Hyponatremia: Low Sodium Levels

What is hyponatremia?

Hyponatremia means low blood sodium levels (Na <135 mmol/liter) ^[6]. Normal blood sodium levels are 135-145 mmol/liter ^[6]. Symptoms can include dizziness, confusion, nausea, muscle weakness, seizures, coma or death. Common causes include excessive water drinking and sodium loss by vomiting, diarrhea or brain or kidney disorders.

Mild hyponatremia can be treated by water restriction and diuretics, while severe hyponatremia usually requires an intravenous infusion of saline.

Symptoms and Signs

Mild to moderate hyponatremia (Na>120-125 mmol/L) ^[9]:

• Headache
• Anorexia, nausea, vomiting, diarrhea
• Muscle weakness and cramps
• Difficulty concentrating
• Irritability, depression
• Incontinence
• Excessive urination or polyuria (in diabetes mellitus, alcoholic ketoacidosis, anorexia nervosa, psychogenic polydipsia)
• Gait disturbance

Severe hyponatremia (Na <115-120 mmol/L) ^[6,9]:

• Confusion, hallucinations
• Seizures (convulsions)
• Dilated pupils
• Decorticate posturing: arms bent toward the body, hands on the chest, fully extended legs
• Decerebrate posturing
• Decreased heart rate (bradycardia)
• Difficulty breathing (dyspnea), hyperventilation or respiratory arrest
• Drowsiness (lethargy, stupor)
• Coma or death

The lower the blood sodium levels and the faster their drop, the more severe are the symptoms ^[6]. In hyponatremia that develops slowly (>48 hours), symptoms can be mild or absent ^[6].

Complications

• Brain swelling or cerebral edema (hyponatremic encephalopathy)
• Lung swelling (pulmonary edema)
• Muscle disintegration (rhabdomyolysis)
• Hypovolemic shock
• Limb paralysis
• Persistent vegetative state or cerebral palsy
• Reference: ^[11]

Risk Factors

Risk Factors for Exercise-Associated Hyponatremia

• Exercise duration longer than 4 hours
• Female sex
• Low body weight
• Drinking 1.5 liters of water per hour or more or pre-exercise overhydration
• Taking nonsteroidal anti-inflammatory drugs (NSAIDs)
• Extremely high or low ambient temperature

Risk Factors for Severe Hyponatremia and Brain Damage (Hyponatremic Encephalopathy)

• Infants and children under 16 years ^[11]:
  • Low body weight and hence small amount of body water, which makes a child more vulnerable to overhydration (water intoxication)
  • Higher brain/skull ratio and hence less room for the brain in case of brain edema than in adults
• Women of childbearing age:
  • Estrogen inhibits brain adaptation to hyponatremia
  • Higher levels of the antidiuretic hormone (ADH) than in men
• Elderly with underlying diseases, such as heart or kidney failure ^[6]
• Malnutrition with low sodium intake: alcoholics, elderly, anorexia nervosa, psychogenic polydipsia, starvation
• Brain injury
• Hypoxemia
• Diabetic ketoacidosis, hyperammonemia, increased bilirubin
• Brain tumor or cyst, encephalitis, meningitis, intracranial bleeding (hematoma) or any other cause of increased intracranial pressure
• Induction of delivery by oxytocin
• References: ^[11]

Pathophysiology

Hyponatremia usually develops due to a combination of water retention and one or more of the following:

• Increased water intake
• Decreased sodium intake
• Increased sodium loss

The drop of sodium makes the blood hypotonic, so water from the blood moves into the body cells which swell. Swelling of the brain (cerebral edema) is the main cause of symptoms in hyponatremia.

Types and Causes of Hyponatremia

According to the blood volume change:

• Hypovolemic hyponatremia
• Isovolemic hyponatremia
• Hypervolemic hyponatremia

According to the blood osmolality change:

• Hypotonic (hypo-osmolar) hyponatremia (most common)
• Isotonic (iso-osmolar) hyponatremia (in SIADH, heart, liver or kidney failure)
• Hypertonic (hyperosmolar) hyponatremia (in hyperglycemia)
  
• Reference: ^[9]

Hypovolemic Hypotonic Hyponatremia

• Decreased total body water and total body sodium (sodium more decreased than water)
• Symptoms and signs resemble those in dehydration: prolonged skin turgor, dark urine, loss of body weight, tiredness, headache.

Causes:

• Severe bleeding
• Vomiting
• Diarrhea
• Excessive sweating
• Thiazide diuretics ^[9]
• Poor salt intake (fasting, starvation, “water diet”)
• Adrenal (mineralocorticoid) insufficiency
• Burns
• Cystic fibrosis ^[11]
• Cerebral salt-wasting syndrome (CSW): meningitis, brain metastases, brain surgery, intracranial bleeding ^[9]
• Ketonuria (low-carb or ketogenic diet, starvation, diabetic or alcoholic ketoacidosis) ^[1,2]
• Renal tubular acidosis
• Osmotic diuresis: mannitol, hyperglycemia, urea
• Bicarbonaturia
• Salt-wasting nephropathies (in polycystic kidney disease, interstitial nephritis, partial urinary tract obstruction) ^[9]
• Reference: ^[9]

Isovolemic Hypotonic Hyponatremia

• Increased total body water, normal total body sodium, isovolemia or mild hypervolemia
• Symptoms: no dehydration or edema.

Water Intoxication

• Excessive water consumption: beer potomania, “tea and toast” diet, “water diet” in women who want to lose weight, psychogenic polydipsia, overhydration in marathon runners (exercise-induced hyponatremia), use of drugs that stimulate thirst: ecstasy, amphetamine, fresh water drowning ^[12]

Syndrome of Inappropriate ADH Secretion (SIADH)

• Lung diseases: mycoplasma pneumonia, tuberculosis, asthma, chronic obstructive pulmonary disease (COPD)
• Brain disorders: brain tumor, stroke, multiple sclerosis, psychosis (schizophrenia)
• Cancer: lung cancer (small-cell carcinoma), mesothelioma, pancreatic and colonic cancer, leukemia, lymphoma
• Surgery
• Drugs: amitriptyline (antidepressant), amphetamine, bromocriptine, carbamazepine, chemotherapeutics, chlorpromazine (antipsychotic), ciprofloxacin (antibiotic), clofibrate, desmopressin, ecstasy (MDMA), ibuprofen (NSAID), lisinopril, metformin, morphine, omeprazole (proton pump inhibitor), phenobarbital (anesthetic), sodium valproate, tramadol
• Other: HIV/AIDS, sepsis
  
• A detailed list of causes of SIADH
• References: ^{[2,3,9,11,12,14]}

Other Causes of Isovolemic Hyponatremia:

• Intravenous infusion of hypotonic fluids, such as 5% glucose (DW5), within 1-5 days after operation when SIADH is often present due to stress, pain, nausea and slight hypovolemia
• Irrigation with hypotonic fluids during endometrial ablation
• Hypothyroidism
• Adrenal insufficiency (low aldosterone resulting in sodium excretion in the kidneys)
• Reset osmostat (thirst at lower sodium concentrations as normally): in pregnancy (probably due to increased hCG levels), in malnutrition, in elderly, in malignancy or other severe chronic disease
• Hyponatremic Hypertensive Syndrome (HHS): severe hypertension in individuals with stenosis of the renal artery
  
• Nephrogenic Syndrome of Inappropriate Diuresis (NSIAD) — a hereditary disease in male infants
  
• References: ^[11]

Hypervolemic Hypotonic Hyponatremia

• Greatly increased total body water, normal total body sodium
• Symptoms: edema

Causes:

• Chronic heart failure (CHF); in CHF the weakened heart cannot push the blood toward the tissues effectively (decreased effective blood volume), so the tissues react the same way as in hypovolemia (release of renin-angiotensin and ADH), which results in water retention greater than sodium retention and therefore hyponatremia
• Liver cirrhosis
• Nephrotic syndrome
• Renal failure (decreased glomerular filtration rate – GFR) ^[11]
• Severe hypoproteinemia ^[9], low protein and sodium intake (“water diet”)
• Reference: ^[11]

Hypertonic (Redistributive) Hyponatremia

• Hyperglycemia (diabetes mellitus, steroid therapy, infection, heart attack)
• The presence of other osmotically active substances in the blood:
  • Mannitol, glycine, sorbitol absorbed in the blood after irrigation of the urinary system during transurethral resection of the prostate (TURP) or during hysteroscopy
  • Contrast agents used in imaging investigations ^[9]

Pseudohyponatremia

Pseudohyponatremia is not true hyponatremia; it is a laboratory measurement error that occurs in hyperlipidemia or hyperproteinemia or after imaging investigations in which contrast substances are used ^[13].

Diagnosis

A doctor will probably ask you about water intake, medications, recent changes in the body weight and underlying chronic diseases. Physical examination will likely include skin turgor test (to check for dehydration), checking for edema and neurological examination.

Blood Tests:

• Blood sodium <135 mmol/L
• Other electrolytes are often normal (potassium is increased in Addison’s disease and decreased in thiazide diuretics overdose)
• Blood glucose (increased in diabetes mellitus, decreased in Addison’s disease)
• Blood osmolality: <280 mOsm/kg, except in hyperglycemia
• Thyroid function test
• Adrenal function test
• Creatine phosphokinase (CPK) (increased in rhabdomyolysis)
• Blood urea nitrogen (BUN) and uric acid (increased in hypovolemic hyponatremia)

Urine Tests:

• Urine sodium: increased (in cerebral salt-wasting syndrome) or decreased (in polydipsia)
• Urine osmolality
  • >100 mOsm/kg: impaired free water excretion (most cases)
  • <100 mOsm/kg: psychogenic polydipsia

Imaging:

• Diffusion-weighted MRI can show brain swelling (cerebral edema) ^[11]

Treatment

Treatment of hyponatremia can include:

• Total water and food restriction for a certain period, like 24 hours
• High-protein diet (which yields urea, which promotes water excretion, which results in the rise of blood Na levels)
• Hypertonic (3%) or isotonic (0.9%) saline
• Loop diuretics: furosemide, which promotes water excretion greater than sodium excretion: in isovolemic or hypervolemic hyponatremia in combination with 3% NaCl.
• Aquaretics, which promote excretion of free water:
  • Vaptans (inhibitors of the ADH (AVP) V2 receptors): conivaptan (restricted to 4 days) and tolvaptan (restricted to 30 days); only in the hospitals. Vaptans can be used in heart failure, but according to some researchers, vaptans alone should not be used in acute symptomatic hyponatremia, because they start to act only after 1-2 hours ^[11].
  • Demeclocycline (needs 3-4 days for maximal effect): in chronic refractory hyponatremia
  • Urea
• References: ^[4,11]

The Rate of Treatment of Hyponatremia

Mild acute or chronic hyponatremia without seizures can be treated with water restriction alone.

Severe acute hyponatremia with seizures or coma should be treated rapidly with hypertonic saline ^[4,11].

Severe chronic hyponatremia (Na<105 mmol/L) should be treated slowly by removing the cause, partial water restriction and, eventually by a high-sodium diet ^[4,8].

Possible Complications of Treatment

Fluid Accumulation in the Lungs (Pulmonary Edema)

• Symptoms: difficulty breathing, hyperventilation and coughing up bloody sputum
• Signs: increased breathing sounds detected by the stethoscope

Osmotic Demyelination Syndrome (ODS) or Central Pontine Myelinolysis

Rapid correction of severe hyponatremia can result in the damage of the part of the brain called the pons; the condition is called central pontine myelinolysis, which is a feature of osmotic demyelination syndrome (ODS).

• Signs typically develop 2-7 days after the onset of treatment and may include confusion, quadriplegia, difficulty swallowing, unusual behavior, coma with a “locked-in stare.”
• Late complications include memory loss, cerebellar ataxia, pseudobulbar palsy and  polyneuropathy.
• Risk factors include rapid correction of chronic hyponatremia (>25 mmol in 24-48 hours), but not necessary the severity of hyponatremia; hyperkalemia, female sex, liver cirrhosis (alcoholism), respiratory arrest and malnutrition ^[11].
• Diagnosis can be made by diffusion-weighted MRI ^[11].

Prognosis of Hyponatremia

Bad prognostic factors in hyponatremia:

• Hyponatremia <105 mmol/L (50% mortality)
• Hypoxia, respiratory arrest
• Alcoholism, liver cirrhosis with ascites
• Cancer
• Reference: ^[11]

• References

  1. Jung DE et al, 2011 Practical Use of the Ketogenic Diet in Childhood Epilepsy IntechOpen
  2. Syndrome Of Inappropriate Antidiuretic Hormone Secretion  Drugs.com
  3. Pillai BP et al, 2011, Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder  PubMedCentral
  4. Simon EE, Hyponatremia, Treatment  Emedicine
  5. Simon EE, Hyponatremia, Medications  Emedicine
  6. Simon EE, Hyponatremia, Overview  Emedicine
  7. Craig S, Hyponatremia in Emergency Medicine  Emedicine
  8. Goh KP, 2005, Management of Hyponatremia  American Family Physician
  9. Simon EE, Hyponatremia, Clinical Presentation  Emedicine
  10. Mydlík M et al, 2013, Differential diagnosis and treatment of hyponatremia  PubMed
  11. Moritz ML et al, 2010, New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children  PubMed Central
  12. O’Donoghue D et al, 2009, SIADH and hyponatraemia: foreword  PubMed Central
  13. Fortgens P et al, 2011, Pseudohyponatremia Revisited   Archives of Pathology
  14. Thomas CP, Syndrome of Inappropriate Antidiuretic Hormone Secretion, Overview Emedicine