Diagnosis and Management of Sodium Disorders: Hyponatremia and Hypernatremia

 


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Hyponatremia and hypernatremia are common findings in the inpatient and outpatient settings. Sodium disorders are associated with an increased risk of morbidity and mortality. Plasma osmolality plays a critical role in the pathophysiology and treatment of sodium disorders. Hyponatremia and hypernatremia are classified based on volume status (hypovolemia, euvolemia, and hypervolemia). Sodium disorders are diagnosed by findings from the history, physical examination, laboratory studies, and evaluation of volume status. Treatment is based on symptoms and underlying causes. In general, hyponatremia is treated with fluid restriction (in the setting of euvolemia), isotonic saline (in hypovolemia), and diuresis (in hypervolemia). A combination of these therapies may be needed based on the presentation. Hypertonic saline is used to treat severe symptomatic hyponatremia. Medications such as vaptans may have a role in the treatment of euvolemic and hypervolemic hyponatremia. The treatment of hypernatremia involves correcting the underlying cause and correcting the free water deficit.

Hyponatremia is a common electrolyte disorder defined as a serum sodium level of less than 135 mEq per L.13 A Dutch systematic review of 53 studies showed that the prevalence of mild hyponatremia was 22.2% in geriatric hospital wards, 6.0% in nongeriatric wards, and 17.2% in the intensive care unit.2 The prevalence of severe hyponatremia (serum sodium level less than 125 mEq per L) was 4.5%, 0.8%, and 10.3%, respectively. It is estimated that hyponatremia occurs in 4% to 7% of the ambulatory population, with rates of 18.8% in nursing homes.24

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferencesComments

In patients with severe symptomatic hyponatremia, the rate of sodium correction should be 6 to 12 mEq per L in the first 24 hours and 18 mEq per L or less in 48 hours.

C

13, 14

Consensus guidelines based on systematic reviews

A bolus of 100 to 150 mL of hypertonic 3% saline can be given to correct severe hyponatremia.

C

13, 14

Consensus guidelines based on small studies

Vaptans appear to be safe for the treatment of severe hypervolemic and euvolemic hyponatremia but should not be used routinely.

C

14

Consensus guidelines based on observational studies

Chronic hypernatremia should be corrected at a rate of 0.5 mEq per L per hour, with a maximum change of 8 to 10 mEq per L in a 24-hour period.

C

33

Expert opinion


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferencesComments

In patients with severe symptomatic hyponatremia, the rate of sodium correction should be 6 to 12 mEq per L in the first 24 hours and 18 mEq per L or less in 48 hours.

C

13, 14

Consensus guidelines based on systematic reviews

A bolus of 100 to 150 mL of hypertonic 3% saline can be given to correct severe hyponatremia.

C

13, 14

Consensus guidelines based on small studies

Vaptans appear to be safe for the treatment of severe hypervolemic and euvolemic hyponatremia but should not be used routinely.

C

14

Consensus guidelines based on observational studies

Chronic hypernatremia should be corrected at a rate of 0.5 mEq per L per hour, with a maximum change of 8 to 10 mEq per L in a 24-hour period.

C

33

Expert opinion


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

Hyponatremia is associated with increased morbidity and mortality.16 In patients with heart failure who undergo cardiac surgery, hyponatremia increases rates of postoperative complications, length of hospital stay, and mortality.5,6 Mild hyponatremia in the ambulatory setting is associated with increased mortality (hazard ratio = 1.94) compared with normal sodium levels.3 Patients who develop hyponatremia during hospitalization have increased mortality rates compared with those who have hyponatremia on admission.7,8 It is unclear if hyponatremia is a marker for poor prognostic outcomes or merely a reflection of disease severity. Its presence suggests a worse prognosis in patients with liver cirrhosis, pulmonary hypertension, myocardial infarction, chronic kidney disease, hip fractures, and pulmonary embolism.1,810

Etiology and Pathophysiology

The most common classification system for hyponatremia is based on volume status: hypovolemic (decreased total body water with greater decrease in sodium level), euvolemic (increased total body water with normal sodium level), and hypervolemic (increased total body water compared with sodium).11

Plasma osmolality has a role in the pathophysiology of hyponatremia. Osmolality refers to the total concentration of solutes in water. Effective osmolality is the osmotic gradient created by solutes that do not cross the cell membrane. Effective osmolality determines the osmotic pressure and the flow of water.11 Plasma osmolality is maintained by strict regulation of the arginine vasopressin (also called antidiuretic hormone [ADH]) system and thirst. If plasma osmolality increases, ADH is secreted and water is retained by the kidneys, thus decreasing serum osmolality. If plasma osmolality decreases, ADH also decreases, resulting in diuresis of free water and a return to homeostasis.12,13

Diagnostic Approach to Hyponatremia

Symptoms of hyponatremia depend on its severity and on the rate of sodium decline. Gradual decreases in sodium usually result in minimal symptoms, whereas rapid decreases can result in severe symptoms. Polydipsia, muscle cramps, headaches, falls, confusion, altered mental status, obtundation, coma, and status epilepticus may indicate the need for acute intervention. Most patients with hyponatremia are asymptomatic, and hyponatremia is noted incidentally. Volume status should be assessed to help determine the underlying cause11,13 (Figure 11116[ corrected]).

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Evaluation of Hyponatremia

Figure 1.

Algorithm for the evaluation of hyponatremia

Information from references 11 through 16.

Evaluation of Hyponatremia


Figure 1.

Algorithm for the evaluation of hyponatremia

Information from references 11 through 16.

The diagnostic workup should include a history and physical examination with specific attention to cardiac, cancer, pulmonary, surgical, endocrine, gastrointestinal, neurologic, and renal histories (Table 1).1113 Diuretics, carbamazepine (Tegretol), and selective serotonin reuptake inhibitors can cause hypovolemia; therefore, medications should be reviewed. Alcohol and illicit drug use (especially beer and 3,4-methylenedioxymethamphetamine [“Ecstasy”]) can cause hyponatremia.1113 Athletes should be asked about training regimens because high endurance activities can lead to hyponatremia.

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Table 1.

Differential Diagnosis and Treatment of Hyponatremia

ConditionDiagnosisTreatment

Pseudohyponatremia

Hyperglycemia (e.g., in diabetic ketoacidosis)

Elevated glucose levels (> 400 mg per dL [22.2 mmol per L]), elevated anion gap

Insulin, intravenous fluids, isotonic saline

Hyperlipidemia

Elevated total and low-density lipoprotein cholesterol levels

Statin therapy

Hyperproteinemia (e.g., in multiple myeloma)

Serum and urinary monoclonal protein, bone marrow biopsy, lytic bone lesions detected on radiography

Chemotherapy

Laboratory errors

Repeat sodium levels

Hypovolemic hyponatremia

Cerebral salt wasting

Diagnosis of exclusion (e.g., head injuries, intracranial hemorrhage); urinary sodium > 20 mEq per L

Isotonic or hypertonic saline

Diuretic use

Clinical; urinary sodium > 20 mEq per L

Stop diuretic therapy

Gastrointestinal loss (e.g., diarrhea, vomiting)

Clinical; urinary sodium < 20 mEq per L

Intravenous fluids

Mineralocorticoid deficiency (e.g., Addison disease [primary], pituitary failure [secondary], hypothalamic failure [tertiary])

Low aldosterone and morning cortisol levels, hyperkalemia, increased plasma renin level, low or increased adrenocorticotropic hormone level (cause-dependent), urinary sodium > 20 mEq per L, positive results on cosyntropin stimulation test, 21-hydroxylase autoantibodies (Addison disease), computed tomography of adrenal glands to rule out infarction

Steroid replacement therapy

Osmotic diuresis

Elevated glucose level, mannitol use

Correct glucose level, stop mannitol use

Renal tubular acidosis

Urinary osmolar gap, increased urinary pH, urinary sodium > 25 mEq per L, fractional excretion of bicarbonate > 15% to 20%, hyperchloremic acidosis, decreased serum bicarbonate level, potassium abnormalities (type dependent)

Correct acidosis, sodium bicarbonate

Salt-wasting nephropathies

Urinary sodium > 20 mEq per L

Correct underlying cause

Third spacing (e.g., bowel obstruction, burns)

Clinical; computed tomography

Intravenous fluids, relieve obstruction

Euvolemic hyponatremia

3,4-methylenedioxymeth-amphetamine (“Ecstasy”) use

Urine drug screen

Beer potomania syndrome

Excessive alcohol consumption, low serum osmolality

Therapy to decrease alcohol use and nutritional counseling to increase protein intake

Exercise-associated hyponatremia

Clinical

Isotonic or hypertonic saline, depending on symptoms

Glucocorticoid deficiency

Low aldosterone, morning cortisol, and adrenocorticotropic hormone levels, hyperkalemia, increased plasma renin level

Steroid replacement therapy

Hypothyroidism

Elevated thyroid-stimulating hormone level, low free thyroxine level

Thyroid replacement therapy

Low solute intake

Clinical

Increase sodium intake

Nephrogenic SIADH

Same as SIADH, with low vasopressin levels

Fluid restriction, loop diuretics

Psychogenic polydipsia

History of schizophrenia with excessive water intake

Psychiatric therapy

Reset osmostat

Free water challenge test, normal fractional excretion of uric acid (urate)

Treat underlying disease

SIADH

Decreased osmolality, urinary osmolality > 100 mOsm per kg, euvolemia, urinary sodium > 20 mEq per L, absence of thyroid disorders or hypocortisolism, normal renal function, no diuretic use

Fluid restriction, consider vaptans

SIADH secondary to medication use (e.g., barbiturates, carbamazepine [Tegretol], chlorpropamide, diuretics, opioids, selective serotonin reuptake inhibitors, tolbutamide, vincristine)

SIADH with use of causative agent

Stop causative medication

Water intoxication

Clinical; excessive water intake

Diuresis

Hypervolemic hyponatremia

Heart failure

Clinical (e.g., jugular venous distention, edema), elevated B-type natriuretic peptide level, echocardiography, urinary sodium < 20 mEq per L

Diuretics, angiotensin-converting enzyme inhibitors, beta blockers

Hepatic failure/cirrhosis

Elevated liver function tests, ascites, elevated ammonia level, biopsy, urinary sodium < 20 mEq per L

Furosemide (Lasix), spironolactone (Aldactone), transplant

Nephrotic syndrome

Urinary protein, urinary sodium < 20 mEq per L

Treat underlying cause

Renal failure (acute or chronic)

Blood urea nitrogen–to-creatinine ratio, glomerular filtration rate, proteinuria, urinary sodium > 20 mEq per L

Correct underlying disease with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers


SIADH = syndrome of inappropriate antidiuretic hormone secretion.

Information from references 11 through 13.

Table 1.

Differential Diagnosis and Treatment of Hyponatremia

ConditionDiagnosisTreatment

Pseudohyponatremia

Hyperglycemia (e.g., in diabetic ketoacidosis)

Elevated glucose levels (> 400 mg per dL [22.2 mmol per L]), elevated anion gap

Insulin, intravenous fluids, isotonic saline

Hyperlipidemia

Elevated total and low-density lipoprotein cholesterol levels

Statin therapy

Hyperproteinemia (e.g., in multiple myeloma)

Serum and urinary monoclonal protein, bone marrow biopsy, lytic bone lesions detected on radiography

Chemotherapy

Laboratory errors

Repeat sodium levels

Hypovolemic hyponatremia

Cerebral salt wasting

Diagnosis of exclusion (e.g., head injuries, intracranial hemorrhage); urinary sodium > 20 mEq per L

Isotonic or hypertonic saline

Diuretic use

Clinical; urinary sodium > 20 mEq per L

Stop diuretic therapy

Gastrointestinal loss (e.g., diarrhea, vomiting)

Clinical; urinary sodium < 20 mEq per L

Intravenous fluids

Mineralocorticoid deficiency (e.g., Addison disease [primary], pituitary failure [secondary], hypothalamic failure [tertiary])

Low aldosterone and morning cortisol levels, hyperkalemia, increased plasma renin level, low or increased adrenocorticotropic hormone level (cause-dependent), urinary sodium > 20 mEq per L, positive results on cosyntropin stimulation test, 21-hydroxylase autoantibodies (Addison disease), computed tomography of adrenal glands to rule out infarction

Steroid replacement therapy

Osmotic diuresis

Elevated glucose level, mannitol use

Correct glucose level, stop mannitol use

Renal tubular acidosis

Urinary osmolar gap, increased urinary pH, urinary sodium > 25 mEq per L, fractional excretion of bicarbonate > 15% to 20%, hyperchloremic acidosis, decreased serum bicarbonate level, potassium abnormalities (type dependent)

Correct acidosis, sodium bicarbonate

Salt-wasting nephropathies

Urinary sodium > 20 mEq per L

Correct underlying cause

Third spacing (e.g., bowel obstruction, burns)

Clinical; computed tomography

Intravenous fluids, relieve obstruction

Euvolemic hyponatremia

3,4-methylenedioxymeth-amphetamine (“Ecstasy”) use

Urine drug screen

Beer potomania syndrome

Excessive alcohol consumption, low serum osmolality

Therapy to decrease alcohol use and nutritional counseling to increase protein intake

Exercise-associated hyponatremia

Clinical

Isotonic or hypertonic saline, depending on symptoms

Glucocorticoid deficiency

Low aldosterone, morning cortisol, and adrenocorticotropic hormone levels, hyperkalemia, increased plasma renin level

Steroid replacement therapy

Hypothyroidism

Elevated thyroid-stimulating hormone level, low free thyroxine level

Thyroid replacement therapy

Low solute intake

Clinical

Increase sodium intake

Nephrogenic SIADH

Same as SIADH, with low vasopressin levels

Fluid restriction, loop diuretics

Psychogenic polydipsia

History of schizophrenia with excessive water intake

Psychiatric therapy

Reset osmostat

Free water challenge test, normal fractional excretion of uric acid (urate)

Treat underlying disease

SIADH

Decreased osmolality, urinary osmolality > 100 mOsm per kg, euvolemia, urinary sodium > 20 mEq per L, absence of thyroid disorders or hypocortisolism, normal renal function, no diuretic use

Fluid restriction, consider vaptans

SIADH secondary to medication use (e.g., barbiturates, carbamazepine [Tegretol], chlorpropamide, diuretics, opioids, selective serotonin reuptake inhibitors, tolbutamide, vincristine)

SIADH with use of causative agent

Stop causative medication

Water intoxication

Clinical; excessive water intake

Diuresis

Hypervolemic hyponatremia

Heart failure

Clinical (e.g., jugular venous distention, edema), elevated B-type natriuretic peptide level, echocardiography, urinary sodium < 20 mEq per L

Diuretics, angiotensin-converting enzyme inhibitors, beta blockers

Hepatic failure/cirrhosis

Elevated liver function tests, ascites, elevated ammonia level, biopsy, urinary sodium < 20 mEq per L

Furosemide (Lasix), spironolactone (Aldactone), transplant

Nephrotic syndrome

Urinary protein, urinary sodium < 20 mEq per L

Treat underlying cause

Renal failure (acute or chronic)

Blood urea nitrogen–to-creatinine ratio, glomerular filtration rate, proteinuria, urinary sodium > 20 mEq per L

Correct underlying disease with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers


SIADH = syndrome of inappropriate antidiuretic hormone secretion.

Information from references 11 through 13.

Laboratory tests include a complete metabolic panel and urinary sodium and creatinine levels.11,13  Serum osmolality and fractional excretion of sodium should be calculated (eTable A). Measurement of thyroid-stimulating hormone, urinary uric acid, adrenocorticotropic hormone, plasma cortisol, and brain natriuretic peptide may be considered in select patients to rule out other causes.13 The diagnosis of reset osmostat (a variation of syndrome of inappropriate antidiuretic hormone secretion [SIADH] in which ADH secretion occurs despite low plasma osmolality) may be aided using fractional excretion of urate (uric acid) in nonedematous patients who have hyponatremia that does not respond to usual treatment.17

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eTable A.

Sodium Equations and Online Calculators

MeasurementEquation

Corrected sodium

Measured sodium + 0.024 × (serum glucose − 100)*

or

Measured sodium + 0.016 × (serum glucose − 100)

Normal = 135 to 145 mEq per L

Online calculators available at http://www.mdcalc.com/sodium-correction-for-hyperglycemia and http://www.medcalc.com/correctna.html

Fractional excretion of sodium

([Plasma creatinine × urinary sodium] / [plasma sodium × urinary creatinine]) × 100

Prerenal < 1%, intrinsic > 1%, and postrenal > 4%

Online calculators available at http://www.mdcalc.com/fractional-excretion-of-sodium-fena and http://www.medcalc.com/fena.html

Infusion rate of sodium

Online calculators for the rate of infusion and the concentration of sodium required are available at http://www.mdcalc.com/sodium-correction-rate-in-hyponatremia, http://www.medcalc.com/sodium.html, and http://www.nephromatic.com/sodium_correction.php

Serum sodium correction should generally not proceed faster than 0.5 mEq per L per hour for the first 24 to 48 hours; however, in severely symptomatic patients, the rate can be 1.0 to 2.0 mEq per L per hour; these situations typically require use of 3% saline

The goal is to raise the serum sodium level not to exceed 10 to 12 mEq per L in the first 24 hours and 18 mEq per L in the first 48 hours

Isotonic saline contains 154 mEq of sodium per L, and 3% saline contains 513 mEq of sodium per L

Serum osmolality

(Sodium × 2) + (glucose / 18) + (blood urea nitrogen / 2.8)

Normal = 280 to 295 mOsm per kg

In patients with hyperglycemia, uncorrected sodium should be used to calculate the osmolality

Online calculators available at http://www.mdcalc.com/serum-osmolality-osmolarity and http://www.medcalc.com/osmol.html

Sodium deficit

Total body water % × weight in kg × (desired sodium − actual sodium)

For total body water %, use 0.6 for men and 0.5 for women

Example: for a 70-kg man with a serum sodium level of 120 mEq per L and a desired serum sodium level of 140 mEq per L, the calculation is 0.6 × 70 (140 − 120) = 42 × 20 = 840 mEq

Online calculator available at http://www.mdcalc.com/sodium-deficit-in-hyponatremia

Water deficit

Volume (L) = (total body water %) × weight in kg × [(sodium − 140) / 140]

For total body water %, use 0.45 for women older than 65 years, 0.5 for women 65 years and younger and for men older than 65 years, and 0.6 for men 65 years and younger and for children

Example: for a 70-kg man with a serum sodium level of 120 mEq per L, the calculation is 0.6 × 70 × ([120 − 140] / 140) = 42 × (−20 / 140) = 42 × (−1 / 7) = −6 L

Online calculators available at http://www.mdcalc.com/free-water-deficit-in-hypernatremia and http://www.medcalc.com/freewater.html


*—A 1999 study that evaluated six healthy patients, induced hyperglycemia, and measured actual serum sodium levels found that a sodium correction factor of 2.4 mEq per L was more accurate than the traditional 1.6 mEq per L.

Information from: Adrogué HJ, et al. Hypernatremia. N Engl J Med. 2000;342(20):1493–1499.

Bhagat CI, et al. Calculated vs measured plasma osmolalities revisited. Clin Chem. 1984;30(10):1703–1705.

Hillier TA, et al. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106(4):399–403.

Katz MA. Hyperglycemia-induced hyponatremia–calculation of expected serum sodium depression. N Engl J Med. 1973;289(16):843–844.

Pfennig CL, et al. Sodium disorders in the emergency department: a review of hyponatremia and hypernatremia. Emerg Med Pract. 2012;14(10):1–26.

eTable A.

Sodium Equations and Online Calculators

MeasurementEquation

Corrected sodium

Measured sodium + 0.024 × (serum glucose − 100)*

or

Measured sodium + 0.016 × (serum glucose − 100)

Normal = 135 to 145 mEq per L

Online calculators available at http://www.mdcalc.com/sodium-correction-for-hyperglycemia and http://www.medcalc.com/correctna.html

Fractional excretion of sodium

([Plasma creatinine × urinary sodium] / [plasma sodium × urinary creatinine]) × 100

Prerenal < 1%, intrinsic > 1%, and postrenal > 4%

Online calculators available at http://www.mdcalc.com/fractional-excretion-of-sodium-fena and http://www.medcalc.com/fena.html

Infusion rate of sodium

Online calculators for the rate of infusion and the concentration of sodium required are available at http://www.mdcalc.com/sodium-correction-rate-in-hyponatremia, http://www.medcalc.com/sodium.html, and http://www.nephromatic.com/sodium_correction.php

Serum sodium correction should generally not proceed faster than 0.5 mEq per L per hour for the first 24 to 48 hours; however, in severely symptomatic patients, the rate can be 1.0 to 2.0 mEq per L per hour; these situations typically require use of 3% saline

The goal is to raise the serum sodium level not to exceed 10 to 12 mEq per L in the first 24 hours and 18 mEq per L in the first 48 hours

Isotonic saline contains 154 mEq of sodium per L, and 3% saline contains 513 mEq of sodium per L

Serum osmolality

(Sodium × 2) + (glucose / 18) + (blood urea nitrogen / 2.8)

Normal = 280 to 295 mOsm per kg

In patients with hyperglycemia, uncorrected sodium should be used to calculate the osmolality

Online calculators available at http://www.mdcalc.com/serum-osmolality-osmolarity and http://www.medcalc.com/osmol.html

Sodium deficit

Total body water % × weight in kg × (desired sodium − actual sodium)

For total body water %, use 0.6 for men and 0.5 for women

Example: for a 70-kg man with a serum sodium level of 120 mEq per L and a desired serum sodium level of 140 mEq per L, the calculation is 0.6 × 70 (140 − 120) = 42 × 20 = 840 mEq

Online calculator available at http://www.mdcalc.com/sodium-deficit-in-hyponatremia

Water deficit

Volume (L) = (total body water %) × weight in kg × [(sodium − 140) / 140]

For total body water %, use 0.45 for women older than 65 years, 0.5 for women 65 years and younger and for men older than 65 years, and 0.6 for men 65 years and younger and for children

Example: for a 70-kg man with a serum sodium level of 120 mEq per L, the calculation is 0.6 × 70 × ([120 − 140] / 140) = 42 × (−20 / 140) = 42 × (−1 / 7) = −6 L

Online calculators available at http://www.mdcalc.com/free-water-deficit-in-hypernatremia and http://www.medcalc.com/freewater.html


*—A 1999 study that evaluated six healthy patients, induced hyperglycemia, and measured actual serum sodium levels found that a sodium correction factor of 2.4 mEq per L was more accurate than the traditional 1.6 mEq per L.

Information from: Adrogué HJ, et al. Hypernatremia. N Engl J Med. 2000;342(20):1493–1499.

Bhagat CI, et al. Calculated vs measured plasma osmolalities revisited. Clin Chem. 1984;30(10):1703–1705.

Hillier TA, et al. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106(4):399–403.

Katz MA. Hyperglycemia-induced hyponatremia–calculation of expected serum sodium depression. N Engl J Med. 1973;289(16):843–844.

Pfennig CL, et al. Sodium disorders in the emergency department: a review of hyponatremia and hypernatremia. Emerg Med Pract. 2012;14(10):1–26.

Pseudohyponatremia

Pseudohyponatremia occurs when seemingly low sodium levels are actually normal. Causes include hyperglycemia, hyperproteinemia, mannitol use, or laboratory errors. Osmolality remains unchanged, and patients are usually euvolemic.12,13  A corrected sodium calculation is needed in the setting of hyperglycemia (eTable A).

Hypovolemic Hyponatremia

There are numerous causes of hypovolemic hyponatremia (Table 1).1113 Patients typically have signs and symptoms associated with volume depletion (e.g., vomiting, diarrhea, tachycardia, elevated blood urea nitrogen–to-creatinine ratio). Urinary sodium levels are typically less than 20 mEq per L unless the kidney is the site of sodium loss. Fractional excretion of sodium is often inaccurately elevated in patients receiving diuretics because of diuretic-induced natriuresis; fractional excretion of urea can be utilized in these patients instead. Fractional excretion of urea less than 35% is more sensitive and specific for diagnosing prerenal azotemia in this setting.18 Treatment generally consists of volume repletion with isotonic (0.9%) saline, occasional use of salt tablets, and treatment of the underlying condition.13,14 Monitoring of urine output is recommended because output of more than 100 mL per hour can be a warning sign of overcorrection.14

Euvolemic Hyponatremia

Euvolemic hyponatremia is most commonly caused by SIADH, but can also be caused by hypothyroidism and glucocorticoid deficiency. Euvolemia is diagnosed by findings from the history and physical examination, low serum uric acid levels, a normal blood urea nitrogen–to-creatinine ratio, and spot urinary sodium greater than 20 mEq per L. Diuretic therapy can artificially elevate urinary sodium, whereas a low-salt diet can artificially lower urinary sodium, thus clouding the diagnosis of hypovolemia vs. euvolemia. Treatment generally consists of fluid restriction and correcting the underlying cause. Fluid restriction should be limited to 500 mL less than the daily urinary volume.13 Salt and protein intake should not be restricted. Predictors of failure with fluid restriction include urinary osmolality greater than 500 mOsm per kg, 24-hour urinary volume less than 1.5 L, an increase in the serum sodium level of less than 2 mEq per L within 24 to 48 hours, and a serum sodium level less than the sum of the urinary sodium and potassium levels.13 Volume status can be difficult to determine; therefore, a trial of intravenous fluids may be warranted.11 Sodium levels in patients with SIADH will decrease further with intravenous fluid administration. The use of demeclocycline (Declomycin) and lithium is not recommended because of an increased risk of harm.14

Hypervolemic Hyponatremia

Hypervolemic hyponatremia occurs when the kidneys cannot excrete water efficiently. In volume overload states, the effective arterial blood volume is decreased compared with venous volume, resulting in excess ADH secretion. The most common causes of hypervolemic hyponatremia are heart failure, cirrhosis, and kidney injury. Treatment consists of correcting the underlying cause, sodium and fluid restriction, and diuretic therapy to increase excretion of solute-free water.13,14 A randomized controlled trial of 46 patients with heart failure showed that restricting fluid intake to 1 L per day improved quality of life 60 days after discharge.19

Severe Symptomatic Hyponatremia

Severe symptomatic hyponatremia occurs when sodium levels decrease over less than 24 hours. Severe symptoms (e.g., coma, seizures) typically occur when the sodium level falls below 120 mEq per L, but can occur at less than 125 mEq per L. Severe symptomatic hyponatremia must be corrected promptly because it can lead to cerebral edema, irreversible neurologic damage, respiratory arrest, brainstem herniation, and death. Treatment includes the use of hypertonic 3% saline infused at a rate of 0.5 to 2 mL per kg per hour until symptoms resolve. At this time, vaptans have no role in the treatment of symptomatic hyponatremia because of the potential for overcorrection of sodium and variable sodium fluctuations.13 Loop diuretics may be needed in patients with concurrent symptomatic hyponatremia and volume overload. The rate of sodium correction should be 6 to 12 mEq per L in the first 24 hours and 18 mEq per L or less in 48 hours.1214 An increase of 4 to 6 mEq per L is usually sufficient to reduce symptoms of acute hyponatremia.20 Rapid correction of sodium can result in osmotic demyelination (previously called central pontine myelinolysis). Overcorrection is common and is typically caused by rapid diuresis secondary to decreasing ADH levels. Every attempt should be made not to overcorrect sodium levels. One study of 25 patients with severe symptoms and sodium levels less than 120 mEq per L showed that concurrent treatment with a weight-based dose of 3% saline and 1 to 2 mcg of desmopressin every six to eight hours resulted in a rate of correction of 3 to 7 mEq per L per hour without causing overcorrection.21 Another study used a 100-mL bolus of 3% saline infused over 10 minutes in marathon runners; symptoms improved without over-correcting. This method increased sodium levels by 1.5 to 2.0 mEq per L per hour.13,22,23 Guidelines from the European Society of Endocrinology recommend infusing one dose of 150 mL of 3% saline over 20 minutes, with sodium monitoring every 20 minutes until symptoms resolve.14 This regimen may be repeated if the patient remains symptomatic or until the goal sodium target of 5 mEq per L is achieved (Figure 213,14,2023[ corrected]).

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Treatment of Severe Symptomatic Hyponatremia

Figure 2.

Algorithm for the treatment of severe symptomatic hyponatremia.

Information from references 13,14, and 20 through 23.

Treatment of Severe Symptomatic Hyponatremia


Figure 2.

Algorithm for the treatment of severe symptomatic hyponatremia.

Information from references 13,14, and 20 through 23.

Vaptans

Vaptans (conivaptan [Vaprisol] and tolvaptan [Samsca]) are vasopressin-receptor antagonists approved for the treatment of hospitalized patients with severe hypervolemic and euvolemic hyponatremia (eTable B). However, their use in the management of hyponatremia is controversial. Several trials have demonstrated that vaptans increase sodium levels in patients with cirrhosis and heart failure.24 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan, patients with hyponatremia and heart failure who received tolvaptan had an associated reduction in cardiovascular morbidity and mortality, although there were several confounding variables, and further study is needed.25 The Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT) trials demonstrated increased sodium levels with tolvaptan in patients with SIADH, cirrhosis, and heart failure.26 An extension of these studies, the SALTWATER trial, showed that long-term use of tolvaptan is safe and effective in increasing sodium levels, although this study did not specify subgroups.27,28 Regardless of their effectiveness in increasing sodium levels, vaptans—specifically tolvaptan—should not be used in patients with hepatic impairment because they may worsen liver function.29,30 The European Society of Endocrinology recommends against the routine use of vaptans, citing a lack of reduction in overall mortality rates and increased risk of rapid overcorrection.14 Further study is needed to clarifiy the role of vaptans.

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eTable B.

Summary of Vaptans

DrugConivaptan (Vaprisol)Tolvaptan (Samsca)

Indications

Short-term use for hospitalized patients with hypervolemic or euvolemic hyponatremia associated with heart failure or syndrome of inappropriate antidiuretic hormone secretion with sodium < 125 mEq per L

Approved for use for up to 30 days for hypervolemic or euvolemic hyponatremia associated with heart failure or syndrome of inappropriate antidiuretic hormone secretion with sodium < 125 mEq per L

Dosing

20 mg intravenously (in 100-mL dextrose 5% solution) infused over 30 minutes as a loading dose, followed by continuous infusion of 20 mg over 24 hours for two to four days; may increase to 40 mg over 24 hours; do not exceed four days

15 mg orally once daily; after 24 hours may increase to 30 mg once daily, then titrate to desired sodium concentration (maximum of 60 mg per day)

Patients with moderate hepatic impairment: 10 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 10 mg over 24 hours (0.42 mg per hour) for two to four days; may increase to a maximum dose of 20 mg over 24 hours (0.83 mg per hour) if serum sodium is not increasing sufficiently; do not exceed four days

Pharmacodynamics

Metabolized by CYP3A4

Metabolized by CYP3A4

Half-life: five to eight hours

Onset: two to four hours

Excretion: feces (83%), urine (12%, primarily as metabolites)

Peak: four to eight hours

Half-life: five to 12 hours

Excretion: feces

Safety

Adverse effects:

Adverse effects:

More common: fever, hypokalemia, injury to intravenous site, orthostatic hypotension

More common: nausea, pollakiuria, polyuria, thirst, xerostomia

Less common: anemia, atrial fibrillation, confusion, constipation, dehydration, diarrhea, dry mouth, electrocardiographic abnormalities, erythema, headache, hematuria, hyperglycemia, hypertension, hypoglycemia, hypomagnesia, hyponatremia, hypotension, insomnia, nausea, oral candidiasis, pain, peripheral edema, pharyngolaryngitis, phlebitis, pneumonia, polyuria, pruritus, thirst, urinary tract infection, vomiting

Less common: anorexia, constipation, fever, gastrointestinal bleeding, hepatotoxicity, hyperglycemia, hypernatremia, weakness

Change intravenous site every 24 hours; avoid corn products

Do not use for more than 30 days or in patients with underlying liver disease because of risk of hepatotoxicity; avoid consumption of grapefruit juice

Contraindicated in patients with anuria or concurrent use of CYP3A inhibitors

Liver function should be monitored frequently

Not recommended for patients with creatinine clearance less than 30 mL per minute per 1.73 m2 (0.50 mL per second per m2)

Contraindicated in patients with hypovolemic hyponatremia, anuria, or concurrent use of CYP3A inhibitors, or when there is an urgent need to increase sodium levels

Not recommended for patients with creatinine clearance less than 10 mL per minute per 1.732 (0.17 mL per second per m2)

Price*

$687 for 100 mL of solution (20 mg of conivaptan)

$3,440 for 10 15- or 30-mg tablets

Considerations

Vaptans should be initiated in the inpatient setting to monitor sodium levels

No reports of osmotic demyelination; however, vaptans can rapidly overcorrect

Hypovolemic hyponatremia should be ruled out before initiating therapy

Should not be used in patients with severe symptomatic hyponatremia

Good safety profile for limited use in current studies; further study needed to evaluate long-term use, effects, cost-effectiveness, and effects on morbidity and mortality

Optimal regimens and dosages are unclear


note: Lixivaptan is awaiting approval from the U.S. Food and Drug Administration for use in patients with euvolemia and hypervolemic hyponatremia.

CYP = cytochrome P.

*—Estimated retail price based on information from https://online.lexi.com/crlsql/servlet/crlonline (subscription required; accessed March 1, 2014).

Information from: Dahl E, et al. Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia. Aliment Pharmacol Ther. 2012;36(7):619–626.

Lehrich RW, et al. Role of vaptans in the management of hyponatremia. Am J Kidney Dis. 2013;62(2):364–376.

Peri A. Clinical review: the use of vaptans in clinical endocrinology. J Clin Endocrinol Metab. 2013;98(4):1321–1332.

eTable B.

Summary of Vaptans

DrugConivaptan (Vaprisol)Tolvaptan (Samsca)

Indications

Short-term use for hospitalized patients with hypervolemic or euvolemic hyponatremia associated with heart failure or syndrome of inappropriate antidiuretic hormone secretion with sodium < 125 mEq per L

Approved for use for up to 30 days for hypervolemic or euvolemic hyponatremia associated with heart failure or syndrome of inappropriate antidiuretic hormone secretion with sodium < 125 mEq per L

Dosing

20 mg intravenously (in 100-mL dextrose 5% solution) infused over 30 minutes as a loading dose, followed by continuous infusion of 20 mg over 24 hours for two to four days; may increase to 40 mg over 24 hours; do not exceed four days

15 mg orally once daily; after 24 hours may increase to 30 mg once daily, then titrate to desired sodium concentration (maximum of 60 mg per day)

Patients with moderate hepatic impairment: 10 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 10 mg over 24 hours (0.42 mg per hour) for two to four days; may increase to a maximum dose of 20 mg over 24 hours (0.83 mg per hour) if serum sodium is not increasing sufficiently; do not exceed four days

Pharmacodynamics

Metabolized by CYP3A4

Metabolized by CYP3A4

Half-life: five to eight hours

Onset: two to four hours

Excretion: feces (83%), urine (12%, primarily as metabolites)

Peak: four to eight hours

Half-life: five to 12 hours

Excretion: feces

Safety

Adverse effects:

Adverse effects:

More common: fever, hypokalemia, injury to intravenous site, orthostatic hypotension

More common: nausea, pollakiuria, polyuria, thirst, xerostomia

Less common: anemia, atrial fibrillation, confusion, constipation, dehydration, diarrhea, dry mouth, electrocardiographic abnormalities, erythema, headache, hematuria, hyperglycemia, hypertension, hypoglycemia, hypomagnesia, hyponatremia, hypotension, insomnia, nausea, oral candidiasis, pain, peripheral edema, pharyngolaryngitis, phlebitis, pneumonia, polyuria, pruritus, thirst, urinary tract infection, vomiting

Less common: anorexia, constipation, fever, gastrointestinal bleeding, hepatotoxicity, hyperglycemia, hypernatremia, weakness

Change intravenous site every 24 hours; avoid corn products

Do not use for more than 30 days or in patients with underlying liver disease because of risk of hepatotoxicity; avoid consumption of grapefruit juice

Contraindicated in patients with anuria or concurrent use of CYP3A inhibitors

Liver function should be monitored frequently

Not recommended for patients with creatinine clearance less than 30 mL per minute per 1.73 m2 (0.50 mL per second per m2)

Contraindicated in patients with hypovolemic hyponatremia, anuria, or concurrent use of CYP3A inhibitors, or when there is an urgent need to increase sodium levels

Not recommended for patients with creatinine clearance less than 10 mL per minute per 1.732 (0.17 mL per second per m2)

Price*

$687 for 100 mL of solution (20 mg of conivaptan)

$3,440 for 10 15- or 30-mg tablets

Considerations

Vaptans should be initiated in the inpatient setting to monitor sodium levels

No reports of osmotic demyelination; however, vaptans can rapidly overcorrect

Hypovolemic hyponatremia should be ruled out before initiating therapy

Should not be used in patients with severe symptomatic hyponatremia

Good safety profile for limited use in current studies; further study needed to evaluate long-term use, effects, cost-effectiveness, and effects on morbidity and mortality

Optimal regimens and dosages are unclear


note: Lixivaptan is awaiting approval from the U.S. Food and Drug Administration for use in patients with euvolemia and hypervolemic hyponatremia.

CYP = cytochrome P.

*—Estimated retail price based on information from https://online.lexi.com/crlsql/servlet/crlonline (subscription required; accessed March 1, 2014).

Information from: Dahl E, et al. Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia. Aliment Pharmacol Ther. 2012;36(7):619–626.

Lehrich RW, et al. Role of vaptans in the management of hyponatremia. Am J Kidney Dis. 2013;62(2):364–376.

Peri A. Clinical review: the use of vaptans in clinical endocrinology. J Clin Endocrinol Metab. 2013;98(4):1321–1332.

Hypernatremia

Hypernatremia is defined as a serum sodium level greater than 145 mEq per L. It is associated with increased morbidity and mortality in the inpatient setting.31,32 Hypernatremia is caused by net water loss (increased loss or decreased intake) or, rarely, sodium gain. Patients at increased risk include those with an impaired thirst mechanism or restricted access to water (e.g., those with altered mental status, intubated patients, infants, older adults).

Symptoms of hypernatremia in infants can include tachypnea, muscle weakness, restlessness, a high-pitched cry, insomnia, lethargy, and coma. Seizures usually occur only in cases of inadvertent sodium loading or rapid rehydration. In adults, symptoms tend to be mild and may include anorexia, muscle weakness, restlessness, nausea, and vomiting. Severe symptoms are likely to occur with acute increases in plasma sodium levels or at concentrations greater than 160 mEq per L. Hypernatremia can cause brain shrinkage, resulting in vascular rupture and intracranial bleeding.33

DIAGNOSTIC APPROACH

The cause of hypernatremia is usually evident from the history and physical examination, and is typically water loss (e.g., gastrointestinal loss, restricted access to water) or sodium gain (Table 2).3,12,33,34 Patients are often asymptomatic but can present with irritability, nausea, weakness, altered mental status, or coma. Water loss can be pure water loss (e.g., in diabetes insipidus) or hypotonic fluid loss (e.g., renal, gastrointestinal, or cutaneous losses). Sodium gain is usually iatrogenic from the infusion of hypertonic solutions. Laboratory studies are not necessary if the cause is apparent from the history, but frequent electrolyte checks are recommended during correction. When the cause is not clear, laboratory studies should be guided by the history12 (Figure 335).

View/Print Table

Table 2.

Differential Diagnosis and Treatment of Hypernatremia

ConditionDiagnosisTreatment

Hypovolemic hypernatremia

Body fluid loss (e.g., burns, sweating)

Clinical

Free water replacement

Diuretic use

Clinical

Stop diuretic

Gastrointestinal loss (e.g., vomiting, diarrhea, fistulas)

Clinical

Free water replacement

Heat injury

Elevated temperature, myoglobinuria, elevated creatinine level

Intravenous fluids, supportive care

Osmotic diuresis (e.g., hyperosmolar nonketotic coma, mannitol use, enteral feeding)

Elevated glucose level; sodium level often elevated after correction

Correct glucose level, stop causative agent

Post-obstruction

Clinical

Supportive care

Euvolemic hypernatremia

Central diabetes insipidus

Clinical history of central nervous system insult; urinary concentration after administration of desmopressin

Treatment is rarely required unless thirst is impaired

Fever

Clinical

Treat underlying cause

Hyperventilation/mechanical ventilation

Clinical

Adjust ventilation

Hypodipsia

Clinical

Increase free water consumption

Medications (e.g., amphotericin, aminoglycosides, lithium, phenytoin [Dilantin])

Medication review

Stop causative medication

Nephrogenic diabetes insipidus

History of nephrotoxic medication use (amphotericin, demeclocycline [Declomycin], foscarnet, lithium, methoxyflurane), failure to concentrate urine after administration of desmopressin

Stop causative medication

Sickle cell disease

Hemoglobin electrophoresis

Treat underlying disease

Suprasellar and infrasellar tumors

Magnetic resonance imaging

Treat underlying disease

Hypervolemic hypernatremia

Cushing syndrome

24-hour urinary cortisol and adrenocorticotropic hormone levels, dexamethasone suppression test

Treat underlying disease

Hemodialysis

Clinical history

Treat underlying disease

Hyperaldosteronism

History of hypertension and hypokalemia, plasma aldosterone-to-renin ratio,3 history of hypertension and hypokalemia

Treatment usually not needed for hypernatremia

Iatrogenic (e.g., salt tablet or salt water ingestion, saline infusions, saline enemas, intravenous bicarbonate, enteral feedings)

Recent administration of hypertonic saline, enteral feedings, sodium bicarbonate infusion, or hypertonic dialysis

Stop causative medication, rapid free water replacement


Information from references 3, 12, 33, and 34.

Table 2.

Differential Diagnosis and Treatment of Hypernatremia

ConditionDiagnosisTreatment

Hypovolemic hypernatremia

Body fluid loss (e.g., burns, sweating)

Clinical

Free water replacement

Diuretic use

Clinical

Stop diuretic

Gastrointestinal loss (e.g., vomiting, diarrhea, fistulas)

Clinical

Free water replacement

Heat injury

Elevated temperature, myoglobinuria, elevated creatinine level

Intravenous fluids, supportive care

Osmotic diuresis (e.g., hyperosmolar nonketotic coma, mannitol use, enteral feeding)

Elevated glucose level; sodium level often elevated after correction

Correct glucose level, stop causative agent

Post-obstruction

Clinical

Supportive care

Euvolemic hypernatremia

Central diabetes insipidus

Clinical history of central nervous system insult; urinary concentration after administration of desmopressin

Treatment is rarely required unless thirst is impaired

Fever

Clinical

Treat underlying cause

Hyperventilation/mechanical ventilation

Clinical

Adjust ventilation

Hypodipsia

Clinical

Increase free water consumption

Medications (e.g., amphotericin, aminoglycosides, lithium, phenytoin [Dilantin])

Medication review

Stop causative medication

Nephrogenic diabetes insipidus

History of nephrotoxic medication use (amphotericin, demeclocycline [Declomycin], foscarnet, lithium, methoxyflurane), failure to concentrate urine after administration of desmopressin

Stop causative medication

Sickle cell disease

Hemoglobin electrophoresis

Treat underlying disease

Suprasellar and infrasellar tumors

Magnetic resonance imaging

Treat underlying disease

Hypervolemic hypernatremia

Cushing syndrome

24-hour urinary cortisol and adrenocorticotropic hormone levels, dexamethasone suppression test

Treat underlying disease

Hemodialysis

Clinical history

Treat underlying disease

Hyperaldosteronism

History of hypertension and hypokalemia, plasma aldosterone-to-renin ratio,3 history of hypertension and hypokalemia

Treatment usually not needed for hypernatremia

Iatrogenic (e.g., salt tablet or salt water ingestion, saline infusions, saline enemas, intravenous bicarbonate, enteral feedings)

Recent administration of hypertonic saline, enteral feedings, sodium bicarbonate infusion, or hypertonic dialysis

Stop causative medication, rapid free water replacement


Information from references 3, 12, 33, and 34.

View/Print Figure

Evaluation of Hypernatremia

Figure 3.

Algorithm for the evaluation of hypernatremia.

Evaluation of Hypernatremia


Figure 3.

Algorithm for the evaluation of hypernatremia.

Diabetes insipidus is caused by a defect in ADH, either at the level of the central nervous system (central diabetes insipidus) or kidneys (nephrogenic diabetes insipidus). Inappropriately dilute urine (osmolality less than 300 mOsm per kg) in the setting of hypernatremia suggests diabetes insipidus. Hyperaldosteronism can cause mild hypernatremia but is rarely clinically relevant. Hyperglycemia can also cause hypernatremia, even after correction of glucose levels.36

TREATMENT

The treatment of hypernatremia involves treating the underlying cause and correcting the water deficit. Determining volume status and calculating the total body water deficit are important (eTable A). When correcting the total body water deficit, oral or enteral free water should be used whenever possible. When intravenous fluids are required, hypotonic solutions should be used. Rapid over-correction can result in cerebral edema; therefore, the least amount of fluid possible should be used.33 eTable C lists the sodium content of various intravenous fluids.

In patients with rapid development of hypernatremia, sodium can be corrected quickly with isotonic saline or water without increasing the risk of cerebral edema. A correction rate of 1 mEq per L per hour is considered safe in these patients.12,36 In patients with hypernatremia that developed over a longer period, the sodium level should be corrected at a rate of 0.5 mEq per L per hour, with no more than an 8 to 10 mEq per L decrease over 24 hours.33,36,37 The target sodium level should be 145 mEq per L.33

View/Print Table

eTable C.

Sodium Concentration of Intravenous Fluids

FluidSodium concentration (mEq per L)

Dextrose 5%

0

Dextrose 5% with sodium chloride 0.2%

34

Sodium chloride 0.45%

77

Lactated Ringer solution

130

Sodium chloride 0.9%

154

eTable C.

Sodium Concentration of Intravenous Fluids

FluidSodium concentration (mEq per L)

Dextrose 5%

0

Dextrose 5% with sodium chloride 0.2%

34

Sodium chloride 0.45%

77

Lactated Ringer solution

130

Sodium chloride 0.9%

154

Data Sources: We searched the Cochrane database, Dynamed, PubMed, PEPID, Clinical Evidence, the National Guideline Clearinghouse, UpToDate, and OVID using the key terms hyponatremia, hypernatremia, vaptans, diagnosis, and treatment. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Search dates: November 15, 2013; March 1, 2014; and October 5, 2014.

The views expressed are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the U.S. government.

The Authors

show all author info

MICHAEL M. BRAUN, DO, is associate residency director of the Family Medicine Residency at Madigan Army Medical Center, Tacoma, Wash....

CRAIG H. BARSTOW, MD, is a faculty member in the Family Medicine Residency at Womack Army Medical Center, Fort Bragg, N.C.

NATASHA J. PYZOCHA, DO, is a third-year resident in the Family Medicine Residency at Madigan Army Medical Center.

Address correspondence to Michael M. Braun, DO, Madigan Army Medical Center, 9040 Fitzsimmons Dr., Tacoma, WA 98431 (e-mail: michael.m.braun.civ@mail.mil). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

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show all references

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