Epidemiology

• Frequency: more common in hospitalized patients
• Frequency in Hospitalized Adults
  • Incidence: 0.97% of hospitalized adults
  • Prevalence: 2.48% of hospitalized adults
• Frequency in Elderly
  • Hyponatremia occurs in 7% of healthy elderly
  • Hyponatremia occurs in 15% of elderly in chronic care facilities

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Physiology of Serum Sodium

Definition of Hyponatremia

• Definition of Hyponatremia: serum sodium <135 mEq/L

Composition of Serum

• Serum Water: accounts for 93% of the serum volume
  • Serum sodium is restricted to the serum water fraction
• Nonaqueous Components: accounts for 7% of the serum volume
  • Nonaqueous components are mainly lipids and proteins

Definition of Serum Osmolality and Tonicity

• Serum Tonicity: serum tonicity reflects the concentrations of solutes which do not easily cross cell membranes (mostly sodium salts, glucose to some extent) -> this affects the movement of water between cells and extracellular fluid
  • Water Freely Crosses All Cell Membranes: moves from area of lower tonicity (higher water content) to area of higher tonicity (lower water content)
  • Serum Tonicity is Detected by Osmoreceptors and it Determines the Transcellular Distribution of Water
• Serum Osmolality: in contrast, in addition to the solutes noted which do not cross cell membranes, serum osmolality also includes the contributions of urea/ethanol/other alcohols/glycols, which are considered “ineffective osmoles” (since they equilibrate across membranes and have litter effect on water movement)

Physiologic Changes Associated with Acute Hyponatremia

• Symptoms Attributable to Acute Hyponatremia Occur Mainly Due to Neurologic Dysfunction Associated with Cerebral Edema and the Adaptive Responses of Brain Cells to Osmotic Swelling
  • Decreased Serum Osmolality Results in an Osmolal Gradient Which Favors the Movement of Water into Brain Cells, Culminating in Brain Edema
  • Hyponatremia-Induced Cerebral Edema Occurs Primarily with a Rapid Decrease in Serum Sodium Concentration (Over Usually <24 hrs)
  • Hyponatremia is Almost Always Associated with a Decrease in Plasma Osmolality: however, there are disorders in which hyponatremia may occur in association with normal-high serum osmolality
    • Example: 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
    • Example: Hyperglycemia (in Uncontrolled Diabetes Mellitus) Presents with Elevated Serum Osmolality, Since Glucose is an Effective Osmole Which Does Not Freely Enter Cells (In Contrast to Urea)

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Etiology of Hyponatremia

Pseudohyponatremia

• Hyperglycemia (see Hyperglycemia, Hyperglycemia)
  • Mechanism: presence of osmotically active solute
• Hyperlipidemia (see Hyperlipidemia, Hyperlipidemia): increased mass of the nonaqueous lipid component of serum and a concomitant decrease in the proportion of water component (note: sodium is restricted to the serum water component)
• Hyperproteinemia (see Hyperproteinemia, Hyperproteinemia): increased mass of the nonaqueous protein component of serum and a concomitant decrease in the proportion of water component (note: sodium is restricted to the serum water component)
• Intravenous Mannitol (for Treatment of Increased Intracranial Pressure) (see Mannitol, Mannitol)
  • Mechanism: presence of osmotically active solute
  • Check serum osmolality
• Intravesical Mannitol (During Trans-Urethral Resection of the Prostate, TURP) (see Mannitol, Mannitol)
  • Mechanism: presence of osmotically active solute
  • Check serum osmolality

Hypovolemic Hyponatremia with Renal Sodium and Water Loss

• Cerebral Salt Wasting (see Cerebral Salt Wasting, Cerebral Salt Wasting): likely mediated by brain natriuretic peptide and ouabain-like peptide -> leads to increased urine sodium (>25 mmol/L), high urine osmolarity, polyuria, and clinical hypovolemia (the aspect of clinical hypovolemia distinguishes it from SIADH)
  • Brain Tumor
  • Traumatic Brain Injury (TBI) (see Traumatic Brain Injury, Traumatic Brain Injury)
  • Intracerebral Hemorrhage (see Intracerebral Hemorrhage, Intracerebral Hemorrhage)
  • Subarachnoid Hemorrhage (SAH) see Subarachnoid Hemorrhage, Subarachnoid Hemorrhage)
  • Other Neurologic Disorders
• Diuretic Phase of Acute Tubular Necrosis (ATN) (see Acute Kidney Injury, Acute Kidney Injury)
• Diuretics
  • Bumetanide (Bumex) (see Bumetanide, Bumetanide): less common cause of hyponatremia than thiazides
  • Furosemide (Lasix) (see Furosemide, Furosemide): less common cause of hyponatremia than thiazides
  • Hydrochlorothiazide (HCTZ) (see Hydrochlorothiazide, Hydrochlorothiazide): most common class of diuretic associated with hyponatremia
    • Risk Factors
      • Hypokalemia
      • Institutionalized Elderly Patient
      • Low Body Weight
      • Indapamide Administration
    • Probable Mechanism: hypovolemia-stimulated ADH release and interference with urinary dilution in cortical diluting segment
  • Spironolactone (Aldactone) (see Spironolactone, Spironolactone): less common cause of hyponatremia than thiazides
• Glucosuria (Glycosuria)-Related Osmotic Diuresis
• Mineralocorticoid Deficiency: may be associated with hyperkalemia
  • Adrenal Insufficiency (Addison’s Disease) (see Adrenal Insufficiency, Adrenal Insufficiency): note that hyperkalemia is absent in 33% of patients with Addison’s disease
  • Hypoaldosteronism (see Hypoaldosteronism, Hypoaldosteronism)
• Post-Obstructive Diuresis (see Acute Kidney Injury, Acute Kidney Injury)
• Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, Chronic Kidney Disease)
• Salt-Wasting Nephropathy (see Salt-Wasting Nephropathy, Salt-Wasting Nephropathy)
  • Advanced Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, Chronic Kidney Disease)
  • Analgesic Nephropathy
  • Medullary Cystic Disease
  • Obstructive Uropathy
  • Polycystic Kidney Disease (PCKD) (see Polycystic Kidney Disease, Polycystic Kidney Disease)
  • Type 2 Proximal Renal Tubular Acidosis (RTA) with Mild Renal Insufficiency (see Type 2 Proximal Renal Tubular Acidosis, Type 2 Proximal Renal Tubular Acidosis)
• Urea-Related Osmotic Diuresis

Hypovolemic Hyponatremia with Extrarenal Sodium and Water Loss

• Acute Pancreatitis (see Acute Pancreatitis, Acute Pancreatitis)
• Ascites (see Ascites, Ascites)
• Hemorrhage
• Burns (see Burns, Burns)
• Gastrointestinal Fluid Loss
  • Bowel Preparation: pre-operative/pre-procedural bowel preparation with sodium picosulfate solutions may result in dehydration and hyponatremia (due to gastrointestinal sodium and water loss)
  • Diarrhea (see Diarrhea, Diarrhea)
• Peritonitis (see Peritonitis, Peritonitis)
• Sweating (see Diaphoresis, Diaphoresis)

Euvolemic Hyponatremia (with Normal Extracellular Volume and No Edema)

• Acute Intermittent Porphyria (see Acute Intermittent Porphyria, Acute Intermittent Porphyria)
• Acute Kidney Injury (AKI) (see Acute Kidney Injury, Acute Kidney Injury)
• Adrenal Insufficiency (Addison’s) (see Adrenal Insufficiency, Adrenal Insufficiency): although typically hypovolemic, may be euvolemic in some cases
• Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, Chronic Kidney Disease)
• Decreased Sodium Intake
  • Beer Potomania
  • Tea and Toast Diet
• Guillain-Barre Syndrome (GBS) (see Guillain-Barre Syndrome, Guillain-Barre Syndrome)
• Hypothyroidism (see Hypothyroidism, Hypothyroidism)
• Hypotonic Intravenous Fluid Administration: particularly with D5W
• Marathon-Induced Hyponatremia: due to excessive water intake combined with sodium loss
• Psychogenic Polydipsia (see Polydipsia, Polydipsia): high-volume water intake overtasks the renal diluting mechanism
  • Unclear etology of such compulsive water intake (proposed mechanisms include hyperactivity of the hypothalamic thirst center, neuroleptic drugs, and resetting of the hypothalamic osmostat)
• Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (see Syndrome of Inappropriate Antidiuretic Hormone Secretion, Syndrome of Inappropriate Antidiuretic Hormone Secretion)
  • Mechanism: excessive ADH release produces renal water reabsorption, and the body’s intracellular and extracellular fluid compartments are expanded, resulting in hyponatramia
• Temporary Impairment of Water Diuresis (with ADH Secretion)
  • Emotion
  • Opiates (see Opiates, Opiates)
  • Pain

Hypervolemic Hyponatremia (Expanded Intracellular and Extracellular Fluid Volume + Decreased Effective Arteial Blood Volume

• Acute Kidney Injury (AKI) (see Acute Kidney Injury, Acute Kidney Injury)
• Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, Chronic Kidney Disease)
• Cirrhosis/End-Stage Liver Disease (ESLD) (see Cirrhosis, Cirrhosis)
• Congestive Heart Failure (CHF) (see Congestive Heart Failure, Congestive Heart Failure)
• Nephrotic Syndrome (see Nephrotic Syndrome, Nephrotic Syndrome)

Post-Operative Hyponatremia

• Etiologic Factors
  • Administration of Hypotonic Intravenous Fluid (IVF) During Surgery
  • Increased Secretion of Arginine Vasopressin (ADH) (due to pain/drugs/nausea/stress/low circulating blood volume) -> water retention
  • Excessive Intravenous Fluid (IVF) Administration -> increased circulating blood volume and overexpansion of ECF volume -> increased volume of hypertonic urine (sodium loss)

Other

• Vasopressin Administration in Septic Shock (see Vasopressin, Vasopressin): case reports of hyponatremia have been described
  • Mechanism: low serum osmolality was present in the described cases, suggesting either hypovolemia or an SIADH-type mechanism [MEDLINE]

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Diagnosis of Hyponatremia

Serum Sodium

• Laboratory Serum Sodium Measurement Technology
  • Flame Photometry Assay of Serum Sodium: measures sodium concentration in whole plasma
    • In the presence of hyperproteinemia or hyperlipidemia (with expansion of nonaqueous component of the serum), pseudohyponatremia may be seen with this assay method
  • Sodium-Selective Electrode Assay of Sodium: measures sodium activity in serum water -> this assay gives the true, physiologically relevant sodium concentration as it measures sodium activity in serum water alone
    • Indirect Potentiometry: current assay used in many hospital laboratories
    • Direct Potentiometry

Serum Osmolality (see Serum Osmolality, Serum Osmolality)

• Normal Serum Osmolality: 275-290 mosmol/kg
• Measurement is Useful in Specific Scenarios: when isotonic/hypertonic hyponatremia are suspected
  • Recent Transurethral Prostate Surgery/Laparoscopy/Hysteroscopy: due to potential use of glycine/sorbitol/mannitol irrigant
  • Recent Use of Mannitol (see Mannitol, Mannitol)
  • Recent Use of Glycerol (see Glycerol, Glycerol)
  • Recent Use Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin, Intravenous Immunoglobulin): IVIG is usually suspended in hypertonic mannitol, maltose, or sucrose
  • Presence of Lipemic Serum
  • Presence of Obstructive Jaundice
  • Known/Suspected Plasma Cell Dyscrasia

Urine Sodium + Urine Osmolarity

• Beer Potomania: low urine osm
• Cerebral Salt Wasting: high urine sodium (>25 mmol/L) + high urine osm
  • Laboratory criteria resemble that of SIADH, except that patient has clinical hypovolemia
• Diuretics: high urine sodium (due to the natriuretic effect of diuretics)
• Gastrointestinal Sodium and Water Loss: low urine sodium (due to avid renal sodium retention) + xxxx urine osm
• SIADH: low serum osmolarity (<270 mosm/l) and inappropriately high urine osmolarity of >100 mosm/kg in a euvolemic patient in whom hypopituitarism, hypoadrenalism, hypothyroidism, renal insufficiency, and diuretic use have been excluded

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Clinical Manifestations of Hyponatremia

General Comments

• Acute Hyponatremia is More Likely to Produce Symptoms than Chronic Hyponatremia

Gastrointestinal Manifestations

• Nausea/Vomiting (see Nausea and Vomiting, Nausea and Vomiting)
  • Nausea is an Early Finding: occurs when serum sodium falls below 125-130 mEq/L

Neurologic Manifestations

• Confusion/Delirium (see Delirium, Delirium)
• Ataxia/Gait Disturbance (see Ataxia, Ataxia): may occur in chronic hyponatremia
  • Increased Fall Risk with Increased Risk of Fractures: observed in elderly patients with hyponatremia
• Headache (see Headache, Headache): occurs when serum sodium falls below 115-120 mEq/L
• Malaise: early finding (occurs when serum sodium falls below 125-130 mEq/L)
• Myalgias/Muscle Cramps (see Myalgias, Myalgias): may occur with chronic hyponatremia
• Obtundation/Coma (see Obtundation-Coma, Obtundation-Coma): lethargy/obtundation/coma occur when serum sodium falls below 115-120 mEq/L
  • Acute Hyponatremic Encephalopathy is Generally Reversible: however, permanent neurologic damage may occur, particularly in premenopausal women
• Seizures (see Seizures, Seizures): occur when serum sodium falls below 115-120 mEq/L

Pulmonary Manifestations

• Non-Cardiogenic Pulmonary Edema: may occur in some cases when serum sodium falls below 115-120 mEq/L
• Respiratory Arrest (see Acute Hypoventilation, Acute Hypoventilation): occurs when serum sodium falls below 115-120 mEq/L

Rheumatologic Manifestations

• Increased Fall Risk with Increased Risk of Fractures: observed in elderly patients with hyponatremia
• Increased Risk of Osteoporosis (see Osteoporosis, Osteoporosis): may be seen in chronic hyponatremia (due to loss of bone sodium)

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Treatment of Hyponatremia

General Comments

• Clinical Efficacy
  • Correction of Hyponatremia is Associated with Decreased Mortality (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

Hypovolemic Hyponatremia

• Lactated Ringers (LR) (see Lactated Ringers, Lactated Ringers): contains 130 mEq Na/L
• Normal Saline (NS) (see Normal Saline, Normal Saline): contains 154 mEq Na/L
• Hypertonic Saline (3%) (see Hypertonic Saline, Hypertonic Saline): contains 512 mEq Na/L
  • Indications: severe hyponatremia with significant neurologic deficits or seizures
  • Approximate Infusion Rate: desired rate of correction per hr (ex: 1 mEq/L/hr) x lean BW (in kg)

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

• Demeclocycline (see Demeclocycline, Demeclocycline): 300 mg PO BID
• Normal Saline (NS) (see Normal Saline, Normal Saline): however, normal saline may worsen hyponatremia in the setting of SIADH
• Hypertonic Saline (3%) (see Hypertonic Saline, Hypertonic Saline):contains 512 mEq Na/L
  • Indications: severe hyponatremia with significant neurologic deficits or seizures
  • Approximate Infusion Rate: desired rate of correction per hr (ex: 1 mEq/L/hr) x lean BW (in kg)
• Vasopressin Receptor Antagonists
  • Conivaptan (Vaprisol) (see Conivaptan, Conivaptan): V1a/V2 vasopressin receptor antagonist -> aquaretic (water loss)
  • Tolvaptan (Samsca) (see Tolvaptan, Tolvaptan): V2 vasopressin receptor antagonist -> aquaretic (water loss)

Hypervolemic Hyponatremia

• Vasopressin Receptor Antagonists
  • Conivaptan (Vaprisol) (see Conivaptan, Conivaptan): V1a/V2 vasopressin receptor antagonist -> aquaretic (water loss)
  • Tolvaptan (Samsca) (see Tolvaptan, Tolvaptan): V2 vasopressin receptor antagonist -> aquaretic (water loss)

Post-Operative Hyponatremia

• Avoid Peri-Operative Hypotonic Intravenous Fluids and Excessive Intravenous Fluid Administration
• Treat Pain
• Vasopressin Receptor Antagonists
  • Conivaptan (Vaprisol) (see Conivaptan, Conivaptan): V1a/V2 vasopressin receptor antagonist -> aquaretic (water loss)
  • Tolvaptan (Samsca) (see Tolvaptan, Tolvaptan): V2 vasopressin receptor antagonist -> aquaretic (water loss)

Rate of Hyponatremia Correction

• General Comments: during correction of hyponatremia, the reuptake of brain solutes occurs more slowly than the loss of brain solutes during the onset of hyponatremia
• Acute Hyponatremia: correct at 1 mEq/L/hr
  • Since Patients with Acute Hyponatremia Have Cerebral Edema, the Treatment of Cerebral Edema Probably Outweighs the Risk of Central Pontine Myelinolysis (CPM) (see Central Pontine Myelinolysis, Central Pontine Myelinolysis)
• Chronic Hyponatremia: correct at 0.5 mEq/L/hr
  • Risk Factors Which Increase Risk of Central Pontine Myelinolysis (see Central Pontine Myelinolysis, Central Pontine Myelinolysis)
    • Burns (see Burns, Burns)
    • Hypokalemia (see Hypokalemia, Hypokalemia)
    • Cirrhosis/End-Stage Liver Disease (see Cirrhosis, Cirrhosis)
    • Malnutrition (see Malnutrition, Malnutrition)
  • Protective Factors Which Decrease Risk of Central Pontine Myelinolysis
    • Elevated Blood Urea Nitrogen (BUN) in the Setting of Renal Failure

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Prognosis

• Hyponatremia Increases 30-Day and 1-Year Mortality Rates (Independent of Underlying Disease) in Internal Medicine Inpatients (Eur J Endocrinol, 2015) [MEDLINE]
• Pre-Operative Hyponatremia Increases Multiple Peri-Operative Surgical Risks (Arch Int Med, 2012) [MEDLINE]:
  • Increases Post-Operative 30-Day Mortality Rate (5.2% vs 1.3%): especially in patients undergoing non-emergency surgery and ASA class 1-2
  • Increases Rate of Peri-Operative Coronary Events
  • Increases Wound Infection Rates
  • Increases Pneumonia Rates
  • Prolongs the Median Length of Stay: by approximately 1 day

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References

• The management of hyponatremic emergencies. Crit Care Clin 1991; 7:127-42
• New approach to disturbances in the plasma sodium concentration. Am J Med 1986; 81:1033
• Common fluid-electrolyte and acid-base problems in the intensive care unit: selected issues. Semin Nephrol 1994; 14:8-22
• Tolvaptan, a selective vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099-2112
• Pseudohyponatremia: does it matter in current clinical practice? Electrolyte Blood Press. 2006 Nov;4(2):77-82. doi: 10.5049/EBP.2006.4.2.77 [MEDLINE]
• Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST Outcome Trial. JAMA 2007;297:1319-1331
• Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 2007;27:447-457
• Hyponatraemia in clinical practice. Postgrad Med J. Jun 2007; 83(980): 373–378. doi: 10.1136/pgmj.2006.056515 [MEDLINE]
• Preoperative hyponatremia and perioperative complications. Arch Intern Med. 2012 Oct 22;172(19):1474-81. doi: 10.1001/archinternmed.2012.3992 [MEDLINE]
• Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature Review. J Intensive Care Med. 2015 Jul;30(5):253-8. doi: 10.1177/0885066613507410. Epub 2013 Oct 7 [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]
• Disorders of plasma sodium–causes, consequences, and correction. N Engl J Med. 2015 Jan;372(1):55-65 [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]