Hyponatremia

Definition

• Serum sodium <135 mEq/L (135 mmol/L)
  • Mild: Na 130-135 mEq/L
  • Moderate: Na 125-129 mEq/L
  • Severe: Na <125 mEq/L

Causes of hypotonic (hypoosmotic) hyponatremia

Hypovolemic hypotonic hyponatremia

• Net loss of sodium in excess of net loss of free water
• Usually due to the administration of hypotonic fluid in the setting of fluid losses
  • Hypovolemia stimulates the release of antidiuretic hormone (ADH, AKA arginine vasopressin or AVP) regardless of the serum osmolality, leading to the retention of water and potentially leading to hyponatremia
    • RAAS is also stimulated in hypovolemia and aldosterone stimulates sodium reabsorption, so if sufficient sodium is given with the fluids it
    • Distinguished from SIADH because while the retention of free water is driven by ADH, this is an “appropriate” response to hypovolemia
      • RAAS is not stimulated in SIADH will help prevent hyponatremia
  • Conditions associated with increased fluid losses:
    • Polyuria
    • Gastroenteritis
      • Secretory or osmotic diarrhea
    • Nasogastric suction
      • Drains/fistulas/ostomies
    • Skin (burns)
    • Respiratory
• Diuretics
  • More common with thiazide diuretics than loop diuretics, as loop diuretics impair the medullary concentrating ability
  • Thiazide diuretics enhance water reabsorption (independent of ADH) and can lead to the production of urine with sodium greater than that of plasma, thereby causing hyponatremia independent of water intake
    • Typically associated with alkalosis, azotemia, hypokalemia, hyperuricemia
• Less commonly due to salt wasting, which is also associated with hypovolemia
  • Mineralocorticoid deficiency
    • 21-hydroxylase deficiency, hypoaldosteronism (Addison disease)
  • Cerebral salt wasting (extremely rare)
• Non-kidney (extrarenal) losses
  • Diarrhea, especially if secretory
  • Vomiting
  • Skin (burns, sweating)
  • Third-spacing (e.g., ascites)
  • Hemorrhage
  • Intense exercise

Euvolemic (isovolemic) hypotonic hyponatremia

• Increased ADH states
  • These conditions are exacerbated by high water intake
  • Primary SIADH
    • Nephrogenic syndrome of inappropriate diuresis (rare)
  • Hospitalization
  • Respiratory illness
    • Pneumonia
    • Bronchiolitis
    • Mechanical ventilation
  • Recent surgery
  • Pain
    • E.g., marathon runners (also constantly encouraged to drink)
  • CNS injury/infection
  • Medications/drugs
    • E.g., SSRIs, MDMA (Molly/ecstasy)
  • Hypothyroidism
  • Adrenal insufficiency (hypoadrenalism, cortisol deficiency)
    • Classically associated with hypoglycemia, hyperkalemia, and hypotension/severe illness (inadequate vascular tone)
• Reset osmostat (rare)
• Exercise-associated hyponatremia
• Water intoxication
  • Primary polydipsia (psychogenic polydipsia)
  • Forced water drinking (e.g., hazing rituals)
  • Inability to excrete free water in urine due to very low dietary solute (e.g., “tea and toast” syndrome)
    • Dietary carbohydrates are metabolized to CO2 and H2O which do not contribute to solute load
    • Water excretion requires solute (Na, K, urea), at least 50-100 mOsm per liter of urine, so a very low solute load limits the ability of the kidney to excrete water
    • Presents with maximally dilute urine

Hypervolemic hypotonic hyponatremia

• Decreased effective circulating volume
  • ↓ kidney perfusion → ⊕ RAAS → ↑ ADH (via angiotensin II) → ↑ water retention
  • Cirrhosis, heart failure, nephrotic syndrome
• Kidney failure
  • ↓ GFR → impaired free water excretion

Signs and symptoms

• Muscle weakness, gait disturbance
• Malaise, fatigue
• Headache
• Encephalopathy: lethargy, confusion, coma
• Ataxia
• Seizures
• Postmenarchal females more likely to have neurological sequelae
  • Estrogen upregulates ADH and ↑ ADH secretion
  • Estrogens also ↓ brain cell Na-K-ATPase → ↓ Na pumped out of cells → ↑ brain edema

Evaluation

• Serum osmolality to confirm “true” hypotonic hyponatremia

Low osmolality = true hypotonic hyponatremia

Normal osmolality = isotonic hyponatremia

• Pseudohyponatremia or artifactual hyponatremia
  • Lab artifact caused by increased fraction of solids in the plasma compartment (e.g., hyperlipidemia, hyperproteinemia)
    • Can have transient hyperproteinemia from IVIG infusion
    • If caused by hyperlipidemia, the patient’s blood will likely be lipemic
  • Increased fraction of solids in plasma makes it appear that the sodium content is contained in a larger fluid volume, causing the measurement to be more dilute even though the concentration of sodium in the plasma may be normal
    • Affects indirect ion-selective electrodes (ISE, as is typically used in main laboratory analyzers) [PMID 37373769]
      • Plasma Na is low by indirect potentiometry and normal by direct potentiometry
  • Plasma osmolality is measured as normal but calculates as low (i.e., there is an osmolal gap)
• Iso-osmolar irrigation solutions (e.g., mannitol, sorbitol) are not routinely used in pediatric procedures but can cause a true hyponatremia with normal plasma osmolality
  • Osmolal gap is present but plasma Na measures low by both indirect and direct potentiometry

High osmolality = hypertonic hyponatremia

• Sodium is displaced out of the plasma by the presence of other effective osmoles (e.g., hyperglycemia, ethylene glycol ingestion)
  • While the sodium is actually low (and not merely measured as low, as with pseudohyponatremia), the hyponatremia is not clinically significant as the negative clinical effects of hyponatremia are due to the associated decreased serum osmolality rather than the hyponatremia per se
• Causes:
  • Hyperglycemia
    • Glucose is usually a minor serum osmole as it is rapidly transported into cells, but in some circumstances (e.g., diabetes, insulin resistant states) it can have a more significant impact on serum osmolality
  • Hypertonic mannitol
  • Hypertonic sucrose or hypertonic maltose in IVIG
• Assess volume status
  • Consider aldosterone, cortisol, ADH (copeptin proAVP), ACTH, free T4 and TSH
• Urine sodium
  • In SIADH, the urine sodium is not low, as the ADH is inappropriately increased and is not an appropriately high ADH in response to a kidney-perceived volume deficit (e.g., cirrhosis, heart failure)
• Uric acid
  • Typically low in SIADH

Treatment

• Depends upon the cause, chronicity, and clinical status of the patient
  • Rapid overcorrection, particularly in chronic (≥48 hours) hyponatremia, can cause osmotic demyelination syndrome (ODS)
    • This is not a concern in acute hyponatremia as the brain has not yet adapted

Acute hyponatremia with severe symptoms

• Can be difficult to know with confidence that it is acute (<48 hours)
• Severe symptoms include seizures, loss of consciousness, lethargy, coma
• Assess for other possible causes of symptoms such as intoxication, drug ingestion, or trauma
  • Exercise caution if alternative explanations for symptoms may be present, as this will cloud the assessment of treatment response
• Treat with 3% (hypertonic) saline until symptoms resolve or serum Na has increased by >5 mEq/L
  • Dose: 2-3 mL/kg over 20 minutes, x1-3 doses
    • 1 mL/kg of 3% NaCl will increase the plasma sodium by about 1 mEq/L
      • 3% NaCl = 512 mEq/L = 0.5 mEq/mL
• Once severe symptoms have resolved, proceed with more gradual correction of hyponatremia

Avoiding overcorrection

• If the patient’s ADH corrects and they begin to have significant water diuresis, they may self correct at an unsafe rate
• Can use DDAVP and D5W as urine output replacement to stop and reverse overcorrection [PMID 18235152]
• Alternatively, use DDAVP and 3% NaCl from the beginning of treatment to proactively control the rate of correction [PMID 20709440]

Restore intravascular volume if necessary

• Hyponatremia in children is typically associated with hypovolemia, in which cause there is a need to restore both water and electrolyte status
  • If clinically significant hypovolemia present, fluid resuscitation is the next priority
    • Bolus with 20-60 mL/kg of 0.9% (normal) saline

Correcting hypovolemic hyponatremia

• Sodium deficit (in mEq) = Current total body water (TBW, in L) x (desired change in plasma Na)
  • See: kidney.wiki TBW calculator
    • Alternatively, crude estimate of TBW = 600 mL/kg (0.6 L/kg)
  • Desired change in plasma Na = (desired Na) - (current Na)
• Replace with IVF, target rate usually 8-10 mEq/L per 24 hours
  • Do not want to increase serum Na by more than 0.5 mEq/L/hour

Euvolemic hyponatremia (SIADH)

• Fluid restriction
  • 2x insensible losses (400 mL/m²/day)
    • See: kidney.wiki BSA calculator
• Increasing solute load may allow for more liberal fluid restriction
  • Salt supplementation
  • Urea supplementation
    • UreaAide, ure-Na
• Furosemide (Lasix)
  • May be more effective when combined with sodium supplementation

Complications

Osmotic demyelination syndrome (ODS)

• Includes central pontine myelinolysis and extrapontine myelinolysis
• Rare in children
• Can be fatal or cause debilitating neurological defects
• Most commonly caused by hyponatremia
  • Other comorbidities in adults include long-term alcohol abuse, malnutrition, liver transplantation
  • Severe hypokalemia in the ICU is also a risk factor for ODS
• Higher risk in patients with chronic (>48 hours) hyponatremia who have rapid correction
  • Acute hyponatremia causes brain cells to increase in size temporarily as water moves into the cell
  • Compensatory mechanisms export osmoles out of the cells along with water to normalize the cell volume, equalizing the osmotic gradient between intra- and extracellular space
    • Osmoles include osmolytes, osmotically-active organic substances (e.g., myo-inositol, taurine, glutamine, glutamate, etc.) and inorganic ions (e.g., potassium, chloride)
  • With rapid correction, brain cells respond to the osmotic stress of the hypertonic milieu by contracting, and apoptosis begins

Presentation

• Rapid correction precedes symptoms by 1-14 days (typically 2-4 days)
• Highly variable, may be asymptomatic but can cause encephalopathy, quadriparesis, speech disturbances, locked-in syndrome, chorea, dystonia, gait disturbances