The essence in brief:
Hyponatremia is a condition where the sodium concentration in the blood falls below 135 mmol/l. It is the most common electrolyte disorder, often seen in older patients. Hyponatremia can range from mild to severe and is associated with various neurological symptoms due to brain swelling. The condition can be life-threatening, and even mild cases require investigation and treatment as they have higher mortality rates. Hyponatremia can be caused by various factors, such as heart failure, infections, kidney problems, and certain medications. Prompt diagnosis and appropriate management are essential to prevent serious complications.
Hyponatremia occurs when the sodium concentration in the blood falls below 135 mmol/l. It is the most common electrolyte disorder, with an incidence of 30%. Hyponatremia is more prevalent among older patients. Severe hyponatremia is a life-threatening condition, but even mild cases must be investigated and treated, as they are associated with higher mortality rates. Severe illnesses such as heart failure, meningitis, sepsis, and pneumonia have a significantly worse prognosis when accompanied by untreated hyponatremia.
Hyponatremia manifests with nonspecific neurological symptoms of cerebral edema: headache, loss of appetite, nausea, dizziness, muscle weakness, disorientation, seizures, and eventually coma. Brain cells start to swell as water shifts from extracellular to intracellular compartments due to hyponatremia. The cause is the difference in osmolarity between the brain and plasma. The brain attempts to adapt, and the adaptation process takes 24-48 hours, which is the differentiating factor between acute and chronic hyponatremia.
The release of ADH (Vasopressin) by central and peripheral osmoreceptors depends on serum osmolality. Stretch receptors in the atria, carotid sinus, and aortic arch inhibit ADH release when circulating fluid volume increases. A decrease in fluid volume increases ADH secretion. A 5% decrease in blood pressure significantly raises ADH concentration. The release of ADH by osmoreceptors or baroreceptors is interrelated.
Mild Hyponatremia: 130-135 mmol/l
Moderate Hyponatremia: 125-129 mmol/l
Severe Hyponatremia: <125 mmol/l
Mild hyponatremia is associated with cognitive and mental impairment, making it often overlooked in older patients.
Determining the volume status (hydration status) is difficult and a frequent source of misdiagnosis. Although the volume status should be assessed, its significance in diagnosis must be considered.
Hypovolemia: Dry mucous membranes, dry skin (skin fold remains elevated), thirst, low blood pressure, increased pulse, orthostatic complaints. Creatinine, uric acid, total protein, and hematocrit are elevated.
Hypervolemia: Edema, distended neck veins, weight gain. Creatinine, uric acid, total protein, and hematocrit are decreased due to dilution.
Euvolemia: Absence of clinical signs of hypovolemia or hypervolemia. Laboratory values are normal. Blood pressure and pulse within normal range.
Osmolality describes the molar concentration (mol/l) of osmotically active particles in 1 liter of water. The measurement is temperature-dependent.
Serum Osmolality = 2 x S-Na+ + Urea + Glucose (concentrations in mmol/l)
In clinical chemistry, osmolality indicates the number of osmotically active particles per kilogram of water. Serum osmolality (normal: 175-300 mosmol/kg) is tightly regulated. Serum sodium is the most crucial factor, along with glucose and urea. Hyponatremia is associated with hypoosmolality. In rare cases, severe hyperglycemia (blood sugar > 500 mg/dl) can cause hyperosmolar hyponatremia.
A 1% increase in serum sodium stimulates osmoreceptors in the hypothalamus, leading to ADH release. ADH binds to the vasopressin-2 receptor in the renal collecting ducts, enhancing the reabsorption of electrolyte-free water, resulting in more concentrated urine.
Hypervolemic Hyponatremia:
The cause is organ diseases such as heart failure, liver cirrhosis, or nephrotic syndrome. Fluid overload is evident in the tissues, and blood pressure is low.
Hypovolemic Hyponatremia:
Extra-renal causes include vomiting, diarrhea, gastroenteritis, extensive burns, excessive sweating, and pancreatitis, leading to sodium loss. The decreased arterial blood volume stimulates ADH secretion. Urine sodium is decreased.
Renal causes include primary polydipsia, resulting in low-concentration urine (urine osmolality < 200 mosmol/kg). Serum osmolality decreases, and ADH secretion is suppressed, leading to increased water excretion. This condition can cause severe hyponatremia with values below 120.
Acute kidney failure disrupts sodium reabsorption and increases sodium excretion.
Diuretic-induced Hyponatremia:
Thiazide diuretics frequently cause hyponatremia in older patients, usually 2-3 weeks after starting therapy. Hyponatremia can also be caused by loop diuretics but less commonly.
The essence in brief:
SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion) is a condition characterized by the excessive release of antidiuretic hormone (ADH) even when the body does not require it. This leads to water retention, decreased urine output, and dilutional hyponatremia (low sodium levels in the blood). SIADH can be caused by various factors, including malignancies, infections, medications, and certain medical conditions. Key diagnostic criteria for SIADH include low serum osmolality, high urine osmolality, and elevated urine sodium levels. Treatment aims to address the underlying cause and may involve fluid restriction, medications, or ADH antagonists. SIADH can be a serious condition, and prompt diagnosis and appropriate management are essential to prevent complications.
Euvolemic hyponatremia is the most common form of hyponatremia and is referred to as the Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) or Schwarz-Bartter syndrome. It is characterized by excessive secretion of antidiuretic hormone (ADH), which reduces water excretion, leading to water retention and a compensatory increase in renal sodium excretion.
SIADH can be caused by various factors, such as malignancies (e.g., small-cell lung carcinoma, gastrointestinal carcinomas, urogenital tract carcinomas, brain tumors, lymphomas, and sarcomas), severe infections (e.g., pneumonia, tuberculosis, Aspergillosis, encephalitis, meningitis), and other conditions like asthma, subarachnoid hemorrhage, and head trauma. Additionally, certain medications can trigger or exacerbate SIADH, including diuretics, antidepressants (SSRIs and tricyclic antidepressants), neuroleptics, MAO inhibitors, antiepileptics, analgesics, chemotherapeutics, and certain addictive substances.
Key diagnostic criteria for SIADH include:
Serum osmolality < 275 mosmol/kg
Corresponding urine osmolality > 100 mosmol/kg
Urinary sodium > 30 mmol/l (with normal salt intake)
Copeptin (CT-proAVP)
Clinical euvolemia
Exclusion of hypothyroidism, adrenal insufficiency, and hypopituitarism
No use of diuretics
Additional criteria for confirmation of diagnosis include:
Lack of a significant increase in serum sodium after administering 0.9% saline solution
Increase in serum sodium following fluid restriction
Increase in serum sodium after administering an ADH antagonist such as Tolvaptan
Serum uric acid < 0.24 mmol/l
Serum urea < 3.6 mmol/l
A urine osmolality > 200 mosmol/kg in the presence of hyponatremia indicates a pathologically concentrated urine due to AVP (ADH) insufficiency suppression. The cause could be inappropriate (SIADH) or non-osmotic AVP secretion.
If the urinary sodium concentration is < 30 mmol/l, it may indicate effective arterial volume depletion. A urinary sodium concentration > 30 mmol/l suggests renal salt loss with secondary AVP release. Misdiagnosis is common when diuretics are involved. Fractional excretion of uric acid (FE-UA) can be used when diuretics are taken. A low effective arterial blood volume is likely when the fractional excretion of uric acid (FE-UA) is less than 8%. An FE-UA > 12% indicates SIADH (differential diagnosis includes glucocorticoid deficiency).
ADH measurement is not commonly performed in diagnosis due to its instability and difficulty in determination. Copeptin, a stable prohormone formed in the hypothalamus, correlates with ADH levels.
Differential diagnosis for chronic hyponatremia (serum sodium < 135 mmol/l) involves determining the serum osmolality using the formula:
Serum osmolality = 2 x S-Na+ + Urea/2.8 + Glucose/18 (urea and glucose in mg/dl)
If the serum osmolality is > 290 and urine osmolality is < 100 mosmol/kg, possible causes for hyponatremia include primary polydipsia, reduced salt intake, or excessive beer consumption.
If urine osmolality is > 100 mosmol/kg and urine sodium is < 30 mmol/l, or FE-UA < 12% (with diuretic use), possible causes may include volume depletion or fluid loss due to conditions like heart failure, liver cirrhosis, nephrotic syndrome, angioedema, gastrointestinal fluid loss, pancreatitis, or peritonitis.
If urine osmolality is > 100 mosmol/kg and urine sodium is > 30 mmol/l, or FE-UA > 12% (with diuretic use), possible causes may include the effects of diuretics, mineralocorticoid deficiency, renal tubular acidosis, cerebral salt-wasting syndrome, adrenal insufficiency, hypopituitarism, renal failure, or exercise-induced hyponatremia.
When the above diagnoses are excluded, SIADH is the likely syndrome present.
The essence in brief:
For acute hyponatremia with neurological symptoms, the primary goal is to increase serum sodium levels quickly and carefully. This can be achieved with a 3% saline solution and calculating the saline deficit based on body weight. In milder cases, the correction should be slower, while in severe cases, rapid correction is necessary. Hypertonic saline can be administered, and the treatment’s success is measured by symptom improvement and serum sodium levels reaching specific targets.
Increase serum sodium by 5 mmol/l in 1-3 hours using a 3% saline solution.
Calculate the saline deficit using the formula: (Desired serum sodium – Initial serum sodium) x Total Body Water (in mmol/l).
Total Body Water (in liters):
Children: 0.6 x body weight
Women: 0.5 x body weight
Men: 0.6 x body weight
Older women: 0.45 x body weight
Older men: 0.5 x body weight
Use a saline deficit calculator available online: https://www.mdcalc.com/sodium-deficit-hyponatremia
For mild symptoms, correct sodium levels slowly (0.5-1 mmol/l). For severe symptoms, correct rapidly (1-2 mmol/l).
Administer hypertonic saline under close monitoring of serum sodium levels.
Endpoints of hypertonic saline infusion: Improvement of symptoms, increase in serum sodium to 120 mmol/l, or by >18 mmol/l.
Maximum sodium substitution of 10 mmol/l in 24 hours and 18 mmol/l in 48 hours.
Therapy for Chronic Hyponatremia with Neurological Symptoms:
Chronic hyponatremia with neurological symptoms requires a slower correction to avoid complications like central pontine myelinolysis. In hypovolemic forms, isotonics saline or salt-containing beverages/foods may help, but sodium substitution should be avoided to prevent overcorrection.
Elevate sodium levels slowly to avoid central pontine myelinolysis.
Mild hypovolemic forms can be treated with isotonic saline infusion, salty beverages, or salty foods.
Avoid sodium substitution as overcorrection may lead to central pontine myelinolysis.
Hypervolemic Hyponatremia:
Hypervolemic hyponatremia is treated by addressing the underlying condition and restricting fluid intake. Diuretics and fluid restriction may be helpful in some cases, while urea can induce an osmotic diuresis to increase water excretion.
Overall, the treatment approach depends on the underlying cause and the severity of the condition, and close monitoring of serum sodium levels and patient response is crucial throughout the treatment process.
Treat the underlying condition and restrict fluid intake. Loop diuretics can be supportive in some cases.
Fluid restriction may have poor compliance in cases of polydipsia.
Urea induces an osmotic diuresis with increased water excretion. Recommended dosage is 0.5 g per kg body weight per day. Urea may have a bitter taste and is often declined. In the pharmacy, powder mixtures containing 10 g of urea, 200 mg of sucrose, and hydrogen carbonate/citric acid buffer can be prepared to make a solution.
Euvolemic Hyponatremia – SIADH:
For euvolemic hyponatremia (SIADH), fluid restriction is the mainstay of treatment, and urea or low-dose loop diuretics may be used if needed. Tolvaptan is an option for elevating serum sodium levels, but it must be administered under close monitoring in the hospital.
Treat SIADH with fluid restriction. If target levels are not achieved, urea and low-dose loop diuretics can be used.
Urea may have a bitter taste and is often declined. In the pharmacy, powder mixtures containing 10 g of urea, 200 mg of sucrose, and hydrogen carbonate/citric acid buffer can be prepared to make a solution.
Tolvaptan (Samsca®) inhibits the vasopressin-2 receptor in the kidney’s collecting ducts and is approved for SIADH treatment since 2009. Tolvaptan reduces ADH-mediated water reabsorption, leading to increased daily water excretion without affecting electrolyte excretion. This results in an increase in serum sodium levels. Dosage adjustments must be done in the hospital due to the need for frequent monitoring of sodium levels and volume status.
Elevating serum sodium in euvolemic or hypervolemic hyponatremia with Tolvaptan 16-60 mg/day is no longer recommended according to European guidelines. Tolvaptan is contraindicated in hypovolemia.
Hypovolemic Hyponatremia:
Renal causes: Diuretics, adrenal insufficiency, renal salt-wasting syndrome, proximal renal tubular acidosis, ketonuria, osmotic diuresis.
Extrarenal causes: Vomiting, diarrhea, transdermal salt loss, pancreatitis, extensive trauma, cerebral salt-wasting syndrome.
Replace fluid deficit with a balanced electrolyte solution, avoid rapid correction, and closely monitor laboratory values.
Source: Clinical practice guideline on diagnosis and treatment of hyponatraemia. G. Spasovski et. al. European Journal of Endocrinology, 2014, Vol. 170, G1-G47