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Hyponatremia

Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality Plasma osmolality Volume Depletion and Dehydration, which is very tightly controlled via antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia (ADH) release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology from the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus and by the thirst mechanism. The basic pathophysiology of all etiologies of hyponatremia is an abnormal increase in total body water Total body water Body Fluid Compartments ( TBW TBW Body Fluid Compartments), which dilutes the total body sodium (TBNa+) concentration. The clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor varies greatly, from asymptomatic to subtle cognitive deficits, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and death. Management is guided by etiology, acuity, and duration of symptoms, usually involving oral fluid restriction or administration of IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids that contain Na. Sodium must be replaced slowly, as overly rapid correction of hyponatremia can lead to irreversible neurologic complications and death, known as the osmotic demyelination Demyelination Multiple Sclerosis syndrome (ODS).

Last updated: 1 Feb, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Physiology and classification

Etiology

The etiologies of hyponatremia are most commonly organized according to their volume status.

Hypovolemic:

  • GI losses ( diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, nasogastric tube Nasogastric tube Malnutrition in children in resource-limited countries (NG tube)/surgical drain output)
  • Bleeding 
  • Diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
  • Insensible losses Insensible losses Loss of water by diffusion through the skin and by evaporation from the respiratory tract. Volume Depletion and Dehydration ( tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination, sweating, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns)
  • Third-spacing ( pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis)
  • Other (salt-wasting nephropathies)

Euvolemic Euvolemic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH):

  • SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
  • Primary polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus (psychogenic polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus)
  • Low solute intake (beer potomania, tea-and-toast diet)
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
  • Thiazide induced

Hypervolemic:

  • Congestive heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) ( CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure)
  • Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome
  • Advanced renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome

Pathophysiology

  • Antidiuretic hormone (ADH) is released by the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus.
  • Acts at the collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma in the kidney via V2 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Results in the insertion of aquaporin channels Channels The Cell: Cell Membrane (AQPs) → facilitates water reabsorption 
  • ↑ Plasma tonicity Tonicity Plasma tonicity refers to the concentration of only the osmotically active solutes in blood Renal Sodium and Water Regulation → ADH released → water retention → tonicity Tonicity Plasma tonicity refers to the concentration of only the osmotically active solutes in blood Renal Sodium and Water Regulation normalizes 
  • ↓ Plasma volume → ADH released → water retention and vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure
    • Only occurs if > 10% blood volume lost
    • The purpose is to maintain blood pressure at all costs.
    • It occurs even if plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products tonicity Tonicity Plasma tonicity refers to the concentration of only the osmotically active solutes in blood Renal Sodium and Water Regulation is normal or low.
    • ADH also has systemic vasoconstrictor effects.
  • When intake of water is greater than excretion water → ↑ TBW TBW Body Fluid Compartments → net dilution of TBNa+
  • ↓ In TBNa+ (i.e., hypovolemia Hypovolemia Sepsis in Children) contributes to hyponatremia

Clinical Presentation

Acute (< 48 hours)

  • Symptoms are due to acute shift of water into the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification cerebral edema Cerebral edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries. An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive hydrocephalus). Increased Intracranial Pressure (ICP)
  • Relatively smaller drop in sNa+ sufficient to cause symptoms (i.e., sNa+ approximately 130 mEq/L)
  • Mild symptoms:
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Lethargy
    • Anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
    • Vomiting
  • Severe symptoms: 
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Severe altered mental status Altered Mental Status Sepsis in Children
    • Herniation Herniation Omphalocele coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure, death

Chronic (> 48 hours)

  • Brain adaptation to hyponatremia:
    • Occurs quickly (within approximately 48 hours) 
    • Brain cells excrete solutes (“organic osmolytes”) to equalize the tonicity Tonicity Plasma tonicity refers to the concentration of only the osmotically active solutes in blood Renal Sodium and Water Regulation.
    • Results in much lower degree of fluid shift Fluid Shift Translocation of body fluids from one compartment to another, such as from the vascular to the interstitial compartments. Fluid shifts are associated with profound changes in vascular permeability and water-electrolyte imbalance. The shift can also be from the lower body to the upper body as in conditions of weightlessness. Volume Depletion and Dehydration into the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
  • Symptoms are more subtle due to brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification adaptations:
  • Relatively large drop in sNa+ necessary to cause severe symptoms (i.e., sNa+ < 120 mEq/L) 
Effects of hyponatremia on the brain

Effects of hyponatremia on the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification

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Diagnosis

The 3 most important tests that need to be completed are serum osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation, urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation, and urinary sodium concentration.

Serum or plasma osmolality Plasma osmolality Volume Depletion and Dehydration

Urine osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation

  • Determines the activity of ADH
  • Urine osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation < 100 mOsm/kg: ADH appropriately absent 
    • Low solute intake 
    • Primary polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus
  • Urine osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation > 100 mOsm/kg: ADH present 

Estimate clinical volume status (TBNa+)

  • Clearly hypovolemic or hypervolemic → no further testing needed
  • Euvolemic Euvolemic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) or possibly hypovolemic → need further testing
  • Euvolemic Euvolemic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) vs. possibly hypovolemic:
    • Screen for hypothyroidism and adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison’s Disease ( cortisol Cortisol Glucocorticoids, adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones (ACTH) stimulation test)
    • Review medication list for common offenders
    • Review history for common nonosmotic ADH stimuli
  • Check additional labs:
    • Urine Na+: ↓ suggests hypovolemia Hypovolemia Sepsis in Children, ↑ suggests SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
    • BNP BNP A peptide that is secreted by the brain and the heart atria, stored mainly in cardiac ventricular myocardium. It can cause natriuresis; diuresis; vasodilation; and inhibits secretion of renin and aldosterone. It improves heart function. It contains 32 amino acids. Renal Sodium and Water Regulation: ↓ suggests hypovolemia Hypovolemia Sepsis in Children
    • Serum uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis: ↓ suggests SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
    • BUN: ↓ suggests SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) 
  • Fluid challenge with repeat urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat studies if diagnosis is still unclear

Diagnosis of underlying condition

  • SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH):
    • Excessive levels of ADH result in excessive renal free water reabsorption.
    • ADH release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology can be stimulated by many causes: 
      • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, stress
      • Centrally acting medications, CNS disorders
      • Postoperative state
      • Malignancy Malignancy Hemothorax (most commonly small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer)
      • Lung disorders (i.e., pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia)
  • Primary polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus and low solute intake:
    • Water intake in excess of kidney’s maximal excretion capabilities
    • Highly dependent on dietary solute intake and the concept of obligate osmolar excretion
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism and thiazide induced: The mechanisms are incompletely understood.
  • CHF CHF Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure/cirrhosis/nephrotic syndrome: nonosmotic release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of ADH due to the kidney’s perception Perception The process by which the nature and meaning of sensory stimuli are recognized and interpreted. Psychiatric Assessment of a hypovolemic state
  • Advanced renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome:
    • Water intake in excess of kidney’s impaired excretion capabilities
    • Only in very severe renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome (usually GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests < 15 mL/min)
    • Usually clinically obvious and not requiring comprehensive workup 

Management

General considerations

Acuity and severe symptoms are the primary determinants of this, and the aggressiveness and urgency of treatment will vary according to the risk assessment Risk assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. Preoperative Care.

Acuity:

  • Acute (< 48 hours):
    • Adaptive mechanisms have not yet occurred:
      • ↑ Risk for acute cerebral edema Cerebral edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries. An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive hydrocephalus). Increased Intracranial Pressure (ICP)
      • ↓ Risk for osmotic demyelination Demyelination Multiple Sclerosis syndrome (ODS) 
    • Hyponatremia should be corrected quickly (i.e., within 24 hours)
  • Chronic (> 48 hours):
    • Adaptive mechanisms have occurred:
      • ↑ Risk for ODS
      • ↓ Risk for acute cerebral edema Cerebral edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries. An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive hydrocephalus). Increased Intracranial Pressure (ICP)
    • Hyponatremia must be corrected slowly (i.e., < 6–8 mmol/L/day).
  • If unknown, then hyponatremia must always be assumed to be chronic!

Symptoms:

  • Severe:
    • Seizure, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure, severe altered mental status Altered Mental Status Sepsis in Children
    • Urgent treatment with 3% NaCl is indicated.
  • Nonsevere:
    • Mostly nonspecific symptoms (headache, nausea, fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, confusion)
    • Nonsevere cases usually do not need urgent treatment with 3% NaCl.

Specific risk factors for ODS:

  • Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease
  • Alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome
  • sNa+ < 105 mmol/L on presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor
  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia

Urgent therapy

Involves giving 3% NaCl ( hypertonic Hypertonic Solutions that have a greater osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation saline) in order to increase the sNa+ by 6 mmol/L within several hours. 

  • Absolute indications (symptoms from acute cerebral edema Cerebral edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries. An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive hydrocephalus). Increased Intracranial Pressure (ICP)):
  • Relative indications (↑ risk for progression to being overtly symptomatic):
    • Asymptomatic, known acute hyponatremia Acute Hyponatremia Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), regardless of severity of sNa+:
      • Primary polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus
      • Excessive postoperative hypotonic Hypotonic Solutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids
    • Known acute, mildly symptomatic, mild hyponatremia (sNa+ < 130) from any cause
    • Chronic, asymptomatic, severe hyponatremia (sNa+ < 120)
  • Management:
    • IV 3% NaCl, with frequent recheck of sNa+
    • Initial goal: ↑ sNa+ by 6 mmol/L within the first 6 hours
      • Should resolve any acute symptoms caused by hyponatremia
      • If symptoms persist, then investigate other etiologies.
    • After sNa+ ↑ by 6 mmol/L:
  • Monitoring:

Nonurgent therapy

  • Hyponatremia that does not require urgent therapy is almost exclusively chronic and usually asymptomatic or mildly symptomatic. 
  • Management decisions are guided by the severity of the sNa+ level, with wide variation in the clinician Clinician A physician, nurse practitioner, physician assistant, or another health professional who is directly involved in patient care and has a professional relationship with patients. Clinician–Patient Relationship’s preferences for aggressiveness of treatments.
  • Monitoring of sNa+ levels is indicated in all cases.

Severe (sNa+ < 125 mmol/L):

  • Requires admission
  • Hypervolemic:
    • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics ( furosemide Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for edema and chronic renal insufficiency. Loop Diuretics, bumetanide Bumetanide A sulfamyl diuretic. Loop Diuretics, torsemide Torsemide A pyridine and sulfonamide derivative that acts as a sodium-potassium chloride symporter inhibitor. It is used for the treatment of edema associated with congestive heart failure; chronic renal insufficiency; and liver diseases. It is also used for the management of hypertension. Loop Diuretics)
    • General measures: 
      • Oral fluid restriction, discontinue offending medications
      • Liberal salt diet not recommended (potential for worsening fluid overload)
  • Hypovolemic:
    • 3% or 0.9% NaCl ( clinician Clinician A physician, nurse practitioner, physician assistant, or another health professional who is directly involved in patient care and has a professional relationship with patients. Clinician–Patient Relationship‘s preference)
    • General measures: 
      • Oral fluid restriction, liberal salt diet, discontinue offending medications
      • Oral fluid restriction can be relaxed once sNa+ improves to > 125.
  • Euvolemic Euvolemic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): general measures
    • Oral fluid restriction, liberal salt diet, discontinue offending medications
    • Address any nonosmotic ADH stimuli ( pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, nausea, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).).

Moderate (sNa+ 125–130):

  • Clinician’s preference regarding admission decision
  • Hypervolemic:
    • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics 
    • General measures: 
      • Oral fluid restriction, discontinue offending medications.
      • Liberal salt diet not recommended (potential for worsening fluid overload)
  • Hypovolemic:
    • 0.9% NaCl until euvolemic
    • General measures: 
      • Oral fluid restriction, liberal salt diet, discontinue offending medications
      • Oral fluid restriction can be relaxed once sNa+ improves.
  • Euvolemic Euvolemic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): general measures
    • Oral fluid restriction, liberal salt diet, discontinue offending medications
    • Address any nonosmotic ADH stimuli ( pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, nausea, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder).

Mild (sNa+ > 130):

  • Rarely require admission
  • Hypervolemic:
    • Loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics 
    • General measures: 
      • Oral fluid restriction, discontinue offending medications
      • Liberal salt diet not recommended (potential for worsening fluid overload)
  • Hypovolemic:
    • 0.9% NaCl until euvolemic
    • General measures: 
      • Liberal salt diet, discontinue offending medications
      • Oral fluid restriction not necessary 
  • Euvolemic Euvolemic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): general measures only
    • Oral fluid restriction, liberal salt diet, discontinue offending medications
    • Address any nonosmotic ADH stimuli ( pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, nausea, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder).

Differential Diagnosis

  • Syndrome of inappropriate secretion Secretion Coagulation Studies of antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia ( SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)): an inappropriately high level of circulating ADH. Etiology includes medications, malignancies, lung disease, HIV HIV Anti-HIV Drugs, hypothyroidism, intracranial processes, and nonosmotic stimuli. Management is water restriction.
  • Other euvolemic hyponatremias: thiazide-induced hyponatremia, adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison’s Disease, and hypothyroidism are causes of euvolemic hyponatremia euvolemic hyponatremia Euvolemic hypernatremia is due to loss of water only. It is caused by conditions such as diabetes insipidus, lack of water access, or impaired thirst mechanism. Hypernatremia that have incompletely understood mechanisms. Such conditions can be diagnosed relatively easily (medication list review, cortisol Cortisol Glucocorticoids/ACTH stimulation test, and thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy-stimulating hormone (TSH)). If a condition is found, treating the underlying condition should correct the hyponatremia.
  • Osmotic demyelination Demyelination Multiple Sclerosis syndrome (ODS): characterized by irreversible neurologic symptoms, which can occur if sNa+ is corrected too quickly. Symptoms occur several days after the overcorrection Overcorrection Volume Depletion and Dehydration and are related to fluid shifts after the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification has already adapted to chronic hyponatremia Chronic Hyponatremia Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH). Diagnosis is by history and MRI. Management involves therapeutic lowering of the sNa+ and supportive care.
  • Hypertonic hyponatremia: low sNa+, but not managed as true hyponatremia because the sNa+ is discordant with the plasma osmolality Plasma osmolality Volume Depletion and Dehydration and tonicity Tonicity Plasma tonicity refers to the concentration of only the osmotically active solutes in blood Renal Sodium and Water Regulation. Examples are hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus and mannitol Mannitol A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. Osmotic Diuretics use. Water is drawn into the extracellular fluid Extracellular fluid The fluid of the body that is outside of cells. It is the external environment for the cells. Body Fluid Compartments (ECF) and results in a dilution of the sNa+, despite the plasma osmolality Plasma osmolality Volume Depletion and Dehydration remaining high from the glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance or mannitol Mannitol A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. Osmotic Diuretics
  • Hyponatremia in advanced renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome: when plasma osmolality Plasma osmolality Volume Depletion and Dehydration is high but the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products tonicity Tonicity Plasma tonicity refers to the concentration of only the osmotically active solutes in blood Renal Sodium and Water Regulation and sNa+ are low. Urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle is in high concentrations but is an ineffective osmole, so it causes no water shifts, dilution of the TBNa+, or decrease in the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products tonicity Tonicity Plasma tonicity refers to the concentration of only the osmotically active solutes in blood Renal Sodium and Water Regulation. Advanced renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome causes a decrease in water excretion, retention of water, increased TBW TBW Body Fluid Compartments, diluted TBNa+, and a true hypotonic Hypotonic Solutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation hyponatremia.
  • Pseudohyponatremia: occurs when a characteristic lab error Error Refers to any act of commission (doing something wrong) or omission (failing to do something right) that exposes patients to potentially hazardous situations. Disclosure of Information results in a low measured sNa+, despite the true sNa+ and true plasma osmolality Plasma osmolality Volume Depletion and Dehydration being within the normal range. High serum lipid (i.e., hypertriglyceridemia Hypertriglyceridemia A condition of elevated levels of triglycerides in the blood. Lipid Disorders associated with pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis, hypercholesterolemia Hypercholesterolemia A condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population. Lipid Disorders with biliary obstruction) or protein levels ( plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cell dyscrasias) result in inaccuracy in lab processing and falsely low reported sNa+.
  • Water intoxication: a true acute hyponatremia Acute Hyponatremia Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) that may have significant symptoms with a relatively small decrease in sNa+, which will require rapid correction of hyponatremia with 3% NaCl. Etiologies are psychogenic polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus, exercise-associated hyponatremia, fraternity hazing rituals, and MDMA MDMA An n-substituted amphetamine analog. It is a widely abused drug classified as a hallucinogen and causes marked, long-lasting changes in brain serotonergic systems. It is commonly referred to as mdma or ecstasy. Stimulants abuse. These patients must be monitored very closely.

References

  1. Emmett, M, et al. (2020). Hyponatremia following transurethral resection, hysteroscopy, or other procedures involving electrolyte-free irrigation. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/hyponatremia-following-transurethral-resection-hysteroscopy-or-other-procedures-involving-electrolyte-free-irrigation
  2. Sterns, RH. (2019). Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/pathophysiology-and-etiology-of-the-syndrome-of-inappropriate-antidiuretic-hormone-secretion-siadh
  3. Sterns, RH. (2020). Overview of the treatment of hyponatremia in adults. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-hyponatremia-in-adults
  4. Sterns, RH. (2020). Causes of hypotonic hyponatremia in adults. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/causes-of-hypotonic-hyponatremia-in-adults
  5. Sterns, RH. (2020). Diagnostic evaluation of adults with hyponatremia. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/diagnostic-evaluation-of-adults-with-hyponatremia

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