Hyponatremia

Background

• Decrease in serum sodium concentration, often reflecting an increase in total free water
• May be mild (130-135 mmol/L), moderate (125-129 mmol/L), or severe (<125 mmol/L)
• May be acute (onset within 48 hours) or chronic (onset greater than 48 hours), or unknown (usually presumed chronic)

Etiologies

• Pseudohyponatremia from lab error, related to high lipids or proteins
• Isotonic or translocational hyponatremia from mannitol, glycine,hyperglycemia
• Medications: thiazide and thiazide-type diuretics, mannitol, IVIG, desmopressin (dDAVP), ecstasy (methylenedioxymethamphetamine), and some antidepressants, antiepileptics, and antipsychotics

By Volume Status

• Hypovolemic
  • U_Na >20: Renal losses, including mineralocorticoid deficiency
  • U_Na <10: Non-renal losses
• Euvolemic
  • U_osm >100: SIADH, hypothyroidism, glucocorticoid deficiency
  • U_osm <100: Primary polydipsia, low solute intake
  • U_osm variable: Reset osmostat
• Hypervolemic
  • U_Na <10: CHD, cirrhosis, nephrosis
  • U_Na >20: Renal failure

By Acuity

• Acute (less than 48 hours): postoperative, post-prostate resection, post-endoscopic uterine surgery, polydipsia, exercise, recent thiazide start, MDMA/Ecstasy, colonoscopy prep, cyclophosphamide (IV), oxytocin, recent desmopressin/terlipressin/vasopressin

Pathophysiology

• Depends on cause, but many act through the activation of water retention but activating baroreceptor-mediated vasopressin release from the pituitary
• Hypovolemic
  • Non-renal sodium loss:
    • Severe diarrhea: kidneys attempt to retain sodium
    • Vomiting: metabolic alkalosis causes renal sodium loss, accompanied by chloride and ammonium
    • Skin losses (sweating, cystic fibrosis, extensive burns)
  • Renal sodium loss:
    • Diuretics: volume depletion leading to vasopressin release, or direct induction of vasopressin
    • Primary adrenal insufficiency: hypoaldosteronism leading to renal sodium loss
    • Cerebral salt wasting (SAH)
    • Intrinsic kidney dysfunction: tubulopathy after chemotherapy, analgesic nephropathy, medullary cystic kidney disease, some drugs
  • Third-spacing (bowel obstruction, pancreatitis, sepsis, muscle trauma): decreases effective circulating volume causing vasopressin release
    • May be worsened by infusion of hypotonic fluids
• Euvolemic
  • SIADH (multiple causes, including GA, nausea, pain, stress, and many drugs): vasopressin secreted inappropriately from pituitary or ectopic production
  • Secondary adrenal insufficiency: decreased ACTH leads to hypocortisolism, leading to vasopressin release; aldosterone production less impaired than primary AI
  • Hypothyroidism: rare and mild cause, with approximately 0.14 mmol/L decrease in S_Na for every 10 mU/L increase in TSH
  • High water and low solute intake ("tea and toast", beer potomania, anorexia nervosa): not enough solute for the kidneys to be able to excrete the amount of water needed
• Hypervolemic
  • Intrinsic kidney dysfunction (CKD, tubular injury): kidney loses the ability to dilute urine (i.e. excrete free water)
  • Heart failure: effective circulating volume decreases, leading to vasopression secretion and activation of RAS system
  • Liver failure: decreased effective circulating volume, leading to vasopressin release
  • Nephrotic syndrome: decreased serum oncotic pressure leading to decrease blood volume and secretion of vasopressin

Clinical Manifestations

• Depends on acuity and severity
• Mild, chronic symptoms can include gait abnormalities, increased falls, and cognitive deficits
• Moderately symptomatic: nausea, confusion, headache
• Severely symptomatic: vomiting, cardiorespiratory distress, abnormal deep sleep, seizures, and coma

Investigations

• Serum and urine sodium, and serum and urine osmolality (prior to treatment)
• TSH and AM cortisol
• Glucose: accounts for 2.4 mmol/L of urine for every 5.5 mmol of glucose above baseline of 5.5 (i.e. adjust by 2.4 x (glucose - 5.5)/5.5)

Diagnosis by Lab Criteria

• Measure serum osmolality (S_osm) and urea level (S_urea)
• S_osm ≥ 280: normotonic/hypertonic
  • Differential includes pseudohyponatremia (from hyperlipidemia, hyperparaproteinemia, etc.), or presence of osmotically active substances (glucose, mannitol, glycine)
• S_osm <280 mOsm/kg: true hyponatremia
  • Measure urine osmolality (U_osm)
  • U_osm <100 mOsm/kg: normal water excretion with maximally dilute urine
    • Primary polydipsia, reset osmostat syndrome, beer potomania, low solute intake
  • U_osm ≥ 100 mOsm/kg: impaired water excretion
    • Exclude hypothyroidism and adrenal insufficiency with morning cortisol and TSH
    • Measure urine sodium (U_Na)
    • U_Na < 20-30 mmol/L: hypovolemia (diarrhea, vomiting, third-spacing, remote diuretics), and other causes of low effective circulating volume (heart failure, cirrhosis, nephrotic syndrome)
    • U_Na > 30-40 mmol/L: diuretics, kidney disease, euvolemic (SIADH, reset osmostat, secondary adrenal insufficiency, hypothyroidism, occult diuretics), and hypovolemic (renal salt wasting, diuretics, vomiting, primary adrenal insufficiency, cerebral salt wasting, occult diuretics)
      • Salt supplementation and water restriction
      • Normal S_urate and reduced FE_urate: SIADH
      • Hypouricemia and unchanged FE_urate: renal salt wasting
    • U_Na between 20 and 40 mmol/L
      • Bolus 2 L/day normal saline for 2 days and trend sodium
      • If S_Na increases by ≥ 5 mmol/L: hypovolemia
      • If S_Na increases by <5 mmol/L: SIADH or reset osmostat
        • FE_urea >55%, S_urate <0.24, and FE_urate >10%: SIADH
        • Oral or IV water-loading test: reset osmostat

Management

• Depends on cause
  • Hypovolemic: fluid resuscitation
  • Euvolemic: fluid restriction
  • Hypervolemic: fluid restriction and/or diuretics
• Goal rate of correction in chronic hyponatremia should be 4 to 6 mEq/L in 24 hours (max of 8 mEq) in order to reduce the risk of osmotic demyelination syndrome

Severe Symptoms

• For patients with hyponatremia with severe symptoms (coma, seizure); not used for any other patients
• Monitored setting
• Start hypertonic saline 3% 150 mL IV bolus over 20 minutes
• Then check serum sodium after 20 minutes, while repeating the infusion
• Repeat process twice or until increase of 5 mmol/L, then stop

Further Reading

• Milionis HJ, Liamis GL, and Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166(8):1056-1062.