Hyponatremia

Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. The basic pathophysiology of all etiologies of hyponatremia is an abnormal increase in total body water (TBW), which dilutes the total body sodium (TBNa+) concentration. The clinical presentation varies greatly, from asymptomatic to subtle cognitive deficits, seizures, and death. Management is guided by etiology, acuity, and duration of symptoms, usually involving oral fluid restriction or administration of IV fluids that contain Na. Sodium must be replaced slowly, as overly rapid correction of hyponatremia can lead to irreversible neurologic complications and death, known as the osmotic demyelination syndrome (ODS).

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Overview

Physiology and classification

  • A normal serum sodium (sNa+) concentration is 135–145 mEq/L.
  • Na+ is the most important contributor to plasma tonicity.
  • Hyponatremia is defined as an sNa+ concentration < 135 mmol/L.
  • Overt neurologic symptoms, most often in an sNa+ levels < 120 mEq/L
  • Can be classified by:
    • Concentration:
      • Mild: 130–134 mmol/L
      • Moderate: 125–129 mmol/L
      • Profound: < 125 mmol/L
    • Volume status:
      • Hypovolemic: ↓ in total body water (TBW) with a greater ↓ in total body sodium (TBNa+)
      • Euvolemic: normal TBNa+ with ↑ in TBW
      • Hypervolemic: ↑ TBNa+ with greater ↑ in TBW

Etiology

The etiologies of hyponatremia are most commonly organized according to their volume status.

Hypovolemic:

  • GI losses (diarrhea, vomiting, nasogastric tube (NG tube)/surgical drain output)
  • Bleeding 
  • Diuretics
  • ↑ Insensible losses (tachypnea, sweating, fever, burns)
  • Third-spacing (pancreatitis)
  • Other (salt-wasting nephropathies)

Euvolemic:

  • SIADH
  • Primary polydipsia (psychogenic polydipsia)
  • Low solute intake (beer potomania, tea-and-toast diet)
  • Hypothyroidism
  • Thiazide induced

Hypervolemic:

  • Congestive heart failure (CHF)
  • Cirrhosis
  • Nephrotic syndrome
  • Advanced renal failure

Pathophysiology

  • Antidiuretic hormone (ADH) is released by the hypothalamus.
  • Acts at the collecting duct in the kidney via V2 receptors
  • Results in the insertion of aquaporin channels (AQPs) → facilitates water reabsorption 
  • ↑ Plasma tonicity → ADH released → water retention → tonicity normalizes 
  • ↓ Plasma volume → ADH released → water retention and vasoconstriction
    • Only occurs if > 10% blood volume lost
    • The purpose is to maintain blood pressure at all costs.
    • It occurs even if plasma tonicity is normal or low.
    • ADH also has systemic vasoconstrictor effects.
  • When intake of water is greater than excretion water → ↑ TBW → net dilution of TBNa+
  • ↓ In TBNa+ (i.e., hypovolemia) contributes to hyponatremia

Clinical Presentation

Acute (< 48 hours)

  • Symptoms are due to acute shift of water into the brain → cerebral edema
  • Relatively smaller drop in sNa+ sufficient to cause symptoms (i.e., sNa+ approximately 130 mEq/L)
  • Mild symptoms:
    • Headache
    • Lethargy
    • Anorexia
    • Nausea
    • Vomiting
  • Severe symptoms: 
    • Seizures
    • Severe altered mental status
    • Herniation → coma, respiratory failure, death

Chronic (> 48 hours)

  • Brain adaptation to hyponatremia:
    • Occurs quickly (within approximately 48 hours) 
    • Brain cells excrete solutes (“organic osmolytes”) to equalize the tonicity.
    • Results in much lower degree of fluid shift into the brain
  • Symptoms are more subtle due to brain adaptations:
    • Mild cognitive deficits
    • Gait instability
  • Relatively large drop in sNa+ necessary to cause severe symptoms (i.e., sNa+ < 120 mEq/L) 
Effects of hyponatremia on the brain

Effects of hyponatremia on the brain

Image by Lecturio.

Diagnosis

The 3 most important tests that need to be completed are serum osmolality, urine osmolality, and urinary sodium concentration.

Serum or plasma osmolality

  • ↑ Plasma osmolality: hypertonic hyponatremia 
    • Serum Na+ does not correlate with plasma tonicity.
    • Treat underlying disorder to ↓ plasma osmolality
  • Normal plasma osmolality: pseudohyponatremia
    • Serum Na+ does not correlate with plasma tonicity.
    • Examples: ↑ serum lipids or protein, lab error
    • No further workup or management
  • ↓ Plasma osmolality: hypotonic hyponatremia
    • Serum Na+ correlates with plasma tonicity.
    • True hyponatremia

Urine osmolality

  • Determines the activity of ADH
  • Urine osmolality < 100 mOsm/kg: ADH appropriately absent 
    • Low solute intake 
    • Primary polydipsia
  • Urine osmolality > 100 mOsm/kg: ADH present 

Estimate clinical volume status (TBNa+)

  • Clearly hypovolemic or hypervolemic → no further testing needed
  • Euvolemic or possibly hypovolemic → need further testing
  • Euvolemic vs. possibly hypovolemic:
    • Screen for hypothyroidism and adrenal insufficiency (cortisol, adrenocorticotropic hormone (ACTH) stimulation test)
    • Review medication list for common offenders
    • Review history for common nonosmotic ADH stimuli
  • Check additional labs:
    • Urine Na+: ↓ suggests hypovolemia, ↑ suggests SIADH
    • BNP: ↓ suggests hypovolemia
    • Serum uric acid: ↓ suggests SIADH
    • BUN: ↓ suggests SIADH 
  • Fluid challenge with repeat urine studies if diagnosis is still unclear

Diagnosis of underlying condition

  • SIADH:
    • Excessive levels of ADH result in excessive renal free water reabsorption.
    • ADH release can be stimulated by many causes: 
      • Nausea, pain, anxiety, stress
      • Centrally acting medications, CNS disorders
      • Postoperative state
      • Malignancy (most commonly small cell lung cancer)
      • Lung disorders (i.e., pneumonia)
  • Primary polydipsia and low solute intake:
    • Water intake in excess of kidney’s maximal excretion capabilities
    • Highly dependent on dietary solute intake and the concept of obligate osmolar excretion
  • Hypothyroidism and thiazide induced: The mechanisms are incompletely understood.
  • CHF/cirrhosis/nephrotic syndrome: nonosmotic release of ADH due to the kidney’s perception of a hypovolemic state
  • Advanced renal failure:
    • Water intake in excess of kidney’s impaired excretion capabilities
    • Only in very severe renal failure (usually GFR < 15 mL/min)
    • Usually clinically obvious and not requiring comprehensive workup 

Management

General considerations

Acuity and severe symptoms are the primary determinants of this, and the aggressiveness and urgency of treatment will vary according to the risk assessment.

Acuity:

  • Acute (< 48 hours):
    • Adaptive mechanisms have not yet occurred:
      • ↑ Risk for acute cerebral edema
      • ↓ Risk for osmotic demyelination syndrome (ODS) 
    • Hyponatremia should be corrected quickly (i.e., within 24 hours)
  • Chronic (> 48 hours):
    • Adaptive mechanisms have occurred:
      • ↑ Risk for ODS
      • ↓ Risk for acute cerebral edema
    • Hyponatremia must be corrected slowly (i.e., < 6–8 mmol/L/day).
  • If unknown, then hyponatremia must always be assumed to be chronic!

Symptoms:

  • Severe:
    • Seizure, coma, respiratory failure, severe altered mental status
    • Urgent treatment with 3% NaCl is indicated.
  • Nonsevere:
    • Mostly nonspecific symptoms (headache, nausea, fatigue, confusion)
    • Nonsevere cases usually do not need urgent treatment with 3% NaCl.

Specific risk factors for ODS:

  • Malnutrition
  • Liver disease
  • Alcoholism
  • sNa+ < 105 mmol/L on presentation
  • Hypokalemia

Urgent therapy

Involves giving 3% NaCl (hypertonic saline) in order to increase the sNa+ by 6 mmol/L within several hours. 

  • Absolute indications (symptoms from acute cerebral edema):
    • Seizure
    • Coma
    • Respiratory failure
    • Severe altered mental status
  • Relative indications (↑ risk for progression to being overtly symptomatic):
    • Asymptomatic, known acute hyponatremia, regardless of severity of sNa+:
      • Primary polydipsia
      • Excessive postoperative hypotonic IV fluids
    • Known acute, mildly symptomatic, mild hyponatremia (sNa+ < 130) from any cause
    • Chronic, asymptomatic, severe hyponatremia (sNa+ < 120)
  • Management:
    • IV 3% NaCl, with frequent recheck of sNa+
    • Initial goal: ↑ sNa+ by 6 mmol/L within the first 6 hours
      • Should resolve any acute symptoms caused by hyponatremia
      • If symptoms persist, then investigate other etiologies.
    • After sNa+ ↑ by 6 mmol/L:
      • Goal: ↑ in sNa+ by no more than 6–8 mmol/L/day
      • Target small daily ↑ in case there is overshoot
  • Monitoring:
    • Necessary to ensure that sNa+ does not ↑ too quickly
    • Recheck sNa+ and urine output frequently.
    • ↑ Urine output signals impending overcorrection 

Nonurgent therapy

  • Hyponatremia that does not require urgent therapy is almost exclusively chronic and usually asymptomatic or mildly symptomatic. 
  • Management decisions are guided by the severity of the sNa+ level, with wide variation in the clinician’s preferences for aggressiveness of treatments.
  • Monitoring of sNa+ levels is indicated in all cases.

Severe (sNa+ < 125 mmol/L):

  • Requires admission
  • Hypervolemic:
    • Loop diuretics (furosemide, bumetanide, torsemide)
    • General measures: 
      • Oral fluid restriction, discontinue offending medications
      • Liberal salt diet not recommended (potential for worsening fluid overload)
  • Hypovolemic:
    • 3% or 0.9% NaCl (clinician’s preference)
    • General measures: 
      • Oral fluid restriction, liberal salt diet, discontinue offending medications
      • Oral fluid restriction can be relaxed once sNa+ improves to > 125.
  • Euvolemic: general measures
    • Oral fluid restriction, liberal salt diet, discontinue offending medications
    • Address any nonosmotic ADH stimuli (pain, nausea, anxiety, etc.).

Moderate (sNa+ 125–130):

  • Clinician’s preference regarding admission decision
  • Hypervolemic:
    • Loop diuretics 
    • General measures: 
      • Oral fluid restriction, discontinue offending medications.
      • Liberal salt diet not recommended (potential for worsening fluid overload)
  • Hypovolemic:
    • 0.9% NaCl until euvolemic
    • General measures: 
      • Oral fluid restriction, liberal salt diet, discontinue offending medications
      • Oral fluid restriction can be relaxed once sNa+ improves.
  • Euvolemic: general measures
    • Oral fluid restriction, liberal salt diet, discontinue offending medications
    • Address any nonosmotic ADH stimuli (pain, nausea, anxiety).

Mild (sNa+ > 130):

  • Rarely require admission
  • Hypervolemic:
    • Loop diuretics 
    • General measures: 
      • Oral fluid restriction, discontinue offending medications
      • Liberal salt diet not recommended (potential for worsening fluid overload)
  • Hypovolemic:
    • 0.9% NaCl until euvolemic
    • General measures: 
      • Liberal salt diet, discontinue offending medications
      • Oral fluid restriction not necessary 
  • Euvolemic: general measures only
    • Oral fluid restriction, liberal salt diet, discontinue offending medications
    • Address any nonosmotic ADH stimuli (pain, nausea, anxiety).

Differential Diagnosis

  • Syndrome of inappropriate secretion of antidiuretic hormone (SIADH): an inappropriately high level of circulating ADH. Etiology includes medications, malignancies, lung disease, HIV, hypothyroidism, intracranial processes, and nonosmotic stimuli. Management is water restriction.
  • Other euvolemic hyponatremias: thiazide-induced hyponatremia, adrenal insufficiency, and hypothyroidism are causes of euvolemic hyponatremia that have incompletely understood mechanisms. Such conditions can be diagnosed relatively easily (medication list review, cortisol/ACTH stimulation test, and thyroid-stimulating hormone (TSH)). If a condition is found, treating the underlying condition should correct the hyponatremia.
  • Osmotic demyelination syndrome (ODS): characterized by irreversible neurologic symptoms, which can occur if sNa+ is corrected too quickly. Symptoms occur several days after the overcorrection and are related to fluid shifts after the brain has already adapted to chronic hyponatremia. Diagnosis is by history and MRI. Management involves therapeutic flowering of the sNa+ and supportive care.
  • Hypertonic hyponatremia: low sNa+, but not managed as true hyponatremia because the sNa+ is discordant with the plasma osmolality and tonicity. Examples are hyperglycemia and mannitol use. Water is drawn into the extracellular fluid (ECF) and results in a dilution of the sNa+, despite the plasma osmolality remaining high from the glucose or mannitol. 
  • Hyponatremia in advanced renal failure: when plasma osmolality is high but the plasma tonicity and sNa+ are low. Urea is in high concentrations but is an ineffective osmole, so it causes no water shifts, dilution of the TBNa+, or decrease in the plasma tonicity. Advanced renal failure causes a decrease in water excretion, retention of water, increased TBW, diluted TBNa+, and a true hypotonic hyponatremia.
  • Pseudohyponatremia: occurs when a characteristic lab error results in a low measured sNa+, despite the true sNa+ and true plasma osmolality being within the normal range. High serum lipid (i.e., hypertriglyceridemia associated with pancreatitis, hypercholesterolemia with biliary obstruction) or protein levels (plasma cell dyscrasias) result in inaccuracy in lab processing and falsely low reported sNa+.
  • Water intoxication: a true acute hyponatremia that may have significant symptoms with a relatively small decrease in sNa+, which will require rapid correction of hyponatremia with 3% NaCl. Etiologies are psychogenic polydipsia, exercise-associated hyponatremia, fraternity hazing rituals, and MDMA abuse. These patients must be monitored very closely.

References

  1. Emmett, M, et al. (2020). Hyponatremia following transurethral resection, hysteroscopy, or other procedures involving electrolyte-free irrigation. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/hyponatremia-following-transurethral-resection-hysteroscopy-or-other-procedures-involving-electrolyte-free-irrigation
  2. Sterns, RH. (2019). Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/pathophysiology-and-etiology-of-the-syndrome-of-inappropriate-antidiuretic-hormone-secretion-siadh
  3. Sterns, RH. (2020). Overview of the treatment of hyponatremia in adults. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-hyponatremia-in-adults
  4. Sterns, RH. (2020). Causes of hypotonic hyponatremia in adults. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/causes-of-hypotonic-hyponatremia-in-adults
  5. Sterns, RH. (2020). Diagnostic evaluation of adults with hyponatremia. UpToDate. Retrieved March 21, 2021, from https://www.uptodate.com/contents/diagnostic-evaluation-of-adults-with-hyponatremia

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