Hospital Medicine

Hyponatremia

I. Problem/Condition.

Disorders of sodium are usually due to changes in body water and not sodium. It is the most common electrolyte abnormality encountered in Hospital medicine practice. It can be seen in up to 30% of hospitalized patients and can increase the risk of death by more than 50%. One study showed that hyponatremia was associated with a 7.6% increase in hospital length of stay (LOS), an 8.9% increase in hospital costs, and a 9% increase in intensive care unit (ICU) costs. Another study revealed that hyponatremia in heart failure patients was associated with a 25.6% increase in overall hospital costs compared to heart failure patients without hyponatremia.

Normal sodium physiology

Sodium (Na) homeostasis and water balance are under the regulation of the renin-angiotensin system and antidiuretic hormone, respectively. Renin, an enzyme produced by the kidney is released in response to decreases in circulating intravascular volume. Renin catalyzes the production of angiotensin 1 which is then converted to angiotensin 2 in the lung. Angiotensin 2 stimulates the production of aldosterone, produced by the zona glomerulosa of the adrenal glands. Aldosterone enhances Na reabsorption and potassium (K) excretion in the distal nephron.

Antidiuretic hormone (ADH) is synthesized in the hypothalamus and secreted from the posterior pituitary. ADH is released primarily in response to rises in serum osmolality but also to decreases in plasma volume. ADH may be secreted even in the face of hypotonicity. ADH enhances renal water absorption by increasing tubular water permeability. Other factors that may stimulate ADH release include angiotensin, catecholamines, opiates, caffeine, hypoglycemia and stress.

Hyponatremia

Hyponatremia is defined as serum Na less than 135 milliequivalents/liter (meq/L).

Hyponatremia can be acute or chronic. Acute hyponatremia refers to hyponatremia that develops in less than 48 hours, and chronic hyponatremia refers to hyponatremia that is present for more than 48 hours. Acute hyponatremia is more common in hospitalized patients who can as a result have neurologic manifestations and cerebral edema such as headache, vomiting, somnolence, confusion and seizures. Chronic hyponatremia usually occurs in the outpatient setting, and neurologic manifestations are generally minimal and brain size remains normal.

It can further be classified as mild, moderate and severe based on the serum Na concentration.

- Mild if the sodium concentration is between 130 and 135 meq/L.

- Moderate hyponatremia if the serum Na concentration is between 125 and 129 meq/L.

- Severe is the serum sodium concentration is less than 126 meq/L.

Manifestations of hyponatremia

Nausea and malaise are the earliest findings which may be followed by headache, lethargy, obtundation and eventually seizures, coma and respiratory arrest, symptoms are due to neurologic dysfunction induced by cerebral edema and increased intracranial pressure. Neurologic symptoms are much less severe with chronic hyponatremia; symptoms that do occur are fatigue, nausea, dizziness and gait disturbances.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Hyponatremia is classified into isotonic hyponatremia, hypertonic hyponatremia or hypotonic hyponatremia based on the tonicity or osmolality.

Isotonic hyponatremia is hyponatremia with normal osmolality; this is seeen in pseudohyponatremia - marked elevations in serum lipids or proteins result in reduction in the fractions of serum that is water and an artificially low serum sodium concentration (e.g., patients with hyperlipidemia and patients with hyperproteinemia such as in multiple myeloma). It can also occur secondary to absorption of glycine or sorbitol irrigation solutions during transurethreal resection of prostrate (TURP) or bladder surgery or during hysteroscopy or laproscopic surgery.

Hypertonic hyponatremia is hyponatremia with high serum osmolality: this occurs in cases with hyperglycemia, in patients with diabetic ketoacidosis (DKA), or hyperosmolar hyperglycemia, and with mannitol administration (for every 100 millgram/deciliter [mg/dL] increase in glucose, Na decreases by 2.4meq/l). In these cases the serum contains additional osmoles that increases osmolality and sodium concentration is decreased because of water movement from intracellular compartment to the extracellular compartment.

Hypotonic hyponatremia is hyponatremia with low serum osmolality. This is the most common scenario; there is true excess of free water relative to Na.

Hypotonic hyponatremia is further classified according to the volume status of the patient as hypovolemic hyponatremia, euvolemic hyponatremia, or hypervolemic hyponatremia.

B. Describe a diagnostic approach/method to the patient with this problem

Hypovolemic hyponatremia

Hypovolemic hyponatremia- These patients have decreased extracellular volume. Determine if your patient has hypovolemia and volume depletion. Hypovolemia can occurdue to gastrointestinal (GI) losses or due to renal losses. GI losses include vomiting, diarrhea, GI suction, or drainage tubes, fistulas and third spacing of fluids (e.g., burns, intraabdominal sepsis, bowel obstruction, pancreatitis).

Renal losses could be secondary to diuretic use, particularly thiazides, Angiotensin Converting Enzyme (ACE) inhibitor, mineralocorticoid deficiency, renal tubular acidosis and salt wasting nephropathy and cerebral salt wasting syndrome (CSW).

Cerebral salt wasting syndrome (CSW)

CSW is a syndrome that occurs after head injury or neurosurgical procedure. The initiating event is a loss of Na and chloride in the urine which results in a decrease in intravascular volume, leading to water retention and hyponatremia because of baroreceptor mediated stimulus to abnormal vasopressin (AVP) secretion.

High AVP level is the primary differentiating event in patients with syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH).

Mineralocorticoid deficiency

In patients with mineralocorticoid deficiency from primary adrenal insufficiency caused by adrenal destruction or hereditary enzyme deficiencies, renal sodium wasting leads to hypovolemia and secondary volume stimulus, to AVP release.

Euvolemic hyponatremia

Euvolemic patients have normal extracellular volume. In euvolemic hyponatremia there is absolute increase in body water. This can be due to increased fluid intake in the setting of an impaired free water excretion either due to inappropriate vasopressin release or due to low intake of solutes. Some of the causes of euvolemic hyponatremia are SIADH, nephrogenic syndrome of inappropriate antidiuresis, glucocorticoid deficiency, hypothyroidism, (although hypothyroidism is a rare cause of hyponatremia except in case of myxedema), low solute intake like in beer drinkers, post-operative hyponatremia, reset osmostat, and primary polydipsia.

Ask yourself if your patient appears euvolemic. Does your patient have any of the causes that could predispose to euvolemic hyponatremia?

Hypervolemic hyponatremia- These patients have increased extracellular volume. These patients have signs of volume overload such as ascites, subcutaneous edema, and pulmonary edema.

Seen in heart failure, cirrhosis, nephrotic syndrome, and acute and chronic renal failure.

1. Historical information important in the diagnosis of this problem.

Obtain history from patient about any fluid loss such as vomiting, diarrhea, diuretic therapy (particularly thiazide diuretic) any history of small cell lung cancer, or any malignancy, any central nervous system (CNS) disease, history of diabetes, any history of recent surgery such as transurethral resection of prostate, mannitol infusion, h/o hyperlipidemia, cirrhosis, heart failure, renal failure, any drug use such as vincristine, cyclophosphamide, selective serotonin reuptake inhibitors (SSRIs), post-operative state, pain, stress, and history of acquire immunodeficiency syndrome (AIDS).

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Examine patients for signs of extracellular volume depletion, such as decreased skin turgor, low jugular venous pressure or orthostatic/persistent hypotension. Look also for any signs of extracellular volume expansion such as peripheral edema and/or ascites which can be due to heart failure, cirrhosis or renal failure, and any signs and symptoms suggestive of adrenal insufficiency or hypothyroidism.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Obtain chemistry panel

This will help to identify hyperglycemia (which could give clues such as DKA, hyperglycemia causing pseudohyponatremia), renal failure.

Serum osmolality, urine osmolality, urine sodium concentration, and uric acid concentration. If symptoms point to any particular disease state such as hypothyroidism, adrenal insufficiency, etc. then can include the appropriate tests.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Clues to diagnosis

  • Isotonic hyponatremia - serum osmolality will be normal

  • Hypertonic hyponatremia - serum osmolality will be high

  • Hypotonic hyponatremia - serum osmolality will be low

Hypovolemic hyponatremia

Obtain possible clues from history. Physical exam may reveal decreased skin turgor, low jugular venous pressure, or orthostatic or persistent hypotension. If hypovolemia is secondary to renal loses urine Na will be greater than 30 meq/L, fractional excretion of sodium (FENa) greater than 1%, and if hypovolemia is secondary to extra renal losses such as dehydration, diarrhea or vomiting, urine Na will be less than 30 meq/L, and FENa will be below 1%.

Mineralocorticoid deficiency

Volume depletion with high urine Na and accompanying hyperkalemia should raise suspicion of mineralocorticoid deficiency.

Euvolemic hyponatremia

SIADH is the most common cause of euvolemic hyponatremia in clinical medicine.

Causes of SIADH are the following:

  • Central nervous system (CNS) diseases such as tumors, meningitis, encephalitis, Guillain-Barre Syndrome, Delirium tremens.

  • Pulmonary diseases such as pneumonia, tuberculosis (TB), lung abscess, pulmonary aspergillosis, cystic fibrosis.

  • Drugs such as diuretics, vincristine, cyclophosphamide, exogenous vasopressin, selective serotonin reuptake inhibitors (SSRIs) and thiazides and antipsychotics.

  • Malignancies such as bronchogenic cancer, small cell cancer, leukemia, lymphomas.

  • Others such as post-operative state, pain, stress, hypokalemia.

  • AIDS

Glucocorticoid deficiency

From adrenocorticotropic hormone (ACTH) deficiency, hyponatremia results from a failure to fully suppress arginine vasopressin (AVP) release in response to hypo-osmolality.

Hypothyroidism

The major cause of impaired water excretion in hypothyroidism appears to be an alteration in renal perfusion and decrease in glomerular filtration rate (GFR) and low cardiac output. If history, signs and symptoms points to hypothyroidism then obtain thyroid-stimulating hormone (TSH) level.

Marathon Runners

Runners are overhydrated as a result of excessive water intake secondary to erroneous advice on water ingestion.

Beer potamania

Hyponatremia occurs in beer drinkers, secondary to increase in fluid intake, in the setting of very low solute intake.

Tea and toast syndrome

Hyponatremia will be present in malnourished patients who have very low solute intake.

Post-operative hyponatremia

Secondary to administration of hypotonic fluids, they appear clinically euvolemic and have measurable levels of AVP in their circulation. AVP release occurs appropriately secondary to pain.

Reset osmostat

This occurs when the threshold for antidiuretic hormone secretion is set downward. This condition is chronic. Hyponatremia, can be caused by pregnancy, quadriplegia, malignancy, malnutrition, or any chronic debilitating disease.

  • In patients with euvolemia, if urine osmolality is greater than 100 milliosomoles/kilogram water (mOsm/kg H20), think of SIADH, adrenal insufficiency, and hypothyroidism.

  • If urine osm is less than 100 mOsm/kg H20, think of primary polydipsia and low solute intake.

  • If urine osmolality is variable, think of reset osmostat.

In SIADH -urine Na is greater than 30 meq/liter, urine osmolality exceeds 100 mosm/kg of water and clinical euvolemia is present, serum osm is <275 mosm/kg, hypouricemia and low blood urea nitrogen (BUN) may also be present.

Hypervolemic hyponatremia

  • In patients with hypervolemic hyponatremia, if urine Na is below 10 meq/L and FENa is below 1%, think of cirrhosis, heart failure, and nephrotic syndrome.

  • If urine Na is greater than 20 meq/L and FENa is greater than 1%, think of renal failure.

Hypervolemic hyponatremia is seen in the following conditions:

  • Heart Failure: Effective circulating blood volume is low in heart failure. Baroreceptor mediated activation causing non-osmotic release of AVP is the cause of water retention and hyponatremia in CHF.

  • Cirrhosis: Reduction of effective arterial blood volume causes vasopressin release which causes water retention and hyponatremia.

  • Nephrotic syndrome and acute and chronic renal failure: Hyponatremia occurs in both acute and chronic renal failure because kidneys cannot maximally exercise excess ingested or infused water. In nephrotic syndrome severe hypoalbuminemia leads to intravascular hypovolemia, and that leads to nonosmotic release of AVP which causes retention of ingested or infused hypotonic fluids.

III. Management while the Diagnostic Process is Proceeding

A. Management of Hyponatremia.

Treatment decision is based on the presence of symptoms, the degree of volume depletion and whether the condition is acute or chronic.

Acute hyponatremia

  • Na less than 125 meq/L id usually associated with symptoms.

  • Acute hyponatremia should be treated urgently because of the risk of cerebral edema and hyponatremia encephalopathy.

  • Correct with hypertonic saline (3% saline) usually a 100 milliliter (ml) bolus given over 10 or 15 minutes and can be repeated if needed. The goal is to raise the Na concentration by less than 10 mEq in the first 24 hours and less than 18 mEq in the first 48 hours.

Chronic hyponatremia

  • Overzealous correction should be avoided because it can lead to central pontine myelinolysis. Stop fluids and medications that can cause hyponatremia.

  • The degree to which one liter of a given solution will initially raise the serum sodium concentration (SNa) can be estimated from the following formula (TBW is the estimated total body water [lean body water times 0.5 for women, 0.6 for men]):

Change in serum Na= (infusate Na-Serum Na)

TBW+1

  • If the infusate also contains potassium in addition to Na then the following formula can be used:

Change in serum Na= (infusate Na + infusate K) - serum Na

TBW +1

Treatment of hypovolemic hyponatremia

  • Fluid resuscitation is the goal of treatment.

  • Patients with vomiting - treat with isotonic saline (add potassium to the fluid if labs show hypokalemia and metabolic alkalosis also with low Na).

  • Patients with diarrhea (with labs revealing metabolic acidosis along with low Na) - infuse isonatric mixture of sodium chloride and sodium bicarbonate.

  • Patients who are on diuretics - stop the diuretics and infuse isotonic saline. If the patient is on thiazide diuretic stop the thiazide and do not rechallenge in future.

  • Patients with cerebral salt wasting syndrome -resuscitate with isotonic saline until they are euvolemic.

  • Patients with Mineralocorticoid deficiency - volume repletion with isotonic saline

Treatment of euvolemic hyponatremia

  • For patients with SIADH - fluid restriction to 800 ml is the treatment of choice, if fluid resuscitation is not successful then pharmacologic therapies can be tried. Preferred drug therapy is Demeclocycline (600 to 1200 mg daily). Avoid Demeclocycline in chronic hyponatremia as there is concern of possible harm. Oral urea is helpful in achieving increased solute intake. Urea has bitter taste hence combining with sweet tasting substances are helpful, however, urea is not readily available in United States.

  • Oral salt tablets - oral salt tablets may be helpful in raising the sodium level.

  • Loop diuretic such as furosemide when given along with salt tablets lowers urine osmolality and increases water excretion.

  • Patients with malignancy - treat the underlying malignant lesion, this often eliminates or reduces the inappropriate AVP secretion.

  • Hypothyrodism - treat with thyroid hormone replacement.

  • Glucocorticoid deficiency - glucocorticoid replacement should be started.

  • Patients with low solute intake - correct by instituting proper nutrition with increased content of solute both as electrolytes and protein.

  • Patients with primary polydipsia - treat with fluid restriction by behavior modification and pharmacologic therapy for psychiatric disorders (as it commonly occurs in patients with schizophrenia), wetting mouth with ice chips or sour candy also is helpful.

Hypervolemic hyponatremia treatment

  • Patients with congestive heart failure (CHF) - sodium restriction, fluid restriction to below 1L/day, diuretic therapy and neurohormonal blockade. The most effective treatment consists of combination of loop diuretics, ACE inhibitors, beta-adrenergic blockers.

  • Patients with cirrhosis - sodium restriction, fluid restriction, diuretic therapy and large volume paracentesis. The potassium sparing diuretic spironolactone is effective.

  • Patients with nephrotic syndrome, acute and chronic renal failure - fluid restriction to amount less than insensible losses plus urine output is generally necessary to cause a negative solute free water balance and correction of hyponatremia.

Newer pharmacological agents (arginine vasopressin receptor antagonists)

These agents, known as vaptans, have aquaretic effect (increase free water clearance without causing Na or Potassium losses). They prevent vasopressin from binding to vasopressin 2 (V2) receptors and cause the collecting duct to be impermeable to water and thereby block the action of vasopressin. They increase the Na by an average of 4 to 8 meq within 24 to 48 hours, however, they will not be effective if serum creatinine is greater than 2 milligram/deciliter (mg/dl).

Oral formulations are tolvaptan, mozavaptan, satavaptan and lixivaptan. They are selective for V2 receptors.

Conivaptan blocks both V1 and V2 receptors. Conivaptan requires intravenous administration. Conivaptan and tolvaptan are approved for treatment of euvolemic and hypervolemic hyponatremia. Tolvapatan should not given to liver disease patients and should not be used longer than 30 days.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Monitoring patients undergoing active treatment with hypertonic saline is essential so that serum Na is not corrected rapidly. Limit the increase in sodium to a total of 10 meq/L during the first 24 hrs and an additional 8 meq/L every 24 hrs thereafter until the sodium concentration reaches 130 meq/L. Monitor serum sodium every 2 to 4 hours to ensure that serum Na does not exceed the recommended levels during the active phase of correction, as rapid correction can cause damage to the myelin sheath of nerve cells resulting in osmotic demyelination syndrome. Neurologic symptoms usually occur 1 to 6 days after correction and often are irreversible.

In patients treated with vaptans, Na should be monitored every 6 to 8 hours during the active phase of correction which is generally the first 24 to 48 hours of therapy. Active treatment with hypertonic saline or vaptans should be stopped when patients’ symptoms are no longer present a safe serum Na, usually 120 meq/l has been achieved or the rate of correction has reached 12 meq/L within 24 hours, or 18 meq/L within 48 hours.

A reasonable period of tolvaptan cessation in order to evaluate for the presence of continued SIADH is 7 days. Serum Na should be monitored every 2 to 3 days after stopping tolvaptan so that the drug can be resumed as quickly as possible in those patients with recurrent hyponatremia because the longer the patient is hyponatremic, the greater the risk of subsequent osmotic demyelination with overly rapid correction of the low serum Na.

Consultation with nephrology is advised in severe symptomatic refractory, complicated cases of hyponatremia, and those who are undergoing aggressive therapies with hypertonic saline, demeclocycline, vasopressin antagonist or dialysis. Consultation should also be considered for patients with end-stage liver or heart disease.

What’s the evidence?

Adrogue, HJ, Madias, NE. "Hyponatremia". N Engl J med. vol. 342. 2000. pp. 1581.

Verbalis, JG, Goldsmith, SR, Greenberg, A, Schrier, RW, Sterns, RH. "Hyponatremia treatment guidelines 2007: expert panel recommendations". Am J Med. vol. 120. 2007. pp. S1.

Liamis, G, Milionis, H, Elisaf, M. "A review of drug induced hyponatremia". AM J Kidney Dis. vol. 52. 2008. pp. 144-53.

Ellison, DH, Beri, T. "Clinical practice. The syndrome of inappropriate antidiuresis". N Engl J Med. vol. 17. 2007. pp. 356.

Lien, YH, Shapiro, JI. "Hyponatremia: Clinical Diagnosis and Management". AM J Med. vol. 120. 2007. pp. 653-658.

Brenner, BM, Rector, FC. "Brenner & Rector’s the Kidney". Saunders Elsevier. 2008.

Marx, J. "Rosen’s Emergency Medicine". Mosby. 2009.

Goh, PK. "Management of Hyponatremia". Am Academy of Family Physicians. vol. 69. 2004.

Waikar, SS, Mount, DB, Curhan, GC. "Mortality after hospitalization with mild, moderate, and severe hyponatremia". AM J Med. vol. 122. 2009. pp. 857-865.

Deitelzweig, S, Amin, A, Christian, R, Friend, K, Lin, J, Lowe, TJ. "Health care utilization, costs and readmission rates associated with hyponatremia". Hosp Pract. vol. 41. 2013. pp. 89-95.

Amin, A, Deitelzweig, S, Christian, R, Friend, K, Lin, J, Lowe, TJ. "Healthcare resource burden associated with hyponatremia among patients hospitalized for heart failure in the US". J Med Econ. vol. 16. 2013. pp. 415-420.

Spasovski, G, Vanholder, R, Allolio, B. "Clinical practice guideline on diagnosis and treatment of hyponatremia". Eur J Endocrinol. vol. 29. 2014. pp. 2ii1-ii39.

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