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
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)
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)
- 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
- 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)
- Urea-Related Osmotic Diuresis
Hypovolemic Hyponatremia with Extrarenal Sodium and Water Loss
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)
Hypervolemic Hyponatremia (Expanded Intracellular and Extracellular Fluid Volume + Decreased Effective Arteial Blood Volume
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]
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
- 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
Clinical Manifestations of Hyponatremia
General Comments
- Acute Hyponatremia is More Likely to Produce Symptoms than Chronic Hyponatremia
Gastrointestinal Manifestations
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)
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
- 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
- Chronic Hyponatremia: correct at 0.5 mEq/L/hr
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
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]