Hyponatremia

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

Hypovolemic Hyponatremia with Extrarenal Sodium and Water Loss

Euvolemic Hyponatremia (with Normal Extracellular Volume and No Edema)

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

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

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

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


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]