Dysnatremia: Hyponatremia
Also known as: Hypoosmolarity
1. Description of the problem
Hyponatremia is defined as a serum Na less than135 mEq/L. Hyponatremia may occur in the setting of hypotonciity (hypotonic hyponatremia) or as the result of accumulation of a non-electrolyte solute in the extracellular compartment (hypertonic hyponatremia).
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Hypotonic hyponatremia usually results from impaired water homeostasis resulting in water retention relative to effective plasma solute and leading to dilution of the serum Na. The body defense against hypotonichyponatremia is to excrete the excess water by generation of very dilute urine (urine osmolarity 40 to 100 mOsm/L). Urinary dilution and concentration is regulated by the hormone vasopressin; vasopressin secretion is inhibited when the plasma osmolality falls below approximately 280 mEq/L (serum Na level below 135 mEq/L),rendering the collecting ducts impermeable to water.
With the exception of primary polydipsia, hypotonic hyponatremia results from impaired renal free-water excretion. Most commonly, this occurs in conditions where vasopressin release is not suppressed because of inappropriate secretion or as the decreased effective circulating volume.
Hypertonic hyponatremia results from the accumulation of non-electrolyte solutes, such as glucose, in the extracellular fluids. The resultant hypertonicity causes water to shift from the intracellular compartment into the extracellular compartment, diluting the serum Na concentration.
In rare circumstances, hyponatremia may be reported as a laboratory artifact as the result of severe hyperlipidemia or paraprotein retention. This “pseudohyponatremia” is of importance primarily as it needs to be distinguished from true hyponatremia requiring medical therapy. Although the frequency of pseudohyponatremia has markedly diminished with improved laboratory methods, it may still occur.
Clinical features
In hypotonic hyponatremia, water moves into the intracellular compartment to maintain osmotic equilibrium, resulting in cell swelling. Although in the majority of patients, hypotonic hyponatremia is manifested primarily as a laboratory testing abnormality without specific symptoms, symptoms may be seen when hypotonic hyponatremia is severe or has developed rapidly.
The majority of symptoms are neurologic and relate to the development of cerebral edema and range from vague malaise and nausea (serum Na <125 mEq/L) to headache, lethargy, altered mental status (Na 115-120 mEq/L) to seizures, coma and death (Na <110-115mEq/L). Children and premenopausal women are especially at risk for permanent neurologic sequelae from acute hyponatremia.
Osmotic adaptation allows brain cells to restore normal intracellular volume but puts patients at risk for complications during therapy. If treatment of chronic hypotonic hyponatremia is overly rapid, patients are at risk for the development of cerebral pontine myelinolysis (CPM). This demyelinating disease is characterized by quadriparesis, dysarthria, dysphagia and coma. It is usually confirmed by imaging but characteristic brain lesions may not be apparent for a month after the clinical symptoms. Neurologic impairment is often irreversible.
Hypotonic hyponatremia may develop in the setting of hypovolemia, hypervolemia or normal extracellular volume. The specific etiologies of hypotonic hyponatremia differ based on the extracellular volume status.
Hypertonic hyponatremia most commonly develops in the setting of poorly controlled diabetes mellitus; symptoms relate to the underlying etiology of hypertonicity rather than to the hyponatremia. It is primarily important to differentiate hypertonic hyponatremia from true or hypotonic hyponatremia as the clinical management is markedly different. Diagnosis is made based on the recognition of accumulation of non-electrolyte solute in the extracellular fluids, either by direct measurement of the solute (eg, glucose) or based on an elevated (>290 mOsm/kg) plasma osmolality.
Key management points
1. Hyponatremia is diagnosed based on laboratory testing.
2. The initial step in evaluating a patient with hyponatremia is to determine if it represents hypotonic (true) hyponatremia or hypertonic hyponatremia by measuring the plasma glucose concentration and plasma osmolality.
3. If hypotonic hyponatremia is present, the next management step is to assess extracellular fluid volume to determine if the patient is hypovolemic, hypervolemic or euvolemic. The hallmark of hypervolemic hyponatremia is the presence of edema on clinical examination. Although overt hypovolemia is usually readily diagnosed based on clinical exam (eg, orthostasis, dry mucous membranes), subtle hypovolemia may be difficult to differentiate from euvolemic patients. A urine sodium concentration of greater than 30 mEq/L in the absence of diuretic therapy generally defines a patient as not being volume depleted.
4. In hypovolemic patients, treatment is restoration of extracellular volume with isotonic saline. Once extracellular volume is restored, vasopressin secretion should be suppressed and these patients should then have a spontaneous water diuresis. These patients need to be monitored closely (measurement of serum sodium concentration every 1 to 2 hours) as they are at high risk for overly rapid correction of the serum sodium concentration.
5. The primary management of hypervolemic hyponatremia is free-water restriction to a level that is less than obligate free-water losses (usually less than 800 to 1000 mL/day) combined with treatment of the underlying disease causing volume retention (eg, heart failure, cirrhosis).
6. A diagnosis of the syndrome of inappropriate antidiuresis (SIAD) is based on the following criteria:
– Hypotonic hyponatremia (plasma osmolality < 280 mOsm/kg)
– An inappropriately concentrated urine relative to plasma osmolality (urine osmolality > 100 mOsm/kg)
– An elevated urine sodium concentration (> 30 mEq/L), except during dietary sodium restriction
– Absence of hypervolemia (edema) or ECF volume depletion on physical examination
– Normal cardiac, hepatic and kidney function
– Normal thyroid and adrenal function
7. The primary management of euvolemic hypotonic hyponatremia is free-water restriction to a level less than obligate free-water losses (usually less than 800 to 1000 mL/day)
8. The rate of correction of hyponatremia needs to be based on its acuity and on the severity of associated symptoms. Chronic asymptomatic hyponatremia should not be corrected more rapidly than an increase in serum sodium 10 mEq/L over the first 24 hours and 18 mEq/L over the first 48 hours. More rapid initial correction (1 to 2 mEq/L per hour) may be appropriate in severe or symptomatic hyponatremia; however, the maximal increase in serum sodium should be limited to 10 mEq in the first 24 hours and the serum sodium not acutely increased to more than 120 mEq/L using infusions of hypertonic saline.
9. If the correction of the serum sodium concentration is more rapid than desired, relowering of the serum sodium concentration by administration of hypotonic fluids and/or administration of desmopressin may mitigate the risk of developing the cerebral pontine myelinolysis.
10. Adjunctive therapies in the chronic management of SIAD include
– oral salt (sodium chloride) tablets with or without a loop-acting diuretic
– oral demeclocycline
– vasopressin-receptor antagonists (vaptans)
11. Pharmacologic therapy with vaptans may be an adjunct in the treatment of euvolemic or hypervolemic hyponatremia.
2. Emergency Management
1. Asymptomatic chronic hyponatremia with a serum sodium of greater than119 mEq/L does not require emergent management and should initially be treated free-water restriction (unless the patient has ECF volume depletion, in which case the treatment is volume expansion with isotonic saline).
2. Severe (serum sodium <120 mEq/L) or symptomatic hyponatremia requires prompt therapy guided by the patient’s volume status and by the duration of the hyponatremia.
3. Hyponatremia associated with extracellular fluid (ECF) volume depletion should be treated with isotonic (0.9%) saline.
4. Severe or symptomatic euvolemic hyponatremia should be treated with infusions of hypertonic (3%) saline.
5. The primary management of hypervolemic hyponatremia is treatment of the underlying disease process (eg, heart failure). The hyponatremia, per se, is treated with free-water restriction. Hypertonic (3%) saline should be used with extreme caution in patients with ECF volume overload as volume expansion may precipitate or worsen pulmonary edema. If hypertonic saline is administered, it should be combined with a loop diuretic (eg, furosemide) to minimize the risk of worsening volume overload.
6. The rate of correction of hyponatremia needs to be based on its acuity and on the severity of associated symptoms.
– An initial rate of correction in serum sodium of 1 to 2 mEq/L per hour is appropriate in acute (<48 hours) or symptomatic chronic hyponatremia. This rate of correction should be continued for no more than 2 to 4 hours, or until acute symptoms resolve, whichever comes first.
– The maximal increase in serum sodium should be no more than10 mEq in the first 24 hours and the serum sodium not acutely increased to more than 120 mEq/L using infusions of hypertonic saline.
7. Follow the serum sodium concentration every 1 to 2 hours during therapy.
8. Consider relowering of the serum sodium by infusion of hypotonic fluids and/or administration of exogenous desmopressin if the rate of increase of serum sodium is more rapid than desired.
Management points not to be missed
1. Rapid correction (>12 mEq/L per day) of hyponatremia can lead to cerebral pontine myelinolysis.
2. Beware of rapid correction in patients with volume depletion or primary polydipsia.
3. Use hypertonic saline only when hyponatremia is severe (<120 mEq/L) or symptomatic.
4. If the rate of increase in the serum sodium concentration exceeds 12 mEq/L in 24 hours or 18 mEq/L in 48 hours, consider relowering of the serum sodium concentration with infusions of hypotonic fluids and/or desmopressin administration.
5. The primary management of SIAD is fluid restriction to a volume less than obligate free-water losses. This is usually less than 1 L per day. Similar fluid restriction is required in patients with hypervolemic hyponatremia due to heart failure or cirrhosis.
6. Oral sodium chloride tablets, with or without a loop-acting diuretic, demeclocycline and vaptans may be used as adjunctive therapies in chronic hyponatremia.
Adjunctive therapy for SIAD:
– Oral salt tablets 3g TID PO along with or without lasix 20 mg daily
– Demeclocycline 600 to 1200 mg/day
Adjunctive therapy for SIAD and hypervolemic hyponatremia due to heart failure or cirrhosis:
– Conivaptan (IV) loading dose 20 mg followed by 40 to 80 mg/day IV for 4 days
– Tolvaptan 30 to 60 mg PO daily, for euvolemic or hypervolemic hyponatremia
3. Diagnosis
The diagnosis of hypotonic hyponatremia is based on the laboratory findings of a serum sodium concentration of less than 135 mEq/L accompanied by a plasma osmolality less than 280 mOsm/kg
The differential diagnosis for the etiologies of hyponatremia are based on assessment of extracellular fluid (ECF) volume status
Diagnosis of the syndrome of inappropriate antidiuresis (SIAD) is based on the following criteria:
– Hypotonic hyponatremia (plasma osmolality < 280 mOsm/kg)
– An inappropriately concentrated urine relative to plasma osmolality (urine osmolality > 100 mOsm/kg)
– An elevated urine sodium concentration (> 30 mEq/L), unless dietary sodium is restricted
– Absence of hypervolemia (edema) or ECF volume depletion on physical examination
– Normal cardiac, hepatic and kidney function
– Normal thyroid and adrenal function
Diagnostic approach
The initial step in the diagnosis of the patient with confirmed hypotonic (plasma osmolality < 280 mOsm/kg) hyponatremia (serum sodium < 135 mEq/L) is assessment of ECF volume:
History: Assess history of heart failure, liver disease, medication use, recent vomiting or diarrhea, symptoms of orthostasis.
Physical examination: Assess for volume status, stigmata of liver disease or heart failure, neurologic evaluation.
Laboratory studies:
– Serum electrolytes, plasma osmolality, BUN, creatinine, uric acid
– Urine electrolytes, urine osmolality
– Serum cortisol, cosyntropin stimulation test, thyroid function testing
Assess severity of symptoms and determine chronicity of hyponatremia
Normal lab values
If urine osmolality is appropriately dilute in setting of hypotonicity (urine osmolality < 100 mOsm/kg) then renal diluting ability is intact and vasopressin secretion is suppressed.
Potential diagnoses:
– Primary polydipsia
– Malnutrition with low dietary solute intake (eg, beer drinker’s potomania)
– Reset osmostat
– Chronic kidney disease
If the urine osmolality is inappropriately concentrated for the prevailing hypotonicity (urine osmolality > 100 mOsm/kg), then there is evidence of non-osmotic vasopressin secretion and the differential diagnosis can be assessed based on assessment of ECF volume status.
Edema/ECF volume overload—most likely underlying diagnoses accounting for hyponatremia: heart failure,
cirrhosis, nephrotic syndrome.
If not edematous, assess for clinical evidence of ECF volume depletion and urine sodium. If the urine sodium is less than 30 mEq/L or there is evidence of volume depletion on physical examination, then the hyponatremia is most likely related to ECF volume depletion and volume-mediated vasopressin secretion.
Caveats in interpreting the urine sodium concentration:
– The urine sodium may be greater than 30 mEq/L despite ECF volume depletion in patients on diuretics.
– The urine sodium may be less than 30 mEq/L in the absence of volume depletion in patients on chronic low sodium intake (eg, tea and toast diet).
If the urine sodium is greater than 30 mEq/L and there is no evidence of volume depletion on physical examination:
– Exclude adrenal insufficiency by measuring serum cortisol and performing cosyntropin stimulation test. If there is reason to suspect adrenal insufficiency, treat with glucocorticoid replacement pending results of testing.
– Exclude hypothyroidism with thyroid function testing. If hypothyroidism and adrenal insufficiency are ruled out, then the likely diagnosis is SIAD, also known as the syndrome of inappropriate antidiuretic hormone (SIADH)
Measurement of serum uric acid levels may help to differentiate between euvolemic and hypovolemic patients with hyponatremia. Serum uric acid levels tend to be high-normal or elevated in volume-depleted patients. Serum uric acid levels tend to be low normal or low in SIAD.
Pathophysiology
Hypotonic hyponatremia is a disorder of water homeostasis. In hypotonic hyponatremia, free-water intake exceeds excretion leading to dilution of body fluids and hypotonicity. As sodium is the most abundant cation in the extracellular fluids, hypotonicity is reflected by a fall in serum sodium concentration.
Normal renal water homeostasis is regulated by the peptide hormone vasopressin. Vasopressin is synthesized by neurons in the supraoptic and paraventricular nuclei in the hypothalamus that terminate in the posterior pituitary gland. Vasopressin secretion is stimulated primarily by hypertonicity, but is also stimulated in response to hypovolemia. In the kidney, vasopressin binds to specific receptors in the collecting duct and causes the insertion of water channels into the luminal membrane of the collecting duct.
In the absence of vasopressin, the collecting duct is relatively impermeable to water; in the presence of vasopressin, water is reabsorbed along the collecting duct, resulting in the production of concentrated urine.
Renal free-water excretion depends upon three processes:
1. Adequate delivery of water and solute to the diluting segments of the nephron (the thick ascending limb of the loop of Henle and the distal convoluted tubule)
2. Generation of a dilute urine in the diluting segments through the selective reabsorption of sodium and chloride
3. Inhibition of water reabsorption in the collecting duct through suppression of vasopressin secretion
Hyponatremia develops when water intake exceeds maximal renal free-water excretion. Rarely, this may be the result of excessive water ingestion in the absence of any impairment in renal free-water excretion, as is seen in primary (psychogenic) polydipsia. Since maximal free-water excretion in healthy individuals is in excess of 12 to 14 liters per day, the water ingestion required in this setting is massive; the hyponatremia rapidly resolves when water ingestion ceases. In patients with primary polydipsia, urine osmolality is maximally dilute.
Renal free-water excretion may be limited in patients with reduced daily solute intake, and hence decreased solute excretion. In these patients, the urine is maximally dilute, however, the maximal urine volume is limited by solute excretion, leading to the development of hyponatremia with much more modest degrees of water intake than in primary polydipsia. The prototypic example is so-called beer drinker’s potomania; however, this can also be seen in patients with protein-calorie malnutrition.
More commonly, hyponatremia develops because of non-osmotic release of vasopressin. In patients who are volume depleted, vasopressin secretion is stimulated by the decrease in circulating blood volume while in patients with heart failure, cirrhosis and nephrotic syndrome, vasopressin secretion results from a decrease in effective-circulating blood volume. In euvolemic hyponatremia, vasopressin secretion is increased in the absence of osmotic or volume stimuli. Common etiologies of the SIAD include malignancy, CNS disease, intra-thoracic/pulmonary disease, pain, nausea and multiple medications.
Hyponatremia results in an increase in intracellular volume. In the brain, this is manifested by cerebral edema, the severity of which depends upon the rapidity and extent of the decline in serum sodium concentration. The majority of symptoms associated with hyponatremia are believed to be due to the development of cerebral edema.
Epidemiology
Hyponatremia affects 7% of outpatients and up to 30% of acutely hospitalized patients. Most inpatients have mild hyponatremia, only 4% to 6% have moderate hyponatremia (<130 mEq/L) and less than 1% have severe hyponatremia (<120 mEq/L).
It is especially common in the geriatric nursing home residents where it can affect as many as 53% during the course of 1 year and is found in 18% as opposed to 8% of ambulatory age-matched patients. It correlates with a worse prognosis, as it adds to morbidity and complicates management. Even mild hyponatremia, in elderly patients, is associated with increased risk of falls and fractures.
What's the evidence?
Rose, BD, Post, TW. Clinical physiology of acid-base and electrolyte disorders. 2001. pp. 716-19. (Extensive review of hyponatremia with emphasis on pathophysiology and management)
Adrogue, HJ, Madias, NE. “Hyponatremia”. N Engl J Med. vol. 342. 2000. pp. 1581(Review that focuses on methods to estimate fluids and rates needed for correction, along with concrete examples.)
Upadhyay, A, Jaber, BL, Madias, NE. “Incidence and prevalence of hyponatremia”. Am J Med. vol. 119. 2006. pp. S30-5. (This review article focuses on the epidemiology of hyponatremia in different settings and in association with various medical conditions.)
Ellison, DH, Berl, T. “Clinical practice. The syndrome of inappropriate antidiuresis”. N Engl J Med. vol. 356. 2007. pp. 2064(Review of SIADH, diagnosis and treatment)
Verbalis, JG, Goldsmith, SR, Greenberg, A. “Hyponatremia treatment guidelines 2007: expert panel recommendations”. Am J Med. vol. 120. 2007. pp. S1(This review goes over management guidelines including use of intravenous vasopressin receptor antagonist conivaptan.)
Schrier, RW, Gross, P, Gheorghiade, M. “Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia”. N Engl J Med. vol. 355. 2006. pp. 2099-112. (Two multicenter randomized placebo-controlled trials that find oral tolvaptan effective in treatment of euvolemic and hypervolemic hyponatremia)
Berl, T, Quittnat-Pelletier, F, Verbalis, JG. “Oral tolvaptan is safe and effective in chronic hyponatremia”. J Am Soc Nephrol. vol. 21. 2010. pp. 705(Multicenter, open-label SALTWATER trial that followed SALT patients treated with tolvaptan for a total of 700 days, showing the drug to be effective and safe in the long-term treatment of euvolemic and hypervolemic hyponatremia)
Sterns, RH, Cappuccio, JD, Silver, SM, Cohen, EP. “Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective”. J Am Soc Nephrol. vol. 4. 1994. pp. 1522-30. (Retrospective study that shows the high rate of neurologic damage in patients with chronic severe hyponatremia whose treatment exceeds the recommended rate.)
Mohmand, HK, Issa, D, Ahmad, Z. “Hypertonic saline for hyponatremia: risk of inadvertent overcorrection”. Clin J Am Soc Nephrol. vol. 2. 2007. pp. 1110(Retrospective review of 62 patients with hyponatremia treated with hypertonic saline shows that the Adrogue formula overestimates correction in rate in greater than 70% of cases, especially in severe hyponatremia. Hence the necessity of frequent monitoring.)
Renneboog, B, Musch, W, Vandemergel, X. “Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits”. Am J Med. vol. 119. 2006. pp. 71.e1(Case-control study shows increased incidence of falls in patients with mild hyponatremia considered asymptomatic.)
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