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
Severe Hyperproteinemia May Occur in Multiple Myeloma (see Multiple Myeloma)
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)
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)
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
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
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 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
Elevated Serum Osmolal Gap >10 mOsmol/kg Indicates that the Mannitol Has Been Retained (see Elevated Serum Osmolal Gap) (Crit Care Med, 2004) [MEDLINE]
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)
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 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
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)
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]
Malnourished Patient with Ingestion of Large Quantities of Beer (Lancet, 1975) [MEDLINE] (Am J Kidney Dis, 1998) [MEDLINE] (Lancet, 2002) [MEDLINE]
Mechanism
Beer Contains Little or No Sodium/Potassium/Protein to Generate Solutes for Excretion
In Addition, the Alcohol and Carbohydrates in Beer Suppresses Endogenous Protein Degradation and Consequent Urea Excretion
In a Normal Patient (on Normal Diet), There is Generation and Excretion of 600-900 mOsmol of Solute Per Day (Composed Predominantly of Sodium Salts, Potassium Salts, and Urea)
If the Minimum Urine Osmolality is Around 60 mOsmol/kg, the Maximum Urine Output Would Be Around 10-15L Per Day (900 mOsmol Per Day ÷ 60 mOsmol Per kg = 15 L)
However, in a Patient with Beer Potomania, the Daily Solute Excretion May Decrease to <250 mOsmol of Solute Per Day and Even with Maximal Urine Dilution, Daily Free Water Excretion Would Decrease to <4 L/Day (240 mOsmol Per Day ÷ 60 mOsmol Per kg = 4 L)
Therefore, Hyponatremia Can Occur if >4L of Water is Ingested Per Day (This Equates to Approximately 12 Cans of Beer Per Day)
If a Patient Develops Any Superimposed Nausea or Hypovolemia (Both of Which Stimulate Antidiuretic Hormone Secretion). Impairment of Urine Dilution Occurs, Worsening the Hyponatremia
Tea and Toast Diet with Decreased Dietary Sodium (Solute) Intake
Epidemiology
Ingestion of Low Protein/High Water Diet (Lancet, 1975) [MEDLINE] (Am J Kidney Dis, 1998) [MEDLINE] (Lancet, 2002) [MEDLINE]
Mechanism
Low Protein Diet Results in Suppression of Endogenous Protein Degradation and Decreased Urea Excretion, Decreasing the Water Excretory Capacity
If a Patient Develops Any Superimposed Nausea or Hypovolemia (Both of Which Stimulate Antidiuretic Hormone Secretion). Impairment of Urine Dilution Occurs, Worsening the Hyponatremia
Psychiatric Patients with Polydipsia and Hyponatremia Have Unexplained Defects in Urinary Dilution, Osmoregulation of Water Intake, and the Secretion of Vasopressin (NEJM, 1988) [MEDLINE]
In Some Patients, the Osmotic Threshold for Thirst is Decreased Below the Threshold for the Release of Antidiuretic Hormone (Clin Endocrinol-Oxf, 1991) [MEDLINE]: this is in contrast to normal patients, in whom the thirst threshold is roughly equal to or a few mosmol/kg higher than the threshold for antidiuretic hormone release
Some Polydipsia Patients with Hyponatremia Have a Higher Urine Osmolality than is Expected, Suggesting a Concurrent Increase in Antidiuretic Hormone Release and/or Response (Due to Various Mechanisms)
Since Normal Patients Can Excrete >400-600 mL of Urine Per Hour (Mediated by Suppression of Antidiuretic Hormone Secretion and the Subsequent Formation of a Dilute Urine with a Minimum Urine Osmolality of 40-100 mosmol/kg), Assuming Normal Renal Function and Intact Antidiuretic Hormone Regulation, Primary Polydipsia Should Not Result in Clinically Significant Hyponatremia Unless There is a Massive Increase in Water Intake (Q J Med, 1959) [MEDLINE]
In Some Institutionalized Patients with Severe Psychosis, Water Intake May Exceed 400-600 mL Per Hour, Overtasking the Renal Water Excretion Mechanism
Acute Water Loading of 3-4L (Prior to a Radiologic Exam or in an Attempt to Avoid a Positive Urine Drug Test) May Result in Hyponatremia (JAMA, 1991) [MEDLINE]
Primary Polydipsia Can Also Occur with Hypothalamic Thirst Center Lesions (Sarcoidosis, etc)
Disorders with Impaired Urine Dilution, But Normal Suppression of Antidiuretic Hormone (ADH)
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
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
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
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)
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
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
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)
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)
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 May Also Be Secreted in Response to Hypovolemia
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
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
Normal Patients Can Excrete >400-600 mL of Urine Per Hour (Mediated by Suppression of Antidiuretic Hormone Secretion and the Subsequent Formation of a Dilute Urine with a Minimum Urine Osmolality of 40-100 mosmol/kg)
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
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)
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]
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]
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
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]
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 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]
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]
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
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)
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)
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
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
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
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]
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
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
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]
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]
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 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
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 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
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)
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]
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
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
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
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
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]
Seizures (see Seizures): 10% incidence with with plasma sodium <110 mEq/L)
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 During Therapy
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
Treatment of Hypovolemic Hyponatremia (with Fluid Resuscitation) (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
Treatment of Adrenal Insufficiency with Glucocorticoid Steroid Replacement (see Adrenal Insufficiency) (J Clin Invest, 1967) [MEDLINE]
Administration of Glucocorticoid Steroids Directly Inhibits Antidiuretic Hormone Secretion, Resulting in a Water Diuresis
Note: Antidiuretic Hormone has a Half-Life of Only 15-20 min
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, Resulting in a Water Diuresis
Note: Antidiuretic Hormone has a Half-Life of Only 15-20 min
Discontinuation of Thiazide Diuretic (see Thiazides)
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
Proactive (Preventative) Strategy May Be Useful in Patients Who are Likely to Develop Rapid Correction of Their Hyponatremia (i.e. Hypovolemic Patient Who Will Likely Develop a Water Diuresis During the Course of 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)
Clinical Efficacy
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
Reactive Strategy May Be Useful 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)
Typical Desmopressin Dosing: 1-2 μg IV q6-8hrs x 24-48 hrs (see Desmopressin)
Rescue Strategy
Rescue Strategy May Be Used 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) 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)
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]
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 RatesHyponatremia Prolongs the Median Length of Stay (by Approximately 1 Day)
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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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Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan;372(1):55-65 [MEDLINE]
Symptomatic absorption of isotonic saline during transcervical endometrial resection. Acta Anaesthesiol Scand. 2017;61(1):121 [MEDLINE]
Pseudohyponatremia in Hypertriglyceridemia-Induced Acute Pancreatitis: A Tool for Diagnosis Rather Than Merely a Laboratory Error? Pancreas. 2019;48(1):126 [MEDLINE]
Estimated Daily Urine Volume and Solute Excretion from Spot Urine Samples to Guide the Therapy of Hyponatremia in SIADH. J Clin Med. 2019;8(10) [MEDLINE]
The Role of Fractional Excretion of Uric Acid in the Differential Diagnosis of Hypotonic Hyponatraemia in Patients with Diuretic Therapy. Cureus. 2020;12(4):e7762 [MEDLINE]
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]
Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med. 1987;107(5):656 [MEDLINE]
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]
Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med. 1992;117(11):891 [MEDLINE]
Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med. 2000;132(9):711 [MEDLINE]
Clinical studies of thiazide-induced hyponatremia. J Natl Med Assoc. 2004;96(10):1305 [MEDLINE]
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]
Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol. 2011 May;6(5):960-5 [MEDLINE]
Characteristics, symptoms, and outcome of severe dysnatremias present on hospital admission. Am J Med. 2012;125(11):1125.e1 [MEDLINE]
Symptoms and characteristics of individuals with profound hyponatremia: a prospective multicenter observational study. J Am Geriatr Soc. 2015;63(3):470 [MEDLINE]
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]
Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases. Ann Intern Med. 1987;107(5):656 [MEDLINE]
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]
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]
Treatment of hyponatremia. Curr Opin Nephrol Hypertens. 2010;19(5):493 [MEDLINE]
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]
Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan;372(1):55-65 [MEDLINE]
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]
Risk Factors and Outcomes of Rapid Correction of Severe Hyponatremia. Clin J Am Soc Nephrol. 2018 Jul 6;13(7):984-992. doi: 10.2215/CJN.13061117 [MEDLINE]
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]
Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med. 2010;170(3):294 [MEDLINE]
Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol. 2011 May;6(5):960-5 [MEDLINE]
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]
