aldactone) (see Spironolactone): less common cause of hyponatremia than thiazides

Disorders with Impaired Urine Dilution Due to Unsuppressed Antidiuretic Hormone (ADH) Secretion

  • Decreased Effective Circulating/Arterial Blood Volume
    • Cirrhosis/End-Stage Liver Disease (ESLD) (see Cirrhosis)
      • Mechanisms
        • Arterial Vasodilation, Resulting in Decreased Effective Arterial Blood Volume and Consequently, Decreased Blood Pressure Sensed at the Carotid Sinus Baroreceptors
        • Decreased Tissue Perfusion
        • Increased Plasma and Extracellular Fluid Volumes
        • Increased Antidiuretic Hormone Secretion
      • Diagnosis
        • Serum Antidiuretic Hormone Level Correlates with the Severity of the Underlying Cirrhosis
      • Clinical
        • Hypervolemic Hyponatremia (with Peripheral Edema, Ascites, etc)
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
      • Mechanisms
        • Decreased Cardiac Output
        • Decreased Effective Arterial Blood Volume with Decreased Blood Pressure Sensed at the Carotid Sinus Baroreceptors
        • Decreased Tissue Perfusion
        • Increased Plasma and Extracellular Fluid Volumes
        • Increased Antidiuretic Hormone Secretion
      • Diagnosis
        • Serum Antidiuretic Hormone Level Correlates with the Severity of the Underlying Congestive Heart Failure
        • Serum Sodium Predicts Survival in Congestive Heart Failure (Circulation, 1986) [MEDLINE]
      • Clinical
        • Hypervolemic Hyponatremia (with Peripheral Edema, Pulmonary Edema, etc)
    • Hypovolemia (see Hypovolemic Shock)
      • Etiology
        • Dermal Fluid/Sodium Loss (Due to Burns, Heat Stroke, Prolonged Environmental Exposure, etc)
        • Gastrointestinal Fluid/Sodium Loss (Due to Diarrhea, Vomiting, Sodium Picosulfate Solutions for Bowel Preparation, etc)
        • Renal Fluid/Sodium Loss (Excessive Diuresis, Pheochromocytoma, Salt-Wasting Nephropathy, Severe Hyperglycemia, etc)
        • Third-Space Fluid/Sodium Loss (Due to Acute Pancreatitis, Ascites, Bowel Obstruction, Burns, Muscle Trauma, Peritonitis, Large-Volume Paracentesis, etc)
      • Mechanism
        • Increased Antidiuretic Hormone Secretion
      • Diagnosis
        • With Clinical Evidence of Hypovolemia, Low Urine Sodium (<25 mEq/L) Indicates a Diagnosis Such as Gastrointestinal Fluid Loss, Third-Space Fluid Loss, or Prior Diuresis (After the Effect of the Diuretic Has Diminished)
        • With Clinical Evidence of Hypovolemia, High Urine Sodium (>40 mEq/L) with Low Urine Chloride (<25 mEq/L) Indicates a Diagnosis Such as Metabolic Alkalosis Due to Vomiting
        • With Clinical Evidence of Hypovolemia, High Urine Sodium (>40 mEq/L) with High Urine Chloride (>40 mEq/L) Indicates a Diagnosis Such as Renal Salt Loss (Such as During Active Diuretic Therapy, Primary Adrenal Insufficiency with Deficiency of Cortisol and Aldosterone, Cerebral Salt Wasting, etc)
      • Clinical
        • Hypovolemic Hyponatremia
    • Primary Adrenal Insufficiency (see Adrenal Insufficiency)
      • Mechanism
        • Hypotension and Decreased Cardiac Output, Resulting in Decreased Effective Arterial Blood Volume
        • Lack of Cortisol (Which Would Normally Function to Suppress Antidiuretic Hormone Release)
      • Diagnosis
        • While May Be Associated with Hyperkalemia, it is Important to Note that Hyperkalemia is Absent in 33% of Patients with Adrenal Insufficiency
      • Clinical
        • Note that Primary Adrenal Insufficiency is Associated with Hypovolemic Hyponatremia, While Secondary Adrenal Insufficiency (Below, Under SIADH) is Associated with Euvolemic Hyponatremia
  • Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
    • Etiology
      • Endocrine Disease
        • Hypothyroidism (Moderate-Severe) (see Hypothyroidism)
        • Secondary Adrenal Insufficiency (Hypopituitarism) (see Adrenal Insufficiency): note that primary adrenal insufficiency (above) is associated with hypovolemic hyponatremia, while secondary adrenal insufficiency is associated with euvolemic hyponatremia
      • Gastrointestinal Disease
      • Neoplastic Disease
      • Neuropsychiatric Disease
      • Pulmonary Disease
      • Drugs/Toxins
      • Hereditary (Nephrogenic SIADH Due to Abnormal Vasopressin V2 Receptor)
      • Other
      • Idiopathic
    • Mechanism
      • Excessive Antidiuretic Hormone (ADH) Release Causing Renal Water Reabsorption (and Expansion of the Body’s Intracellular and Extracellular Fluid Compartments), Resulting in Hyponatramia
    • Diagnosis
      • Euvolemia
      • Hypoosmolality
      • Increased Urine Sodium (>20 mEq/L and Usually >40 mEq/L)
      • High Urine Osmolality (>100 mosmol/kg)
      • Other Features
        • Normal Serum Potassium Concentration
        • Absence of Acid-Base Disturbance
        • Low Serum Uric Acid Concentration (Frequently)
    • Clinical
      • Euvolemic Hyponatremia

Abnormally Low Osmostat

  • General Comments
    • In These Patients, a Water Load Will Appropriately Suppresses Antidiuretic Hormone Release, But at a Lower Serum Osmolality than in Normal Patients
    • These Patients Typically Present with a Moderate Hyponatremia (Usually 125-135 mEq/L) Which Remains Stable on Multiple Measurements
  • Acquired Reset Osmostat of Chronic Illness
  • Genetic Reset Osmostat
  • Pregnancy (see Pregnancy)
    • Mechanism
      • Human Chorionic Gonadotropin Resetting of Osmostat Downward
    • Diagnosis
      • Usually Mild Hyponatremia: serum sodium decreases only 5 mEq/L

Exercise-Induced Hyponatremia

  • Epidemiology
    • May Occur in Desert Hikers, Football Players, Marathon/Ultramarathon Runners, Military Personnel, etc
  • Mechanism
    • Excessive Water Intake
    • Sodium Loss
    • Persistent Antidiuretic Hormone Secretion with Impaired Water Excretion

Cerebral Salt Wasting (see Cerebral Salt Wasting)

  • Associated Conditions
  • Mechanism
    • Likely Mediated by Brain Natriuretic Peptide and Ouabain-Like Peptide
  • Diagnosis
    • Hypovolemia: this aspect distinguishes it from SIADH (see Adrenal Insufficiency)
    • Increased Urine Sodium (>25 mEq/L)
    • Increased Urine Osmolality (>100 mOsm/kg)
    • Polyuria

Other

  • Ecstasy Intoxication (see Ecstasy)
    • Epidemiology
      • Hyponatremia is a Major Cause of Mortality Related to Ecstasy Intoxication
      • Females are More Likely to Develop Ecstasy-Induced Hyponatremia and are More Likely to Develop Severe Neurologic Complications (Coma, Death)
    • Mechanisms
      • Increased Water Intake
      • SIADH, Resulting in Impairment of Water Excretion
  • Iatrogenic Hyponatremia
    • Mechanism
      • Hypotonic Intravenous Fluid Administration
    • Epidemiology
      • Particularly Occurs with D5W Infusion
  • Postoperative Hyponatremia
    • Mechanisms
      • Administration of Hypotonic Intravenous Fluid During Surgery
      • Increased Secretion of Antidiuretic Hormone (Due to Pain/Drugs/Nausea/Stress/Low Circulating Blood Volume), Resulting in Water Retention
      • Excessive Intravenous Fluid Administration, Resulting in Increased Circulating Blood Volume and Overexpansion of Extracellular Fluid Volume, Culminating in Increased Volume of Hypertonic Urine (Sodium Loss)

Physiology

Definition of Hyponatremia

  • Hyponatremia is Defined as Serum Sodium <135 mEq/L

Definitions of Serum Tonicity and Osmolality

Serum Tonicity Reflects the Concentrations of “Effective Osmoles” (Solutes Which Do Not Move Freely Across Cell Membranes and Obligate Water to Move with Them)

  • “Effective Osmoles”
  • Serum Tonicity is the Property Which is Detected by Osmoreceptors
  • Serum Tonicity Also Modulates the Movement of Water Between Cells and Extracellular Fluid (i.e. the Transcellular Distribution of Water)
    • Water Freely Crosses All Cell Membranes, Moving from an Area of Lower Tonicity (Higher Water Content) to an Area of Higher Tonicity (Lower Water Content)
    • Plasma Hypotonicity Makes Cells Swell, While Plasma Hypertonicity Makes Cells Shrink
  • Hypernatremia Always Indicates Hypertonicity
  • Hyponatremia May Be Hypotonic (in Most Cases), Isotonic, or Hypertonic

Serum Osmolality Reflects the Concentrations of Both “Effective Osmoles” (Solutes Which Do Not Move Freely Across Cell Membranes and Obligate Water to Move with Them) and “Ineffective Osmoles” (Solutes Which Equilibrate Across Cell Membranes and Do Not Obligate Water to Move with Them) (see Serum Osmolality)

Background

Normal Composition of Serum

  • Serum Water Accounts for 93% of the Serum Volume
    • Serum Sodium is Restricted to the Serum Water Fraction
  • Nonaqueous Components (Mostly Lipids and Proteins) Account for 7% of the Serum Volume

Normal Sodium Movement Across Capillary Membranes (NEJM, 2015) [MEDLINE]

  • Under Normal Conditions, Sodium Readily Crosses Systemic Capillary Membranes Via Clefts Between the Endothelial Cells
    • As a Result, Plasma Sodium Concentration and Systemic Interstitial Fluid Sodium Concentration are Nearly Identical (with Only a Small Difference Created by the Presence of Intravascular Albumin)
  • In Contrast, Under Normal Conditions, the Brain Capillaries Have Tight Endothelial Junctions and are Lined by Astrocytic Foot Processes
    • Astrocytes Possess Aquaporin-4 Channels Which Allow Water to Cross, But Not Sodium, Creating a Blood-Brain Barrier Which is Impermeable to Sodium
      • Animal Studies Indicate that Aquaporin-4 Mediates a Significant Portion of Osmotic Water Transport into the Brain (Nat Med, 2000) [MEDLINE]
    • Consequently, an Abnormal Plasma Sodium Concentration Results in Water Entering or Leaving the Brain
    • Due to the Confined Space of the Skull Compartment, Only a Small Degree of Brain Swelling or Shrinkage Can Be Tolerated without Brain Compromise
    • Plasma Sodium, Therefore, Affects Brain Volume
      • For This Reason, Cell Volume Receptors Which Modulate Thirst and Vasopressin Secretion are Located in the Brain
        • Osmoreceptors (Most Accurately Called “Tonicity Receptors”) are Hypothalamic Neurons Which Express Transient Receptor Potential Cation Channel Subfamily Vanilloid Member 1 (TRPV1) and Member 4 (TRPV4) Channels on Their Cell Membranes

Regulation of Plasma Sodium Concentration (NEJM, 2015) [MEDLINE]

  • During Normal Physiologic Osmoregulation, When the Plasm Sodium Concentration is Decreased to <135 mEq/L (<135 mmmol/L), Serum Hypotonicity Results in the Swelling of Osmoreceptor Cells, Causing the Inhibition of Thirst and Inhibition of Posterior Pituitary Vasopressin Antidiuretic Hormone Secretion (the Latter of Which Results in Aquaresis) (Clin J Am Soc Nephrol, 2015) [MEDLINE]
    • In the Absence of Vasopressin, Urine Osmolality Can Decrease to as Low as 50 mOsm/kg
    • At a Plasma Sodium Concentration >135 mEq/L, Vasopressin Levels are Usually Detectable and They Increase Linearly with an Increase in Plasma Sodium Concentration
  • Vasopressin Binds to V2 Receptors on the Basolateral Membranes of the Principal Cells Lining the Renal Collecting Ducts
    • In the Presence of Vasopressin, Aquaporins are Inserted into the Luminal Membranes, Allowing Water to Flow Out, Attracted by the High Solute Concentration of the Surrounding Medullary Interstitium
    • When the Plasma Sodium Concentration Increases to Approximately 145 mEq/L, Vasopressin Levels are Normally Elevated Enough to Result in Maximally Concentrated Urine (About 1200 mOsm/kg)
  • Development of Hypernatremia
    • The Presence of a Dilute Urine When the Plasma Sodium Concentration is >145 mEq/L Indicates Either Deficient Vasopressin Secretion (as Occurs in Neurogenic Diabetes Insipidus) or a Failure of the Kidneys to Respond to Vasopressin (as Occurs in Nephrogenic Diabetes Insipidus) (see Diabetes Insipidus)
    • However, Even Complete Diabetes Insipidus (with Total Absence of Vasopressin or an Absence of Tubular Response to Vasopressin) Typically Does Not Cause Hypernatremia, Because Thirst Results in the Voluntary Replacement of Urinary Water Losses
      • Hypernatremia Can Then Develop if Oral Water Intake Does Not Occur (Due to Inadeqaute Access to Water, Illness/Extremes of Age Preventing Oral Water Intake, Hypodipsia, etc)
  • Development of Hyponatremia
    • The Normal Physiologic Ability to Maximally Dilute the Urine Prevents the Development of Hyponatremia Unless Oral Water Intake Exceeds 1L/hr (as in Schizophrenia with High Water Intake, etc) or in Patients with Low Urinary Solute Excretion (as in Beer Potomania, Where Oral Food Intake is Very Low)
    • Except for These Two Scenarios, Hypotonic Hyponatremia is Associated with Impaired Generation of a Dilute Urine Due to Decreased Sodium Transport in Renal Tubular Diluting Sites (Due Most Commonly to Diuretics, But Also to Presence of Vasopressin, or Rarely, an Inherited Activating Mutation of the Vasopressor Receptor)
    • Because Vasopressin (with Renin/Angiotension/Aldosterone and the Sympathetic Nervous System) Participates in the Neurohumoral Response to Hypovolemia, Vasopressin-Induced Hyponatremia May Complicate Hypovolemia or Edema States (Congestive Heart Failurem, Cirrhosis, etc)

Physiologic Changes Associated with Hyponatremia

General Comments

  • Since Intracellular and Extracellular Osmolality Must Remain Equal, Hyponatremia Causes Cells to Either Swell with Water or Expel Solutes (to Counter the Swelling)
    • Decreased Serum Osmolality Results in an Osmolal Gradient Which Favors the Movement of Water into Brain Cells
      • Within the Confined Space of the Brain, Any Cellular Swelling Can Result in Cerebral Edema (J Am Soc Nephrol, 1992) [MEDLINE] (NEJM, 1995) [MEDLINE] (NEJM, 2015) [MEDLINE]
    • Over Time, Brain Cells Expel Organic Solutes from their Cytoplasm, Allowing the Intracellular Osmolality to Equal Plasma Osmolality Without a Large Increase in Cellular Water

Acute vs Chronic Hyponatremia

  • In Acute Hyponatremia (<48 hrs)
    • Movement of Water into Brain Cells (Cellular Swelling) Occurs Over a Few Hours and Outpaces the Brain’s Ability to Expel Solutes, Resulting in Cerebral Edema (and Potentially Herniation)
  • In Chronic Hyponatremia (≥48 hrs)
    • While There is Propensity of Water to Move into Brain Cells (Causing Cellular Swelling) Over a Period of Days, the Brain is Able to Expel Osmotic Solutes/Organic Osmolytes (Mostly, Choline and Myoinositol, with Glutamine and Glutamate to a Lesser Extent) Via Swelling-Activated Membrane Channels (Which Also Transport Chloride and Other Anions) and Minimize the Development of Cerebral Edema (J Clin Invest, 1995) [MEDLINE]
      • Significant Depletion of Brain Organic Osmolytes Occurs Within 24 hrs (and Additional Losses Occur Over 2-3 Days, Due to Downregulation of the Synthesis and Uptake of These Organic Osmolytes) (J Am Soc Nephrol, 1992) [MEDLINE] (NEJM, 1995( [MEDLINE]
      • As a Result, Patients with Chronic Hyponatremia Have More Modest Clinical Symptoms and Almost Never Die of Cerebral Edema with Brain Herniation
    • During the Correction of Chronic Hyponatremia, the Reuptake of Brain Organic Osmolytes Occurs More Slowly than the Loss of the Organic Osmolytes During the Onset of Hyponatremia: this observation is the basis for corretcing chronic chronic hyponatremia more slowly

Hyponatremia in the Setting of Advanced Renal Failure or Ethanol Intoxication

  • In These Two Clinical Situations, if Hyponatremia is Present, These Patients May Have a Higher Serum Osmolality than that Predicted by their Sodium Concentration Due to the Contribution of Urea or Ethanol in the Extracellular Fluid
    • However, Since Both Urea and Ethanol are “Ineffective Osmoles” (They Can Freely Cross Cell Membranes and Do Not Obligate Water Movement Out of Cells), the Effective Serum Osmolality (Measured Osmolality Minus the Contribution of Urea) is Low
    • For This Reason, Hyponatremic Patients with Advanced Renal Failure or Ethanol Intoxication are as Likely to Develop Clinical Symptoms at a Given Serum Sodium Concentration as Patients without These Conditions

Diagnosis

Suggested Laboratory Evaluation of Hyponatremia

Serum Studies

  • Serum Sodium (see Serum Sodium)
    • Laboratory Serum Sodium Measurement Technology
      • Flame Photometry Assay of Serum Sodium
        • Measures Sodium Concentration in Whole Plasma
        • In the Presence of Hyperproteinemia/Hypertriglyceridemia (with Expansion of Nonaqueous Component of the Serum), Pseudohyponatremia May Be Seen with This Assay Method
      • Sodium-Selective Electrode Assay of Sodium
        • Measures Sodium Activity in Serum Water: this assay gives the true, physiologically relevant sodium concentration as it measures sodium activity in serum water alone
        • Indirect Potentiometry: current assay used in many hospital laboratories
        • Direct Potentiometry
  • Serum Chloride (see Serum Chloride)
  • Serum Osmolality (see Serum Osmolality)
    • Normal Serum Osmolality: 275-290 mosmol/kg
    • Indications for Measurement of Serum Osmolality in the Evaluation of Hyponatremia (i.e. When Either Isotonic or Hypertonic Hyponatremia are Suspected)
      • Recent Transurethral Surgery/Hysteroscopy/Laparoscopy (Due to Use of Glycine/Sorbitol/Mannitol Irrigant)
      • Recent Use of Mannitol (see Mannitol)
      • Recent Use of Glycerol (see Glycerol)
      • Recent Use Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin)
      • Presence of Lipemic (Hypertriglyceridemic) Serum
      • Presence of Obstructive Jaundice
      • Suspected Plasma Cell Dyscrasia (with Hyperproteinemia)

Urine Studies

Laboratory Patterns

Clinically Hypovolemic Patient

  • Dermal Fluid Loss/Gastrointestinal Fluid Loss/Third-Space Fluid Loss/Prior Diuresis (After the Effect of the Diuretic Has Diminished) (see Hypovolemic Shock)
    • Low Urine Sodium (<25 mEq/L): due to hypovolemia-induced renal sodium retention
      • In a Study of Hyponatremic Patients without Edema (n = 58), the Mean Urine Sodium was 18 mEq/L in Patients Who Were Assessed to Hypovolemic (Determined by a Significant Increase in Serum Sodium Following Isotonic Saline Challenge), as Compared to 72 mEq/L in Patients with SIADH (Determined by No Increase in Serum Sodium Following Isotonic Saline Challenge) (Am J Med, 1987) [MEDLINE]
        • Clinical Assessment of Volume Status Correctly Identified Only 48% of the Patients in This Study
  • Metabolic Alkalosis Due to Vomiting (see Metabolic Alkalosis and Nausea and Vomiting)
    • High Urine Sodium (>40 mEq/L)
    • Low Urine Chloride (<25 mEq/L)
  • Active Diuretic Therapy
    • High Urine Sodium (>40 mEq/L): since diuretics are natriuretics
    • High Urine Chloride (>40 mEq/L)
  • Primary Adrenal Insufficiency (i.e. Deficiency of Cortisol and Aldosterone) (see Adrenal Insufficiency)
    • High Urine Sodium (>40 mEq/L)
    • High Urine Chloride (>40 mEq/L)
  • Cerebral Salt Wasting: laboratory parameters resemble that of SIADH, except that the patient has clinical hypovolemia
    • High Urine Sodium (>40 mEq/L)
    • High Urine Chloride (>40 mEq/L)

Clinically Euvolemic Patient

  • Pseudohyponatremia
    • Normal Serum Sodium
    • Normal Serum Osmolality: since osmometers measure the activity of solutes in plasma water
  • Decreased Sodium Intake (Beer Potomania, Tea and Toast Diet)
    • Low Urine Sodium (<25 mEq/L)
    • Low Urine Osmolality (<100 mosmol/kg)
      • In a Study Examining the Additional Utility of Urine Osmolality and Urine Urea and Creatinine Concentrations in Patients Who were Suspected of Having Primary Polydipsia vs Malnutrition as the Etiology of Their Hyponatremia (J Clin Med, 2019) [MEDLINE]
        • Authors Suggested that Patients with Low Solute Intake (FE.Osm<1.4%) and Low Diuresis (V/eCcr<0.8%) Should Increase Their Intake by Taking Oral Urea
        • Authors Suggested that Patients with High Solute Intake (FE.Osm>2.5%) and High Diuresis (V/eCcr>1.5%) Should Be Treated with Mild Water Restriction (<1.5-2L/day)
  • Primary Polydipsia
    • Low Urine Sodium (<25 mEq/L)
    • Low Urine Osmolality (<100 mosmol/kg)
      • In a Study Examining the Additional Utility of Urine Osmolality and Urine Urea and Creatinine Concentrations in Patients Who were Suspected of Having Primary Polydipsia vs Malnutrition as the Etiology of Their Hyponatremia (J Clin Med, 2019) [MEDLINE]
        • Authors Suggested that Patients with Low Solute Intake (FE.Osm<1.4%) and Low Diuresis (V/eCcr<0.8%) Should Increase Their Intake by Taking Oral Urea
        • Authors Suggested that Patients with High Solute Intake (FE.Osm>2.5%) and High Diuresis (V/eCcr>1.5%) Should Be Treated with Mild Water Restriction (<1.5-2L/day)
  • Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
    • Euvolemic Patient in Whom Hypopituitarism, Hypoadrenalism, Hypothyroidism, Renal Insufficiency, and Diuretic Use Have Been Excluded
    • Normal Serum Potassium and Bicarbonate (Typically) (Am J Kidney Dis, 1991) [MEDLINE]
      • While Water Retention May Decrease the Serum Potassium by Dilution, Cells Release Potassium in an Attempt to Minimize Hypoosmolality-Induced Cell Swelling, Raising the Serum Potassium Back Toward Normal
      • While Water Retention May Decrease the Plasma Bicarbonate by Dilution, Increased Acid Excretion Due to Mild Hyperaldosteronism Induced by Hyponatremia Will Raise the Plasma Bicarbonate Back Toward Normal ( J Clin Endocrinol Metab, 2003) [MEDLINE]
    • Decreased Serum Osmolality (see Decreased Serum Osmolality)
    • High Urine Sodium (>40 mEq/L)
      • In a Study of Hyponatremia Patients without Edema (n = 58), the Mean Urine Sodium was 18 mEq/L in Patients Who Were Assessed to Hypovolemic (Determined by a Significant Increase in Serum Sodium Following Isotonic Saline Challenge), as Compared to 72 mEq/L in Patients with SIADH (Determined by No Increase in Serum Sodium Following Isotonic Saline Challenge) (Am J Med, 1987)* [MEDLINE]
        • Clinical Assessment of Volume Status Correctly Identified Only 48% of the Patients in This Study
    • Low Blood Urea Nitrogen (BUN) (<5 mg/dL): due to increased urea clearance
      • However, This Finding is Variable (and its Absence Does Not Exclude the Presence of SIADH)
    • Low Serum Osmolality (<270 mOsm/L)
    • Hypouricemia (<4 mg/dL): due to increased urinary uric acid clearance
      • However, This Finding is Variable (and its Absence Does Not Exclude the Presence of SIADH)
    • High Urine Osmolality (Usually >300 mOsm/L)
    • High Fractional Excretion of Uric Acid (FE Uric Acid >10-12%)
      • FE Uric Acid >12% Has Been Reported in a Small Study to Diagnose SIADH (Over Thiazide-Associated Hyponatremia) with a 100% Positive Predictive Value, While an FE Uric Acid <8% Excluded SIADH with a 100% Negative Predictive Value (J Clin Endocrinol Metab, 2008) [MEDLINE]
        • However, Other Larger Studies Have Not Supported These Findings (Cureus, 2020) [MEDLINE]

Fractional Excretion of Sodium (FENa) (see Fractional Excretion of Sodium)

  • FENa is Not Recommended to Evaluate Patients with Hyponatremia
    • In Patients with Oliguric Acute Kidney Injury (AKI) Where FENa is Typically Employed in the Evaluation of These Patients, FENa Provides a More Accurate Assessment of Volume Status than the Urine Sodium Because it Corrects for the Effect that Variations in Urine Volume Have on the Urine Sodium
    • However, FENa is Far Less Useful in Patients without Oliguria
      • A FENa <1% is Not an Indicator of Effective Hypovolemia in Patients with Normal or Mild-Moderate Renal Dysfunction Who Have a Much Higher Glomerular Filtration Rate and a Much Greater Filtered Sodium Load

Clinical Manifestations

General Comments

Definitions (by the Duration of Hyponatremia)

  • Acute Hyponatremia
    • Definition: hyponatremia of <48 hrs in duration
    • Most Common Etiologies of Acute Hyponatremia
      • Perioperative Intravenous Fluid Administration (with Associated Vasopressin Hypersecretion Associated with Surgery)
      • Self-Induced Water Intoxication (in Competitive Runners, Psychosis with Extreme Polydipsia)
      • Ecstasy Intoxication (see Ecstasy)
    • Probability of Clinical Symptoms
      • Acute Hyponatremia is More Likely to Produce Clinical Symptoms than Chronic Hyponatremia
    • Risk of Complications (of Hyponatremia Itself and/or as a Result of Treatment of Hyponatremia)
      • The More Acute that the Hyponatremia is, the Higher the Risk of Clinical Complications (and the Greater the Need for Aggressive Therapy)
  • Chronic Hyponatremia
    • Defintion: hyponatremia of ≥48 hrs in duration or of unclear duration (if the patient develops hyponatremia in the outpatient setting)
    • Probability of Clinical Symptoms
      • Chronic Hyponatremia is Less Likely to Produce Clinical Symptoms than Acute Hyponatremia
    • Risk of Complications (of Hyponatremia Itself and/or as a Result of Treatment of Hyponatremia)
      • The More Chronic that the Hyponatremia is, the Lower the Risk of Clinical Complications (and the Greater the Risk for Complications from Corrective Therapy Itself)

Severity of Hyponatremia

  • Mild Hyponatremia: serum sodium 130-134 mEq/L
    • Serum Na 130-134 mEq/L Generally Does Not Produce Clinical Symptoms
  • Moderate Hyponatremia: serum sodium 120-129 mEq/L
    • Serum Na <130 mEq/L is Generally Sufficient to Produce Clinical Symptoms
  • Severe Hyponatremia: serum sodium <120 mEq/L

Severity of Clinical Symptoms

  • Asymptomatic
    • Many Apparently “Asymptomatic” Patients with Chronic Hyponatremia (Especially with Moderate Hyponatremia of 120-129 mEq/L) May Have Subtle Neurologic Impairments (Abnormal Mentation, Gait Impairment with Increased Risk of Falls) (Am J Med, 2006) [MEDLINE] (QJM, 2008) [MEDLINE]
  • Mild-Moderate Clinical Symptoms
    • General Comments
      • Mild-Moderate Clinical Symptoms are Most Commonly Encountered in Patients with Chronic, Severe (Na <120 mEq/L) Hyponatremia
      • Mild-Moderate Clinical Symptoms Result from Brain Adaptations Which Minimize the Development of Cerebral Edema, But Modify the Composition of Brain Cells
      • Mild-Moderate Clinical Symptoms are Not Typically Associated with a Increased Risk of Impending Brain Herniation
      • However, in Patients with Very Severe Hyponatremia (Na <110 mEq/L), Mild-Moderate Clinical Symptoms May Precede the Development of Seizures
      • Additionally, the Presence of Mild-Moderate Clinical Symptoms in a Patient with Acute Hyponatremia (Even with Na >120 mEq/L) Should Be Considered as an Ominous Precursor of Seizures/Respiratory Arrest/Cerebral Edema with Brain Herniation (Ann Intern Med, 2000) [MEDLINE]
    • Fatigue (see Fatigue)
    • Headache (see Headache)
    • Lethargy
    • Nausea/Vomiting (see Nausea and Vomiting)
    • Dizziness (see Dizziness)
    • Confusion (see Delirium)
    • Gait Disturbances/Ataxia (see Ataxia)
    • Memory Problems
    • Muscle Cramps/Myalgias (see Myalgias)
  • Severe Clinical Symptoms

Gastrointestinal Manifestations

  • Nausea/Vomiting (see Nausea and Vomiting)
    • Epidemiology
      • Nausea is an Early Finding and Occurs When the Serum Sodium Falls Below 125-130 mEq/L
      • Nausea/Vomiting Occur in Approximately 30% of Patients with Serum Sodum <120 mEq/L (J Natl Med Assoc, 2004) [MEDLINE] (Am J Med, 2012) [MEDLINE] (J Am Geriatr Soc, 2015) [MEDLINE]
    • Clinical
      • In Acute Hyponatremia, Nausea/Vomiting Can Be a Harbinger of Life-Threatening Cerebral Edema
      • In Chronic Hyponatremia, Nausea/Vomiting is Not Typically Associated with Adverse Outcomes

Neurologic Manifestations

  • Ataxia/Gait Disturbance (with Increased Risk of Falls) (see Ataxia)
    • Epidemiology
      • Mild-Moderate Hyponatremia (Na 120-130 mEq/L) is Associated with an Increased Risk of Falls in Elderly Patients (Mean Age 72 y/o), Possibly Due to Marked Gait and Attention Impairment (Am J Med, 2006) [MEDLINE]
      • Correction of Hyponatremia (Usually with Urea) Improved Reaction Time and Gait Performance (Eur J Intern Med, 2017) [MEDLINE]
        • The Effect was Significant Among Patients >65 y/o, But Not in Younger Patients
  • Cerebral Edema (see Increased Intracranial Pressure)
    • Epidemiology
      • Cerebral Edema with Brain Herniation Occurs Almost Exclusively in the Following Hyponatremic Patient Subsets
        • Patients with Hyponatremia Associated with Self-Induced Water Intoxication (Runners, Psychotic Patients with Severe Polydipsia, Ecstasy Users, etc
        • Children/Females with Acute Postoperative Hyponatremia (NEJM, 1986) [MEDLINE] (BMJ, 1992) [MEDLINE] (Ann Intern Med, 1992) [MEDLINE]: this may be due to a hormonally-mediated decrease in the degree of osmotic adaptation, brain size relative to the cranial vault size, or smaller body size with less muscle mass to absorb the excess water (Am J Physiol, 1989) [MEDLINE]
        • Patients with with Hyponatremia Associated with Intracranial Pathology (Traumatic Brain Injury, Intracranial Hemorrhage, Intracranial Surgery, Intracranial Mass, etc)
      • In Other Patient Subsets, Hyponatremia-Induced Cerebral Edema is Rare
        • In One Study of 664 Patients with Hyponatremia <120 mEq/L, Only 1 Patient Died from Cerebral Edema and the Patient Had Concomitant Intracranial Pathology (Clin J Am Soc Nephrol, 2011) [MEDLINE]
      • Concomitant Hypoxemia (of Any Etiology) Increases the Risk of Hyponatremia-Induced Cerebral Edema (Ann Intern Med, 2000) [MEDLINE]
    • Clinical
      • Brain Herniation
  • Confusion/Delirium (see Delirium)
  • Dizziness (see Dizziness)
    • Epidemiology
      • Occurs Predominantly in Chronic Hyponatremia
  • Fatigue (see Fatigue)
    • Epidemiology
      • Occurs Predominantly in Chronic Hyponatremia
  • Headache (see Headache)
    • Epidemiology
      • Occurs When the Serum Sodium Falls <115-120 mEq/L
  • Lethargy
    • Epidemiology
      • Occurs Predominantly in Chronic Hyponatremia
  • Malaise
    • Epidemiology
      • Malaise is an Early Finding Which Occurs When the Serum Sodium Falls <125-130 mEq/L
  • Myalgias/Muscle Cramps (see Myalgias)
    • Epidemiology
      • May Occur with Chronic Hyponatremia
  • Obtundation/Coma (see Obtundation-Coma)
    • Epidemiology
      • Lethargy/Obtundation/Coma Occurs when the Serum Sodium Falls to <115-120 mEq/L
      • Lethargy/Obtundation/Coma May Occur in Acute Hyponatremia Due to a Rapid Decline in the Serum Sodium (Not Allowing the Brain Adequate Time for Adaptation)
    • Prognosis
      • Acute Hyponatremic Encephalopathy is Generally Reversible
        • However, Permanent Neurologic Damage May Occur, Particularly in Premenopausal Females (Ann Intern Med, 1992) [MEDLINE] (Nephrol Dial Transplant, 2003) [MEDLINE]
  • Seizures (see Seizures)
    • Risk of Seizures is Related to the Chronicity of Hyponatremia
      • Seizures are Common in Acute Hyponatremia Due to a Rapid Decline in the Serum Sodium (Not Allowing the Brain Adequate Time for Adaptation)
        • In Acute Hyponatremia with Serum Sodium <110 mEq/L, Seizures Occurred in 30% of Cases (Ann Intern Med, 1987) [MEDLINE]
      • Seizures are Less Common in Chronic Hyponatremia (Even Severe Chronic Hyponatremia)
        • In Chronic Hyponatremia with Serum Sodium <110 mEq/L, Seizures Occurred in Only 7% of Cases (Ann Intern Med, 1987) [MEDLINE]
        • In a Study of 223 Hospitalized Patients with Symptomatic Chronic Thiazide-Induced Hyponatremia, Seizure Incidence was Only 1% (and There were No Cases of Herniation) (J Natl Med Assoc, 2004) [MEDLINE]
        • In Chronic Hyponatremia, the Risk of Seizures May Be Increased in Patients with an Underlying Seizure Disorder or Alcohol Withdrawal
    • Risk of Seizures is Related to the Severity of Hyponatremia (Epilepsia, 2011) [MEDLINE]
      • Serum Sodium 115-119 mEq/L: Seizures Occurred in 2.5% of Cases
      • Serum Sodium 110-114 mEq/L: Seizures Occurred in 5.4% of Cases
      • Serum Sodium <110 mEq/L: Seizures Occurred in 10% of Cases

Pulmonary Manifestations

  • Non-Cardiogenic Pulmonary Edema (see Acute Respiratory Distress Syndrome)
    • Epidemiology
      • May Occur in Some Cases When the Serum Sodium Falls to <115-120 mEq/L (Ann Intern Med, 2000) [MEDLINE]
  • Respiratory Failure (see Respiratory Failure)
    • Epidemiology
      • May Occur in Some Cases When the Serum Sodium Falls <115-120 mEq/L (Ann Intern Med, 2000) [MEDLINE]

Rheumatologic Manifestations

  • Increased Risk of Osteoporosis (with Increased Risk of Fractures) (see Osteoporosis)
    • Epidemiology
      • May Be Seen in Chronic Hyponatremia (Due to Loss of Bone Sodium) (QJM, 2008) [MEDLINE] (J Bone Miner Res, 2010) [MEDLINE]

Treatment of Hyponatremia

General Comments

General Indications for Hospitalization in the Setting of Hyponatremia

  • Acute Hyponatremia
  • Severe Hyponatremia (Na <120 mEq/L)
  • Symptomatic Hyponatremia

Need for Correction of Hyponatremia

  • Correction of Hyponatremia is Associated with a Decreased Mortality Rate (PLoS, 2015) [MEDLINE]
    • Association was Even Stronger When Only Studies with Serum Sodium Threshold of >130 mEq/L were Considered
    • Impact on Mortality is Even Greater in Older Patients and in Those with Lower Serum Sodium on Enrollment

General Goals of Hyponatremia Therapy

Prevent a Further Decline in the Serum Sodium (This Goal is Particularly Applicable in Specific Hyponatremia Patient Groups)

  • Patients with Hyponatremia Associated with Self-Induced Water Intoxication (Runners, Psychotic Patients with Severe Polydipsia, Ecstasy Users, etc)
    • Continuing Absorption of Ingested Water from the Gastrointestinal Tract May Result in a Further Decrease in the Serum Sodium
  • Patients with Hyponatremia Associated with Intravenous Fluid Administration (Postoperative Hyponatremia Associated with Surgery-Associated SIADH, etc)
    • Isotonic Intravenous Fluid Administration Results in Volume Expansion, Resulting in Increased Urinary Sodium Excretion
      • With High Antidiuretic Hormone Levels, Sodium Excretion in a Concentrated Urine Results in a Further Decrease in the Serum Sodium (“Desalination”) (Ann Intern Med, 1997) [MEDLINE]
        • Therefore, Isotonic Saline Administration Should Be Avoided in this Setting (i.e in the Setting of SIADH)

Prevent Brain Herniation (see Increased Intracranial Pressure)

  • Specific Hyponatremia Patient Groups with High-Risk of Herniation
    • Acute Hyponatremia Associated with Massive Water Ingestion (Due to Psychosis, Extreme Exercise, Ecstasy Intoxication)
    • Children/Women with Acute Postoperative Hyponatremia
    • Hyponatremia Associated with Intracranial Pathology (Traumatic Brain Injury, Recent Intracranial Surgery, Intracranial Hemorrhage, Intracranial Neoplasm or Space-Occupying Lesion)
  • Outside of These Patients Group, the Development of Brain Herniation is Rare
    • In a Series of Patients with Hyponatremia, Only 1 Out of 664 Patients with a Na <120 mEq/L Admitted to a Community Hospital Died from Cerebral Edema (and the Patient Had Coexistent Intracranial Pathology) (Clin J Am Soc Nephrol, 2011) [MEDLINE]
  • General Comments
    • In the Above High-Risk Patients, Rapid Progression of Hyponatremia to Na <130 mEq/L, Even with Mild-Moderate Clinical Symptoms, Can Rapidly Progress to Seizures, Respiratory Arrest, and Brain Herniation
      • If Noncardiogenic Pulmonary Edema Occurs, Hypoxemia May Further Exacerbate the Development of Cerebral Edema (Ann Intern Med, 2000) [MEDLINE]
    • Impending Brain Herniation Can Be Effectively Reversed with a Relatively Modest 4-6 mEq/L Increase in the Serum Sodium (Semin Nephrol, 2009) [MEDLINE]

Relieve the Symptoms of Hyponatremia

  • The Urgency to Correct Hyponatremia Varies Depending on the Chronicity of the Hyponatremia, the Serum Sodium Concentration, and the Severity of the Clinical Symptoms
    • Importantly, Even the Most Severe Clinical Symptoms Can Be Effectively Reversed with a Relatively Modest 4-6 mEq/L Increase in the Serum Sodium (Semin Nephrol, 2009) [MEDLINE]
      • This Fact Accentuates the Caution that There is Potential Harm with Correcting Hyponatremia at Faster Rate

Target an Appropriate Rate of Hyponatremia Correction

  • Rationale
    • During the Correction of Hyponatremia, the Reuptake of Solutes by Brain Cells Occurs More Slowly than the Loss of Brain Solutes During the Onset of Hyponatremia
      • For This Reason (and Out of Concern for the Potential Development of Osmotic Demyelination Syndrome), the Rate of Correction of Hyponatremia is Critical
    • Overly Rapid Correction of the Sodium Concentration Can Occur Following Almost All of the Usual Hyponatremia Therapies
      • Elimination of the Underlying Etiology of Hyponatremia
      • Glucocorticoid Therapy in the Setting of Adrenal Insufficiency (see Corticosteroids)
      • Hypertonic 3% Saline (see Hypertonic Saline)
      • Normal Saline Resuscitation in the Setting of Hypovolemia (see Normal Saline)
      • Water Restriction in the Setting with Self-Induced Water Intoxication
      • Vasopressin Receptor Antagonists (see Vasopressin Receptor Antagonists)
    • Association Between the Rate of Hyponatremia Correction and the Risk of Osmotic Demyelination Syndrome
      • In a Retrospective Cohort Study (n = 1490 patients Admitted with Serum Sodium <120 mEq/L), Approximately 88% of ODS Cases Occurred in Patients with Rapid Sodium Correction (>8 mEq/L Over 24 hrs) (Clin J Am Soc Nephrol, 2018) [MEDLINE]
  • Goal Rate of Correction is 4-6 mEq/L in the First 24 hrs
    • Since the Actual Rate of Correction Often Exceeds the Goal Rate of Correction, this Recommendation May Help to Keep the Actual Rate of Correction Below the Maximal Rate of Correction of ≤8 mEq/L in the First 24 hrs
  • Recommended Maximum Rate of Correction is ≤8 mEq/L in the First 24 hrs (Am J Med, 2007) [MEDLINE] (Semin Nephrol, 2009) [MEDLINE] (Curr Opin Nephrol Hypertens, 2010) [MEDLINE] (J Am Soc Nephrol, 2012) [MEDLINE]

Specific Therapies for Selected Etiologies of Hyponatremia

Hypovolemic Hyponatremia

  • Crystalloid Intravenous Fluids
    • Normal Saline (NS) (see Normal Saline): contains 154 mEq Na/L
      • Normal Saline Would Be Expected to Increase Serum Sodium 1 mEq/L for Every Liter of Saline Infused, Since the Normal Saline Has Higher Sodium Concentration than the Hyponatremic Plasma
      • Normal Saline Correction of Hypovolemia Will Remove the Stimulus for Antidiuretic Hormone Secretion, Resulting in a Water Diuresis (Typically Evidence by an Increase in Urine Output)
    • Hypertonic Saline (3%) (see Hypertonic Saline): contains 512 mEq Na/L
      • In Patients with Symptomatic or Severe Hyponatremia (Na <120 mEq/L), Hypertonic Saline is Preferred Over Normal Saline, Since it More Reliably Increases the Serum Sodium (Especially if There is an Element of Coexistent SIADH)
        • In This Setting, Hypertonic Saline Combined with Desmopressin is Likely the Most Effective and Predictable Strategy
      • Approximate Hypertonic (3%) Saline Infusion Rate
        • Desired Rate of Correction Per Hour (ex: 1 mEq/L/hr) x Lean Body Weight (in kg)
    • One Should Avoid Using Lactated Ringers (LR) in a Hyponatremic Patient, Since it is Hypotonic (Contains 130 mEq Na/L) (see Lactated Ringers)
  • Potassium Replacement (When Required for Hypokalemia) (see Potassium Chloride)
    • Potassium is as Osmotically Active as Potassium and Replacing Potassium in the Setting of Hypokalemia Will Increase Serum Osmolality (Am J Kidney Dis, 2010) [MEDLINE]
    • Potassium Movement Intracellularly Increases the Serum Sodium by the Following Mechanisms
      • Intracellular Movement of Potassium Will Result in an Exchange of Sodium into the Extracellular Fluid (to Maintain Intracellular Electroneutrality)
      • Intracellular Movement of Potassium Will Result in an Exchange of Hydrogen Ions into the Extracellular Fluid
        • Hydrogen Ions are Buffered by Extracellular Bicarbonate (and Plasma Proteins), Creating Carbon Dioxide and Water (Bicarbonate is Replaced by Chloride Which was Administered with the Potassium)
      • Intracellular Movement of Potassium Drags Drags Chloride into the Cells, Increasing the Intracellular Osmolality, Which Results in Free Water Movement into Cells
    • Intracellular Movement of Potassium Increases the Intracellular Osmolality, Which Results in Free Water Movement into Cells

Primary Polydipsia

  • Fluid Restriction
    • Obviously, Fluid Restriction is a Key Component in This Subset of Hyponatremic Patients in Which Oral Fluid Intake is the Primary Etiology
    • Effectiveness of Fluid Restriction is Predicted by Urine/Plasma Electrolyte Ratio (Urine Na + Urine K/ Serum Na) <0.5 (Am J Med Sci, 2000) [MEDLINE]
      • Urine/Plasma Electrolyte Ratio >1.0 Suggests that Fluid Restriction Will Not Be Effective

Syndrome of Inappropriate Anti-Diuretic Hormone Secretion (SIADH) (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)

  • Demeclocycline (see Demeclocycline)
    • Pharmacology
      • Demeclocycline Inhibits the Renal Action of Antidiuretic Hormone
        • Demeclocycline Interferes with Intracellular Adenylyl Cyclase Activation After Antidiuretic Hormone Binds to Renal Vasopressin V2 Receptors
    • Dose: 300 mg PO BID
  • Fluid Restriction
    • Fluid Restriction to 50-60% of the Daily Requirement (Approximately <800 mL/Day) May be Required to Achieve Negative Water Balance (NEJM, 2000) [MEDLINE]
    • Effectiveness of Fluid Restriction is Predicted by Urine/Plasma Electrolyte Ratio (Urine Na + Urine K/ Serum Na) <0.5 (Am J Med Sci, 2000) [MEDLINE]
      • Urine/Plasma Electrolyte Ratio >1.0 Suggests that Fluid Restriction Will Not Be Effective
  • Hypertonic Saline (3%) (see Hypertonic Saline)
    • Contains 512 mEq Na/L
    • Approximate Infusion Rate
      • Desired Rate of Correction Per Hour (ex: 1 mEq/L/hr) x Lean Body Weight (in kg)
  • Loop Diuretics
    • Effectiveness
      • In Addition to Other Measures, Loop Diuretics May Be Effective in SIADH if the Urine/Serum Cation Ratio is >1.0
    • Loop Diuretics
      • Furosemide (Lasix) (see Furosemide)
        • Furosemide Inhibits Sodium chloride Reabsorption in the Thick Ascending Limb of the Loop of Henle, Resulting in Interference with the Countercurrent Mechanism and Inducing Renal Antidiuretic Hormone Resistance and Excretion of Water
  • Potassium Replacement (When Required for Hypokalemia) (see Potassium Chloride)
    • Potassium is as Osmotically Active as Potassium and Replacing Potassium in the Setting of Hypokalemia Will Increase Serum Osmolality (Am J Kidney Dis, 2010) [MEDLINE]
    • Potassium Movement Intracellularly Increases the Serum Sodium by the Following Mechanisms
      • Intracellular Movement of Potassium Will Result in an Exchange of Sodium into the Extracellular Fluid (to Maintain Intracellular Electroneutrality)
      • Intracellular Movement of Potassium Will Result in an Exchange of Hydrogen Ions into the Extracellular Fluid
        • Hydrogen Ions are Buffered by Extracellular Bicarbonate (and Plasma Proteins), Creating Carbon Dioxide and Water (Bicarbonate is Replaced by Chloride Which was Administered with the Potassium)
      • Intracellular Movement of Potassium Drags Drags Chloride into the Cells, Increasing the Intracellular Osmolality, Which Results in Free Water Movement into Cells
    • Intracellular Movement of Potassium Increases the Intracellular Osmolality, Which Results in Free Water Movement into Cells
  • Sodium Chloride Tablets (see Sodium Chloride)
    • Commonly Utilized (in Conjunction with Fluid Restriction) in Patients with Na >120 mE/L
    • Hourly Sodium Chloride Tablets Can Even Be Used Instead of Hypertonic (3%) Saline) in Non-Urgent Situations (Clin Nephrol, 2014) [MEDLINE]
      • A Quantity of 9 g of Oral Sodium Chloride Provides a Similar Quantity of Sodium as 1 L of Normal Saline (154 mEq), But without Any Water
      • A Quantity of 1 g of Oral Sodium Chloride is Equivalent to 35 mL of 3% Saline
  • Oral Urea (see Urea) (Nephrol Dial Transplant, 2014) [MEDLINE] (Kidney Int, 2015) [MEDLINE]
    • May Be Useful (and Well-Tolerated) as an Alternative to Oral Sodium Chloride Tablets and Diuretics (Clin J Am Soc Nephrol, 2018) [MEDLINE]
    • Oral Dose: 15 g BID
  • Vasopressin Receptor Antagonists (see Vasopressin Receptor Antagonists) (Kidney Int, 2013) [MEDLINE]
    • Conivaptan (Vaprisol) (see Conivaptan)
      • Pharmacology
        • 1a/V2 Vasopressin Receptor Antagonist: causes aquaresis (water loss)
    • Tolvaptan (Samsca) (see Tolvaptan)
      • Pharmacology
        • V2 Vasopressin Receptor Antagonist: causes aquaresis (water loss)
      • Clinical Efficacy
        • The SALT-1 Trial/SALT-2 Trials Comparing Tolvaptan to Placebo in Patients with Chronic Hyponatremia (None with Clinically Apparent Neurologic Symptoms at Baseline; Almost All Patients Had Na ≥120 mEq/L) Demonstrated a Benefit in Mental Status in Patients with Na 120-129 mEq/L, But Not in Patients with Na 130-134 mEq/L (NEJM, 2006) [MEDLINE]
  • Avoid Use of the Following
    • Normal Saline (see Normal Saline): sodium will generally worsen the hyponatremia in SIADH
      • In Patients with Postoperative Hyponatremia Due to Surgery-Associated SIADH, etc), Isotonic Intravenous Fluid Administration Results in Volume Expansion, Resulting in Increased Urinary Sodium Excretion
        • With High Antidiuretic Hormone Levels, Sodium Excretion in a Concentrated Urine Results in a Further Decrease in the Serum Sodium (“Desalination”) (Ann Intern Med, 1997) [MEDLINE]

Syndrome of Inappropriate Antidiuretic Hormone Secretion in the Setting Subarachnoid Hemorrhage (SAH) (see Subarachnoid Hemorrhage)

  • Avoid Fluid Restriction
    • Since Patients with Subarachnoid Hemorrhage are Susceptible to Cerebral Vasospasm and Infarction, Fluid Restriction is Contraindicated, as it May Cause Hypotension and Exacerbate the Prior Complications (Clin Neurol Neurosurg, 1990) [MEDLINE]
  • Hypertonic (3%) Saline (see Hypertonic Saline)
    • Recommended Regimen is to Start at 20 mL/hr with Serial Sodium Measurement q4-6hrs (Neurocrit Care, 2009) [MEDLINE]
  • Sodium Chloride Tablets (see Sodium Chloride)

Hypervolemic Hyponatremia (Associated with Advanced Renal Failure)

  • Fluid and Sodium Restriction
    • Fluid Restriction to 50-60% of the Daily Requirement (Approximately <800 mL/Day) May be Required to Achieve Negative Water Balance (NEJM, 2000) [MEDLINE]
    • Effectiveness of Fluid Restriction is Predicted by Urine/Plasma Electrolyte Ratio (Urine Na + Urine K/ Serum Na) <0.5 (Am J Med Sci, 2000) [MEDLINE]
      • Urine/Plasma Electrolyte Ratio >1.0 Suggests that Fluid Restriction Will Not Be Effective
  • Avoid Use of the Following

Hypervolemic Hyponatremia (Associated with Cirrhosis)

  • Diuretics
  • Fluid Restriction
    • Fluid Restriction to 50-60% of the Daily Requirement (Approximately <800 mL/Day) May be Required to Achieve Negative Water Balance (NEJM, 2000) [MEDLINE]
    • Effectiveness of Fluid Restriction is Predicted by Urine/Plasma Electrolyte Ratio (Urine Na + Urine K/ Serum Na) <0.5 (Am J Med Sci, 2000) [MEDLINE]
      • Urine/Plasma Electrolyte Ratio >1.0 Suggests that Fluid Restriction Will Not Be Effective
    • Although Fluid Restriction is Commonly Used in Cirrhotic Patients with Ascites, it is Frequently Difficult to Achieve a Fluid Restriction <1-1.5L/Day (Gastroenterology, 2003) [MEDLINE]
  • Potassium Replacement (When Required for Hypokalemia) (see Potassium Chloride)
    • Potassium is as Osmotically Active as Potassium and Replacing Potassium in the Setting of Hypokalemia Will Increase Serum Osmolality (Am J Kidney Dis, 2010) [MEDLINE]
    • Potassium Movement Intracellularly Increases the Serum Sodium by the Following Mechanisms
      • Intracellular Movement of Potassium Will Result in an Exchange of Sodium into the Extracellular Fluid (to Maintain Intracellular Electroneutrality)
      • Intracellular Movement of Potassium Will Result in an Exchange of Hydrogen Ions into the Extracellular Fluid
        • Hydrogen Ions are Buffered by Extracellular Bicarbonate (and Plasma Proteins), Creating Carbon Dioxide and Water (Bicarbonate is Replaced by Chloride Which was Administered with the Potassium)
      • Intracellular Movement of Potassium Drags Drags Chloride into the Cells, Increasing the Intracellular Osmolality, Which Results in Free Water Movement into Cells
    • Intracellular Movement of Potassium Increases the Intracellular Osmolality, Which Results in Free Water Movement into Cells
  • Vasopressin Receptor Antagonists (see Vasopressin Receptor Antagonists)
    • Tolvaptan (Samsca) (see Tolvaptan)
      • The SALT-1 Trial/SALT-2 Trials Comparing Tolvaptan to Placebo in Patients with Chronic Hyponatremia Due to SIADH, Congestive Heart Failure, or Cirrhosis (None with Clinically Apparent Neurologic Symptoms at Baseline; Almost All Patients Had Na ≥120 mEq/L) Demonstrated a Benefit in Mental Status in Patients with Na 120-129 mEq/L, But Not in Patients with Na 130-134 mEq/L (NEJM, 2006) [MEDLINE]
      • While the FDA Recommends Against Using Tolvaptan in the Setting of Liver Disease/Cirrhosis (Due to Worsening of Liver Function), it Might Be Considered in a Patient with End-Stage Liver Disease Awaiting Liver Transplant (J Hepatol, 2012) [MEDLINE]
    • Conivaptan (Vaprisol) is Generally Avoided in Cirrhosis, Due to the Adverse Effects of Hypotension and Esophageal Variceal Hemorrhage (see Conivaptan)
  • Treat Hypotension
    • Discontinue β-Blockers and Other Antihypertensives (When MAP is <82 mm Hg)
      • MAP <82 mm Hg are Associated with Hyponatremia and Increased Mortality Rate in Cirrhotic Patients with Ascites (Gastroenterology, 1988) [MEDLINE] (J Hepatol, 2014) [MEDLINE]
    • Midodrine (see Midodrine) (J Hepatol, 2012) [MEDLINE] (Front Med-Lausanne, 2017) [MEDLINE]
  • Specific Treatment of Severe Symptomatic Hyponatremia (Na <120 mEq/L) in the Setting of Cirrhosis
    • Albumin (see Albumin)
      • Intravenous Albumin Infusion (Approximately 50-100 g Per Day) May Be Useful to Increase the Serum Sodium While Other Therapies are Initiated (Gut, 1990) [MEDLINE] (Am J Gastroenterol, 2018) [MEDLINE]
    • Hemodialysis (see Hemodialysis)
      • Indicated for Cirrhotic Patients with Acute Kidney Injury-Associated Hyponatremia or Pre-Liver Transplant
    • Hypertonic (3%) Saline (Combined with Loop Diuretics or Paracentesis to Prevent Hypervolemia) (see Hypertonic Saline)
      • This Strategy May Be Used Pre-Liver Transplant
  • Avoid Use of the Following
    • Demeclocycline (see Demeclocycline): due to nephrotoxicity
    • Normal Saline (see Normal Saline): due to worsening of hypervolemia
    • Sodium Chloride Tablets (see Sodium Chloride): due to worsening of hypervolemia
    • Oral Urea (see Urea): due to potential worsening of hepatic encephalopathy

Hypervolemic Hyponatremia (Associated with Congestive Heart Failure)

  • Angiotensin Converting Enzyme Inhibitors (ACE-I’s)/Angiotensin II Receptor Blockers (ARB’s) (see Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers)
    • ACE-I’s/ARB’s Improve Cardiac Function, Decreasing the Release of Antidiuretic Hormone and Norepinephrine (Ann Intern Med, 1984) [MEDLINE]
    • Via the Local Generation of Prostaglandins, ACE-I’s Antagonize the Effect of Antidiuretic Hormone on the Collecting Tubules, Decreasing Collecting Tubular Water Reabsorption (Am J Cardiol, 1986) [MEDLINE]
  • Fluid and Sodium Restriction
    • Fluid Restriction is Commonly Used in the Hospital Setting to Manage Hyponatremia in the Setting of Congestive Heart Failure (Am Heart J, 1994) [MEDLINE]
      • Fluid Restriction is Generally Less Effective in the Outpatient Setting (Due to Thirst, etc)
    • Fluid Restriction to 50-60% of the Daily Requirement (Approximately <800 mL/Day) May be Required to Achieve Negative Water Balance (NEJM, 2000) [MEDLINE]
    • Effectiveness of Fluid Restriction is Predicted by Urine/Plasma Electrolyte Ratio (Urine Na + Urine K/ Serum Na) <0.5 (Am J Med Sci, 2000) [MEDLINE]
      • Urine/Plasma Electrolyte Ratio >1.0 Suggests that Fluid Restriction Will Not Be Effective
  • Loop Diuretics
    • Furosemide (Lasix) (see Furosemide)
      • Loop Diuretics Decrease the Concentration Gradient in the Renal Medulla, Decreasing Water Reabsorption in the Collecting Duct (J Am Coll Cardiol, 2015) [MEDLINE]
  • Potassium Replacement (When Required for Hypokalemia) (see Potassium Chloride)
    • Potassium is as Osmotically Active as Potassium and Replacing Potassium in the Setting of Hypokalemia Will Increase Serum Osmolality (Am J Kidney Dis, 2010) [MEDLINE]
    • Potassium Movement Intracellularly Increases the Serum Sodium by the Following Mechanisms
      • Intracellular Movement of Potassium Will Result in an Exchange of Sodium into the Extracellular Fluid (to Maintain Intracellular Electroneutrality)
      • Intracellular Movement of Potassium Will Result in an Exchange of Hydrogen Ions into the Extracellular Fluid
        • Hydrogen Ions are Buffered by Extracellular Bicarbonate (and Plasma Proteins), Creating Carbon Dioxide and Water (Bicarbonate is Replaced by Chloride Which was Administered with the Potassium)
      • Intracellular Movement of Potassium Drags Drags Chloride into the Cells, Increasing the Intracellular Osmolality, Which Results in Free Water Movement into Cells
    • Intracellular Movement of Potassium Increases the Intracellular Osmolality, Which Results in Free Water Movement into Cells
  • Spironolactone (Aldactone) (see Spironolactone)
  • Vasopressin Receptor Antagonists (see Vasopressin Receptor Antagonists) (Kidney Int, 2013) [MEDLINE]
    • Conivaptan (Vaprisol) (see Conivaptan)
      • Pharmacology
        • 1a/V2 Vasopressin Receptor Antagonist: causes aquaresis (water loss)
    • Tolvaptan (Samsca) (see Tolvaptan)
      • Pharmacology
        • V2 Vasopressin Receptor Antagonist: causes aquaresis (water loss)
      • Clinical Efficacy
        • The SALT-1 Trial/SALT-2 Trials Comparing Tolvaptan to Placebo in Patients with Chronic Hyponatremia Due to SIADH, Congestive Heart Failure, or Cirrhosis (None with Clinically Apparent Neurologic Symptoms at Baseline; Almost All Patients Had Na ≥120 mEq/L) Demonstrated a Benefit in Mental Status in Patients with Na 120-129 mEq/L, But Not in Patients with Na 130-134 mEq/L (NEJM, 2006) [MEDLINE]
  • Avoid Use of the Following

Postoperative Hyponatremia

  • Avoid Perioperative Hypotonic Intravenous Fluids and Excessive Intravenous Fluid Administration
  • Treat Pain
  • Potassium Replacement (When Required for Hypokalemia) (see Potassium Chloride)
    • Potassium is as Osmotically Active as Potassium and Replacing Potassium in the Setting of Hypokalemia Will Increase Serum Osmolality (Am J Kidney Dis, 2010) [MEDLINE]
    • Potassium Movement Intracellularly Increases the Serum Sodium by the Following Mechanisms
      • Intracellular Movement of Potassium Will Result in an Exchange of Sodium into the Extracellular Fluid (to Maintain Intracellular Electroneutrality)
      • Intracellular Movement of Potassium Will Result in an Exchange of Hydrogen Ions into the Extracellular Fluid
        • Hydrogen Ions are Buffered by Extracellular Bicarbonate (and Plasma Proteins), Creating Carbon Dioxide and Water (Bicarbonate is Replaced by Chloride Which was Administered with the Potassium)
      • Intracellular Movement of Potassium Drags Drags Chloride into the Cells, Increasing the Intracellular Osmolality, Which Results in Free Water Movement into Cells
    • Intracellular Movement of Potassium Increases the Intracellular Osmolality, Which Results in Free Water Movement into Cells

Postoperative Glycine/Sorbitol/Mannitol-Associated Hyponatremia

Asymptomatic (or Inability to Assess Symptoms Due to General Anesthesia)/Mild Hyponatremia (Decrease <5 mEq/L)
  • No Specific Therapy is Required
    • With Adequate Renal Function, Excretion of Excess Water and the Glycine/Sorbitol/Mannitol Will Occur
    • Metabolism of the Glycine/Sorbitol/Mannitol Will Occur
Symptomatic
  • Severe Hyponatremia, Significantly Decreased Serum Osmolality, or Cerebral Edema
    • Hypertonic (3%) Saline (see Hypertonic Saline)
      • Hypertonic Saline Will Also Replace the Fluid Losses Resulting from Osmotic Diuresis by These Agents
    • Dose
      • Bolus 100 mL of 3% Saline (Provides 51 mEq of Sodium) at 10 min Intervals (as Required)
        • Each Bolus Should Increase the Serum Sodium 2-3 mEq/L.
  • Severe Hyponatremia with Near Normal/Normal Serum Osmolality (>270 mOsmol/kg)
    • Hemodialysis (see Hemodialysis): likely the safest treatment (Am J Kidney Dis, 1994) [MEDLINE]
      • Hemodialysis Corrects the Hyponatremia, Corrects the Osmotic Derangement, Normalizes Volume Status, and Removes the Glycine/Sorbitol/Mannitol Solution (and Their Metabolites)
  • Fluid Overload/Pulmonary Edema (see Cardiogenic Pulmonary Edema)
    • Loop Diuretics (see Furosemide)
      • Importantly, Loop Diuretics are Contraindicated in the Absence of Fluid Overload (as They May Worsen the Hyponatremia)
  • Persistent Hyponatremia Due to Perforate Viscus (with Collection of Irrigant Solution into Perivesical or Peritoneal Space)
    • Surgical Drainage of the Collection of Irrigation Fluid: may be considered in some cases

General Treatment of Hyponatremia within the First 6 hrs

Treatment of Acute Hyponatremia within the First 6 hrs

  • General Measures
    • Treat the Underlying Etiology of Hyponatremia
    • Identify Any Medications Which May Be Etiologic
    • Restrict Oral Free Water Intake
    • Increase Dietary Salt
    • Avoid Hypotonic Intravenous Fluids
    • Treat Underlying SIADH (If Present) (see Syndrome of Inappropriate Antiduretic Hormone Secretion)
  • Asymptomatic Acute Hyponatremia
    • If the Serum Sodium is Autocorrecting Due to a Water Diuresis, Monitor the Serum Sodium Until it Has Increased by 4-6 mEq/L from the Level at Presentation
      • Obviously, Autocorrection Can Be Detected by Remeasuring the Serum Sodium
        • Serum Sodium Should Be Monitored q1-2 hrs (a Point-of-Care Analyzer May Be Useful in This Situation)
      • Autocorrection Can Also Be Evidenced by the Following
        • Etiology of the Hyponatremia Has Been Reversed (Such as in Hypovolemia)
        • Urine Output Has Increased
        • Urine is Dilute (Specific Gravity <1.005, Urine Osmolality <200 mOsmol/kg, and the Sum of the Urine Sodium + Potassium Concentrations is <50% of the Serum Sodium
    • If the Serum Sodium is Not Autocorrecting, Administer 50 mL bolus of 3% Saline to Prevent a Further Decrease in the Serum Sodium
      • A Further Decline in the Serum Sodium Indicates a Lack of Autocorrection or Delayed Absorption of Ingested Water
      • 3% Saline Can Be Safely Administered Via a Peripheral Intravenous Line and Does Not Require a Central Venous Catheter (Am J Crit Care, 2016) [MEDLINE] J Intensive Care Med, 2018) [MEDLINE]
  • Symptomatic (Even Mildly Symptomatic) Acute Hyponatremia with Serum Sodium <130 mEq/L
    • Administer 100 mL bolus of 3% Saline Over 10 min with Two Additional Boluses (as Required by Symptoms to a Max of 300 mL) to a Goal Correction of 4-6 mEq/L Over the First Few Hours (and Goal Correction of <8 mEq/L in the First 24 hrs)
      • The Goal Rate of Correction Balances the Risk of Cerebral Edema Due to Acute Hyponatremia with the Risk of Osmotic Demyelination Syndrome Due to Overly Rapid Correction of Hyponatremia (see Osmotic Demyelination Syndrome)
      • Correction of Hyponatremia by 4-6 mEq/L within 6 hrs (Using Bolus Infusions of 3% Saline, as Required) is Sufficient to Manage the Most Severe Clinical Manifestations of Hyponatremia (Including Cerebral Edema with Potential Brain Herniation) (Semin Nephrol, 2009) [MEDLINE] (Curr Opin Nephrol Hypertens, 2010) [MEDLINE] (Am J Kidney Dis, 2015) [MEDLINE]
      • 3% Saline is the Most Effective Means of Increasing the Serum Sodium and Improve Neurologic Outcomes in Severe, Symptomatic Hyponatremia (Am J Med, 2007) [MEDLINE]
      • Avoid Mannitol/Vasopressin Antagonists (Either Instead of or in Addition to 3% Saline) in the Treatment of Acute Hyponatremia
        • Mannitol is Potentially Nephrotoxic and Can Decrease the Serum Sodium
        • Vasopressin Antagonists Have Variable Efficacy and Their Onset of Action is Too Slow to be Used in the Treatment Acute Hyponatremia

Treatment of Chronic Hyponatremia within the First 6 hrs

  • General Measures
    • Treat the Underlying Etiology of Hyponatremia
    • Identify Any Medications Which May Be Etiologic
    • Restrict Oral Free Water Intake
    • Increase Dietary Salt
    • Avoid Hypotonic Intravenous Fluids
    • Treat Underlying SIADH (If Present) (see Syndrome of Inappropriate Antiduretic Hormone Secretion)
  • Treatment Chronic Hyponatremia with Serum Sodium 130-134 mEq/L
    • Employ General Measures (Above) Only
  • Treatment of Chronic Hyponatremia with Serum Sodium 120-129 mEq/L in Asymptomatic/Mild-Moderately Symptomatic Patient (Fatigue, Headache, Nausea/Vomiting, Gait Disturbance, Confusion) with No Known Intracranial Pathology
    • Employ General Measures Only
  • Treatment of Chronic Hyponatremia with Serum Sodium <120 mEq/L in Asymptomatic/Mild-Moderately Symptomatic Patient (Fatigue, Headache, Nausea/Vomiting, Gait Disturbance, Confusion) with No Known Intracranial Pathology
    • Administer Intravenous 3% Saline at 15-30 mL/hr with Goal Correction of <8 mEq/L in the First 24 hrs
    • The Following Subsets of Patients Have a Rapidly Reversible Etiology of Hyponatremia and May Develop a Water Diuresis During the Course of Therapy
      • True Hypovolemic Hyponatremia (see Hypovolemic Shock)
        • Correction of Hypovolemia Inhibits Antidiuretic Hormone Secretion (Note that Antidiuretic Hormone has a Half-Life of Only 15-20 min), Resulting in a Water Diuresis
      • Adrenal Insufficiency (see Adrenal Insufficiency)
        • Administration of Glucocorticoid Steroids Directly Inhibits Antidiuretic Hormone Secretion (Note that Antidiuretic Hormone has a Half-Life of Only 15-20 min), Resulting in a Water Diuresis
      • Surgery/Drug/Pain-Associated SIADH (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
        • Since Inappropriate Antidiuretic Hormone Secretion is Present, Removal of the Stimulus for its Secretion (Discontinuation of the Drug, Treatment of Pain, etc) May Rapidly Decrease Antidiuretic Hormone Secretion (Note that Antidiuretic Hormone has a Half-Life of Only 15-20 min), Resulting in a Water Diuresis
    • Desmopressin is Recommended (to Prevent Overly Rapid Sodium Correction) in Patients with Rapidly Reversible Etiology of Hyponatremia Who are Likely to Develop a Water Diuresis During the Course of Therapy and in Patients with High Risk for ODS (Alcohol Abuse Burns, Hypokalemia, Liver Disease, Malnutrition, Severe Hyponatremia with Serum Sodium ≤105 mEq/L)
      • Desmopressin is Administered at the Beginning of 3% Saline Infusion (or, if Isotonic Saline was Used, After the Serum Sodium Has Been Corrected by 4-6 mEq/L): 1-2 μg IV/SQ q6-8 hrs x 24-48 hrs (or until the serum sodium has been increased to at least 125 mEq/L) with restricted free water intake
      • During 3% Saline, Desmopressin Makes the Rate of Correction More Predictable Because it Prevents the Unexpected Water Diuresis During the Course of Therapy, Effectively Decreasing the Risk of ODS (Am J Kidney Dis, 2013) [MEDLINE] (Clin J Am Soc Nephrol, 2014) [MEDLINE]
      • While Administration of D5W Can Be Attempted (to Correct Free Water Losses During the Water Diuresis) Instead of Desmopressin, it is Typically Less Effective and More Difficult to Manage
      • Desmopressin in Not Indicated in Patients Who are Unlikely to Develop a Water Diuresis During the Course of Therapy (Edematous Patients with Congestive Heart Failure/Cirrhosis, Recurrent Hyponatremia Due to Chronic SIADH, etc)
  • Treatment of Chronic Hyponatremia with Serum Sodium <130 mEq/L in Severely Symptomatic Patient (Obtundation/Coma, Seizures, Respiratory Arrest) or Patient with Known Intracranial Pathology (Traumatic Brain Injury, Intracranial Hemorrhage, Intracranial Surgery, Intracranial Mass, etc)
    • Administer 100 mL Bolus of 3% Saline Over 10 min with Two Additional Boluses (as Required by Symptoms to a Max of 300 mL) to a Goal Correction of 4-6 mEq/L Over the First Few Hours (and Goal Correction of <8 mEq/L in the First 24 hrs)

Overview of Treatment of Severe Hyponatremia (Na <120 mEq/L) (NEJM, 2015) [MEDLINE]

Hyponatremia Duration of Several Hours

Hyponatremia Duration of 1-2 Days

  • Associated Conditions
    • Hyponatremia Associated with Intracranial Disease
    • Postoperative Hyponatremia (Especially in Women/Children)
  • Clinical Features
  • Therapeutic Goal
    • 100 mL Bolus of 3% Saline Three Times, as Required for Severe Symptoms
    • Increase Plasma Sodium by 4–6 mEq/L in the First 6 hrs
  • Comments
    • Avoid Increasing the Plasma Sodium by >10 mEq/L/Day

Hyponatremia Duration of Unknown Period or ≥2 Days

  • Associated Conditions
    • Conditions Associated with High Risk of Osmotic Demyelination Syndrome (ODS) (Plasma Sodium ≤105 mEq/L, Hypokalemia, Alcohol Abuse, Malnutrition, Liver Disease)
  • Clinical Features
  • Therapeutic Goal
    • Use Extra Caution for Conditions Associated with High Risk of Osmotic Demyelination Syndrome (ODS)
    • 100 mL Bolus of 3% Saline Three Times, as Required for Seizures
    • Increase Plasma Sodium by 4–6 mEq/L in the First 24 hrs
  • Comments
    • Avoid Increasing Plasma Sodium by >8 mEq/L/Day
    • Consider Lowering Again if Limit is Exceeded (Especially in Patients with High Risk of Osmotic Demyelination Syndrome)

Etiology of “Autocorrection” of Hyponatremia

  • General Comments
    • “Autocorrection” is Defined as a Rapid Water Diuresis Occurring During the Course of Hyponatremia Therapy (Generally Manifested by Urine Osmolality <100 mOsmol/kg)
      • If Autocorrection is Unrecognized, Rapid Correction of Hyponatremia May Occur, Exceeding the Recommended Limit of 8 mEq/L Per Day
  • Presence of True Hypovolemic Hyponatremia (see Hypovolemic Shock) (Clin J Am Soc Nephrol, 2018) [MEDLINE]
    • Correction of the Hypovolemia Inhibits Antidiuretic Hormone Secretion (Note that Antidiuretic Hormone has a Half-Life of Only 15-20 min), Resulting in a Water Diuresis
  • Presence of Adrenal Insufficiency (see Adrenal Insufficiency) (J Clin Invest, 1967) [MEDLINE]
    • Administration of Glucocorticoid Steroids Directly Inhibits Antidiuretic Hormone Secretion (Note that Antidiuretic Hormone has a Half-Life of Only 15-20 min), Resulting in a Water Diuresis
  • Resolution of Surgery/Drug/Pain-Associated SIADH (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
    • Since Inappropriate Antidiuretic Hormone Secretion is Present, Removal of the Stimulus for its Secretion (Discontinuation of the Drug, Treatment of Pain, etc) May Rapidly Decrease Antidiuretic Hormone Secretion (Note that Antidiuretic Hormone has a Half-Life of Only 15-20 min), Resulting in a Water Diuresis
  • Discontinuation of Thiazide Diuretic (see Thiazides)
    • Since Thiazides Interfere with Urinary Dilution
  • Treatment of Advanced Renal Failure with Hemodialysis (see Chronic Kidney Disease)
    • However, Osmotic Demyelination Syndrome is Uncommon in This Setting, Since the Increase in Serum Osmolality Associated with the Increase in Serum Sodium During Hemodialysis is Counterbalanced by a Decrease in Serum Osmolality Associated with the Removal of Urea

Strategies During the Treatment of Hyponatremia (J Med, 2015) [MEDLINE]

  • Proactive (Preventative) Strategy
    • Used in Patients Who are Likely to Develop Rapid Correction of Their Hyponatremia (i.e. Hypovolemic Patient Who Will Likely Develop a Water Diuresis During Treatment, etc)
      • Administer Desmopressin at the Beginning of Hyponatremia Treatment and at Regular Intervals (to Induce a State of Iatrogenic SIADH, Preventing Urinary Water Losses), Followed Then by the Use of Hypertonic (3%) Saline (Usually 15-30 mL/hr) to Slowly Increase the Serum Sodium in a Controlled Manner (see Desmopressin)
        • Typical Desmopressin Dosing: 1-2 μg IV q6-8hrs x 24-48 hrs (see Desmopressin)
    • In a Large Study (n = 254 Hyponatremic Patients Treated with Desmopressin), the Proactive Strategy (Although without Hypertonic Saline Use) was More Effective in Achieving Correction at <8 mEq/L (79% vs 30% in the Reactive Strategy Group), But was Less Used than the Reactive Strategy (Am J Med, 2018) [MEDLINE]
  • Reactive Strategy
    • Used in Patients with Concerning Trajectory with a Rapidly Increasing Serum Sodium
      • If Water Diuresis Occurs During Treatment or if the Trajectory is Predicted to Exceed Goal of 8 mEq/L Per Day, Replace Urinary Water Losses with D5W Infusion (Usually Less Effective) or Stop Urinary Water Losses with Desmopressin (Usually More Effective) (see Desmopressin)
  • Rescue Strategy
    • Used in Patients in Patients Who Have Already Exceeded the Sodium Correction Limit
      • Administer Desmopressin (2 μg q6 hrs IV) to Re-Lower the Serum Sodium (at Approximately 1 mEq/L Per Hour) (see Desmopressin)
        • Note that the Efficacy of Desmopressin to Inhibit the Water Diuresis (and Re-Lower the Serum Sodium) is Reduced in Hyponatremic Patients Who Have Been Treated with Vasopressin Receptor Antagonists (Tolvaptan, etc)
        • Although Human Data is Limited, Re-Lowering the Serum Sodium with D5W or Desmopressin May Abort the Development of Osmotic Demyelination Syndrome Following Inadvertent Rapid Correction of Hyponatremia

Complications of Overly Rapid Correction of Hyponatremia

Osmotic Demyelination Syndrome (ODS) (see Osmotic Demyelination Syndrome)

  • Osmotic Demyelination Syndrome (ODS) is a Frequently Irreversible Neurologic Disorder Which Predominantly Occurs in Patients with Severe Hyponatremia (Na ≤120 mE/L) Which Has Been Present for >2-3 Days and in Whom the Serum Sodium Has Been Rapidly Corrected (Ann Intern Med, 1987) [MEDLINE] (J Am Soc Nephrol, 1994) [MEDLINE] (J Med, 2013) [MEDLINE] (Acta Neurol Scand, 2019) [MEDLINE]
    • Osmotic Demyelination Syndrome was Previously Called Central Pontine Myelinolysis
      • However, the Name was Subsequently Changed Since the Demyelination is More Diffuse and Does Not Necessarily Involve the Pons, Not All Patients Have Identifiable Anatomic Lesions, and Not All Patients Have Experienced a Preceding Rapid Correction of the Serum Sodium (Ann Intern Med, 1992) [MEDLINE]
  • Epidemiology
    • Low-Risk Groups for Osmotic Demyelination Syndrome (ODS)
      • Hyponatremic Patients with Self-Induced Water Intoxication (Runners, Psychotic Patients with Severe Polydipsia, Ecstasy Users, etc)
        • These Patients Have Not Had Adequate Time for Brain Cells to Expel Osmotic Substances
      • Patients with Mild-Moderate Hyponatremia (Serum Sodium >120 mEq/L)
        • Since Almost All Patients Who Develop Osmotic Demyelination Syndrome Initially Presented with a Serum Sodium ≤120 mEq/L
    • Risk Factors Which Increase the Risk of Osmotic Demyelination Syndrome (Clin J Am Soc Nephrol, 2018) [MEDLINE] (Acta Neurol Scand, 2019) [MEDLINE]
    • Protective Factors Which Decrease the Risk of Osmotic Demyelination Syndrome (ODS)
      • Elevated Blood Urea Nitrogen (BUN) in the Setting of Renal Failure
  • Relationship of Rate of Correction to the Risk of Osmotic Demyelination Syndrome (ODS)
    • Case Series Examining the Use of 3% Saline to Treat Hyponatremic Encephalopathy in the ED Setting (Am J Kidney Dis, 2015) [MEDLINE]
      • Baseline Mean Serum Sodium was 114.1 ± 0.8 (SEM) mEq/L
        • Mean 3 hr Serum Sodium Correction to 117.9 ± 1.3
        • Mean 12 hr Serum Sodium Correction to 121.2 ± 1.2
        • Mean 24 hr Serum Sodium Correction to 123.9 ± 1.0 (Delta of Approximately 10 mEq/L in the First 24 hrs)
        • Mean 48 hr Serum Sodium Correction to 128.3 ± 0.8 mEq/L
      • No Cases of Osmotic Demyelination were Observed
    • Retrospective Cohort Study of Risk Factors for Rapid Correction of Hyponatremia (Clin J Am Soc Nephrol, 2018) [MEDLINE]: n = 1,490 patients admitted with serum sodium <120 mEq/L
      • Median Change in Serum Sodium at 24 hrs was 6.8 mEq/L (Interquartile Range, 3.4-10.2)
      • Rapid Correction of Hyponatremia Occurred in 41% of Patients
      • Risk Factors Associated with Rapid Correction
        • Younger Age
        • Female Sex
        • Schizophrenia
        • Lower Charlson Comorbidity Index
        • Lower Presentation Serum Sodium
        • Urine Sodium <30 mEq/L
      • Risk Factors Associated with Lower Risk of Rapid Correction
        • Prior Hyponatremia
        • Outpatient Aldosterone Antagonist Use
        • Treatment at an Academic Center
      • Approximately 88% of Patients with Incident Osmotic Demyelination Had a Documented Episode of Rapid Correction of Hyponatremia (with Serum Sodium Increase >8 mEq/L Over 24 hrs)
  • Diagnosis
    • Brain Magnetic Resonance Imaging (MRI) (see Brain Magnetic Resonance Imaging)
      • In a Study of Osmotic Demyelination Syndrome, 51% of Patients Had Central Pontine Demyelination Only, 45% of Patients Had Both Central Pontine Demyelination and Extrapontine Demyelination, and 4% of Patients Had Extrapontine Demyelination Only (Acta Neurol Scand, 2019) [MEDLINE]
  • Clinical
    • Delayed Onset of Symptoms Occurs Approximately 2-6 Days After the Rapid Sodium Correction Event
  • Treatment
    • Supportive Care
      • Respiratory Support (Endotracheal Intubation with Invasive Mechanical Ventilation (If Required)
    • Recommended that the Serum Sodium Be Lowered to a Level Just Below the Initial 48 hr Serum Sodium Target (i.e. to <16 mEq/L Above the Initial Target Serum Sodium)
      • The 48 hr Target is the Most Practical to Implement Since Osmotic Demyelination Syndrome General Presents 2-6 Days After the Rapid Sodium Correction Event
    • Procedure
      • Start Either Hypotonic Intravenous Fluids (D5W, etc) or Desmopressin within Hours of the Onset of Neurologic Symptoms
        • While the Optimal Timing of Re-Lowering is Unclear, it is Recommended to Start Re-Lowering as Soon as Possible

Prognosis

Hyponatremia (Even if Mild) Increases the Mortality Rate in Both Ambulatory and Hospitalized Patients (Am J Med, 2009) [MEDLINE] (Arch Intern Med, 2010) [MEDLINE] (Am J Kidney Dis, 2012) [MEDLINE] (Kidney Int, 2013) [MEDLINE] (Eur J Endocrinol, 2015) [MEDLINE]

  • This May Be Due to Adaptations to Hyponatremia Which Allow the Organs to Function at Decreased Serum Concentrations (Am J Kidney Dis, 2019) [MEDLINE]
  • Interestingly, the Relationship Between Serum Sodium Level and Mortality Rate is Not Linear (with Higher Mortality Rates at Serum Sodium Levels Down to 125 mEq/L and Lower Mortality Rates at Serum Sodium Levels <120 mEq/L) (Clin J Am Soc Nephrol, 2011) [MEDLINE] (Eur J Endocrinol, 2016) [MEDLINE] (BMC Nephrol, 2016) [MEDLINE]
    • This May Be Due to the Fact that Mild-Moderate Hyponatremia is More Likely to Be Associated with a Significant Underlying Disease (Malignancy, Renal Failure, Congestive Heart Failure, Cirrhosis), While Severe Hyponatremia is Most Commonly Drug-Induced
    • Drug-Induced Hyponatremia is More Likely to Resolve After Discontinuation of the Drug (While Disease-Associated Hyponatremia is More Likely to Be Persistent/Chronic)
  • Data from Meta-Analyses (15 Studies, Including 13,816 Hyponatremic Patients) Indicate that Improvement in the Serum Sodium Concentration Results in Decreased Overall Mortality (PLoS One, 2015) [MEDLINE]

Preoperative Hyponatremia Increases Multiple Perioperative Surgical Risks (Arch Int Med, 2012) [MEDLINE]

  • Hyponatremia Increases Postoperative 30-Day Mortality Rate (5.2% vs 1.3%)
    • Especially in Patients Undergoing Non-Emergency Surgery with ASA Class 1-2
  • Hyponatremia Increases Rate of Perioperative Coronary Events
  • Hyponatremia Increases Wound Infection Rates
  • Hyponatremia Increases Pneumonia Rates Hyponatremia Prolongs the Median Length of Stay (by Approximately 1 Day)

References

General

  • Common fluid-electrolyte and acid-base problems in the intensive care unit: selected issues. Semin Nephrol 1994; 14:8-22 [MEDLINE]
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Epidemiology

  • Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med. 1985;102:164–168 [MEDLINE]
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  • Incidence and prevalence of hyponatremia. Am J Med. 2006;119(suppl 1):S30–S35 [MEDLINE]

Etiology

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  • Maltose-induced hyponatremia. Ann Intern Med. 1993;118(7):526 [MEDLINE]
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  • Fluid absorption in endoscopic surgery. Br J Anaesth. 2006;96(1):8 [MEDLINE]
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  • Preventing a drop in effective plasma osmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis. J Pediatr. 2007;150(5):467 [MEDLINE]
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  • The harmful health effects of recreational ecstasy: a systematic review of observational evidence. Health Technol Assess. 2009;13(6):iii [MEDLINE]
  • Acute hyponatremia after cardioplegia by histidine-tryptophane-ketoglutarate–a retrospective study. J Cardiothorac Surg. 2012;7:52 [MEDLINE]
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  • Fluid, electrolyte, and acid-base disturbances. Case 6: Diabetes and acidosis. Nephrol Self Assess Program. 2013;12:193
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  • Pseudohypernatremia and pseudohyponatremia: a linear correction. Nephrol Dial Transplant. 2015 Feb;30(2):252-7 [MEDLINE]
  • Extreme hypercholesterolemia presenting with pseudohyponatremia – a case report and review of the literature. J Clin Lipidol. 2015 Mar-Apr;9(2):260-4 [MEDLINE]
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  • Symptomatic absorption of isotonic saline during transcervical endometrial resection. Acta Anaesthesiol Scand. 2017;61(1):121 [MEDLINE]
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Physiology

  • Regulation of solute and water balance and cell volume in the central nervous system. J Am Soc Nephrol. 1992;3(1):12 [MEDLINE]
  • Regulation of cell volume in health and disease. N Engl J Med. 1995;333(19):1260 [MEDLINE]
  • Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest. 1995;95(2):788 [MEDLINE]
  • Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6(2):159 [MEDLINE]
  • The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant. 2003;18(12):2486 [MEDLINE]
  • Osmotic homeostasis. Clin J Am Soc Nephrol. 2015 May;10(5):852-62 [MEDLINE]

Diagnosis

  • Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician . 2015 Mar 1;91(5):299-307 [MEDLINE]

Clinical

  • Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med. 1986;314(24):1529 [MEDLINE]
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  • Sex differences result in increased morbidity from hyponatremia in female rats. Am J Physiol. 1989;256(4 Pt 2):R880 [MEDLINE]
  • Hyponatremia and death or permanent brain damage in healthy children. BMJ. 1992;304(6836):1218 [MEDLINE]
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  • Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med. 2000;132(9):711 [MEDLINE]
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  • Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e1 [MEDLINE]
  • Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM. 2008;101(7):583 [MEDLINE]
  • Hyponatremia-induced osteoporosis. J Bone Miner Res. 2010;25(3):554 [MEDLINE]
  • Hyponatremia and risk of seizures: a retrospective cross-sectional study. Epilepsia. 2011 Feb;52(2):410-3 [MEDLINE]
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  • Characteristics, symptoms, and outcome of severe dysnatremias present on hospital admission. Am J Med. 2012;125(11):1125.e1 [MEDLINE]
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  • Attention and postural balance are much more affected in older than in younger adults with mild or moderate chronic hyponatremia. Eur J Intern Med. 2017;41:e25 [MEDLINE]
  • Allostasis and the Clinical Manifestations of Mild to Moderate Chronic Hyponatremia: No Good Adaptation Goes Unpunished. Am J Kidney Dis. 2019;73(3):391 [MEDLINE]

Treatment

  • Changing concepts in treatment of severe symptomatic hyponatremia. Rapid correction and possible relation to central pontine myelinolysis. Am J Med. 1985;78(6 Pt 1):897 [MEDLINE]
  • New approach to disturbances in the plasma sodium concentration. Am J Med 1986; 81:1033 [MEDLINE]
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  • The management of hyponatremic emergencies. Crit Care Clin 1991; 7:127-42 [MEDLINE]
  • Endometrial ablation complicated by fatal hyponatremic encephalopathy. JAMA. 1993;270(10):1230 [MEDLINE]
  • Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore). 1993;72(6):359 [MEDLINE]
  • The post-transurethral resection of prostate syndrome: therapeutic proposals. Am J Kidney Dis. 1994;24(1):108 [MEDLINE]
  • Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol. 1996 Sep;46(3):149-69 [MEDLINE]
  • The treatment of severe hyponatremia. Kidney Int Suppl. 1998;64:S6 [MEDLINE]
  • The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant. 2003;18(12):2486 [MEDLINE]
  • Tolvaptan, a selective vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099-2112 [MEDLINE]
  • Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 Suppl 1):S1 [MEDLINE]
  • Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 2007;27:447-457 [MEDLINE]
  • Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST Outcome Trial. JAMA 2007;297:1319-1331 [MEDLINE]
  • The treatment of hyponatremia. Semin Nephrol. 2009;29(3):282 [MEDLINE]
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  • Central pontine and extrapontine myelinolysis: from epileptic and other manifestations to cognitive prognosis. J Neurol. 2010 Jul;257(7):1176-80 [MEDLINE]
  • The challenge of hyponatremia. J Am Soc Nephrol. 2012;23(7):1140 [MEDLINE]
  • Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of literature. Acta Paediatr. 2013 Apr;102(4):e164-8. Epub 2013 Jan 21 [MEDLINE]
  • Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis. 2013 Apr;61(4):571-8 [MEDLINE]
  • Use of desmopressin acetate in severe hyponatremia in the intensive care unit. Clin J Am Soc Nephrol. 2014 Feb;9(2):229-37 [MEDLINE]
  • Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS One. 2015;10(4):e0124105. Epub 2015 [MEDLINE]
  • Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician . 2015 Mar 1;91(5):299-307 [MEDLINE]
  • Treatment of hyponatremic encephalopathy with a 3% sodium chloride protocol: a case series. Am J Kidney Dis. 2015 Mar;65(3):435-42 [MEDLINE]
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  • Safety of Continuous Peripheral Infusion of 3% Sodium Chloride Solution in Neurocritical Care Patients. Am J Crit Care. 2016;26(1):37 [MEDLINE]
  • Treatment of Severe Hyponatremia. Clin J Am Soc Nephrol. 2018;13(4):641 [MEDLINE]
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  • Incidence of Adverse Events During Peripheral Administration of Sodium Chloride 3. J Intensive Care Med. 2018;33(1):48 [MEDLINE]

Prognosis

  • Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med. 2009;122(9):857 [MEDLINE]
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  • Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes. Am J Kidney Dis. 2012;59(2):222 [MEDLINE]
  • Mild hyponatremia is associated with an increased risk of death in an ambulatory setting. Kidney Int. 2013 Apr;83(4):700-6 [MEDLINE]
  • Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS One. 2015;10(4):e0124105. Epub 2015 [MEDLINE]
  • Hyponatremia and mortality risk: a Danish cohort study of 279 ,508 acutely hospitalized patients. Eur J Endocrinol. 2015 Jul;173(1):71-81 [MEDLINE]
  • Long-term outcome of profound hyponatremia: a prospective 12 months follow-up study. Eur J Endocrinol. 2016;175(6):499 [MEDLINE]
  • Prognosis of patients with severe hyponatraemia is related not only to hyponatraemia but also to comorbidities and to medical management: results of an observational retrospective study. BMC Nephrol. 2016;17(1):159 [MEDLINE]