What effect does an increase in antidiuretic hormone ADH have on the volume of extracellular fluid ECF )?

Deficiencies in both total body water and total body sodium exist, although proportionally more sodium than water has been lost; the sodium deficit causes hypovolemia. In hypovolemic hyponatremia, both serum osmolality and blood volume decrease. Vasopressin (antidiuretic hormone [ADH]) secretion increases despite a decrease in osmolality to maintain blood volume. The resulting water retention increases plasma dilution and hyponatremia.

Extrarenal fluid losses, such as those that occur with the losses of sodium-containing fluids as in protracted vomiting, severe diarrhea, or sequestration of fluids in a 3rd space (see table Composition of Body Fluids Composition of Body Fluids

Approximate Sodium Content of Common Beverages

Renal fluid losses resulting in hypovolemic hyponatremia may occur with mineralocorticoid deficiency Addison Disease Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis... read more

Tubulointerstitial Nephritis Tubulointerstitial nephritis is primary injury to renal tubules and interstitium resulting in decreased renal function. The acute form is most often due to allergic drug reactions or to infections... read more

Autosomal Dominant Polycystic Kidney Disease (ADPKD) Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more

Diuretics may also cause hypovolemic hyponatremia. Thiazide diuretics, in particular, decrease the kidneys’ diluting capacity and increase sodium excretion. Once volume depletion occurs, the nonosmotic release of vasopressin causes water retention and worsens hyponatremia. Concomitant hypokalemia shifts sodium intracellularly and enhances vasopressin release, thereby worsening hyponatremia. This effect of thiazides may last for up to 2 weeks after cessation of therapy; however, hyponatremia usually responds to replacement of potassium and volume deficits along with judicious monitoring of water intake until the drug effect dissipates. Older patients may have increased sodium diuresis and are especially susceptible to thiazide-induced hyponatremia, particularly when they have a preexisting defect in renal capacity to excrete free water. Rarely, such patients develop severe, life-threatening hyponatremia within a few weeks after the initiation of a thiazide diuretic. Loop diuretics much less commonly cause hyponatremia.

In euvolemic (dilutional) hyponatremia, total body sodium and thus ECF volume are normal or near-normal; however, TBW is increased.

Primary polydipsia can cause hyponatremia only when water intake overwhelms the kidneys’ ability to excrete water. Because normal kidneys can excrete up to 25 L urine a day, hyponatremia due solely to polydipsia results only from the ingestion of large amounts of water or from defects in renal capacity to excrete free water. Patients affected include those with psychosis or more modest degrees of polydipsia plus renal insufficiency.

Euvolemic hyponatremia may also result from excessive water intake in the presence of Addison disease Addison Disease Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis... read more

Hypothyroidism Hypothyroidism is thyroid hormone deficiency. Symptoms include cold intolerance, fatigue, and weight gain. Signs may include a typical facial appearance, hoarse slow speech, and dry skin. Diagnosis... read more

• The antidiuretic effect of vasopressin on the kidneys

• Direct impairment of renal water excretion by angiotensin II

• Decreased glomerular filtration rate (GFR)

• Stimulation of thirst by angiotensin II

Urine sodium excretion is usually < 10 mEq/L (< 10 mmol/L), and urine osmolality is high relative to serum osmolality.

The syndrome of inappropriate ADH (vasopressin) secretion is attributed to excessive vasopressin release. It is defined as less-than-maximally-dilute urine in the presence of plasma hypo-osmolality (hyponatremia) without volume depletion or overload, emotional stress, pain, diuretics, or other drugs that stimulate vasopressin secretion (eg, chlorpropamide, carbamazepine, vincristine, clofibrate, antipsychotic drugs, aspirin, ibuprofen) in patients with normal cardiac, hepatic, renal, adrenal, and thyroid function. SIADH Syndrome of Inappropriate ADH Secretion (SIADH) The syndrome of inappropriate ADH (vasopressin) secretion is defined as less than maximally dilute urine in the presence of serum hypo-osmolality, in patients with normal adrenal, thyroid, renal... read more is associated with myriad disorders (see table Disorders Associated with SIADH Disorders Associated With Syndrome of Inappropriate Antidiuretic Hormone Secretion

• Administration of drugs that impair renal water excretion

• Administration of hypotonic fluids

• Impaired renal function

• Nonosmotic vasopressin release due to intravascular volume depletion

In addition, adrenal insufficiency has become increasingly common among AIDS patients as the result of cytomegalovirus adrenalitis, mycobacterial infection, or interference with adrenal glucocorticoid and mineralocorticoid synthesis by ketoconazole. SIADH may be present because of coexistent pulmonary or central nervous system infections.

Hyponatremia frequently occurs in patients with brain pathology, including concussion, intracranial hemorrhage, encephalitis, meningitis, and CNS tumors. It is most commonly due to SIADH or less commonly glucocorticoid deficiency. However, cerebral salt wasting has been recognized by some as a separate entity affecting a small group of these patients, especially those with subarachnoid hemorrhage Subarachnoid Hemorrhage (SAH) Subarachnoid hemorrhage is sudden bleeding into the subarachnoid space. The most common cause of spontaneous bleeding is a ruptured aneurysm. Symptoms include sudden, severe headache, usually... read more

Symptoms and Signs of Hyponatremia

Symptoms mainly involve central nervous system dysfunction. However, when hyponatremia is accompanied by disturbances in total body sodium content, signs of ECF volume depletion Volume Depletion Volume depletion, or extracellular fluid (ECF) volume contraction, occurs as a result of loss of total body sodium. Causes include vomiting, excessive sweating, diarrhea, burns, diuretic use... read more or volume overload Volume Overload Volume overload generally refers to expansion of the extracellular fluid (ECF) volume. ECF volume expansion typically occurs in heart failure, kidney failure, nephrotic syndrome, and cirrhosis... read more also occur. In general, older chronically ill patients with hyponatremia develop more symptoms than younger otherwise healthy patients. Symptoms are also more severe with faster-onset hyponatremia. Symptoms generally occur when the effective plasma osmolality falls to < 240 mOsm/kg (< 240 mmol/kg). Symptoms can be subtle and consist mainly of changes in mental status, including altered personality, lethargy, and confusion. As the serum sodium falls to < 115 mEq/L (< 115 mmol/L), stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma, and death can result.

Severe cerebral edema may occur in premenopausal women with acute hyponatremia, perhaps because estrogen and progesterone inhibit brain Na+,K+-ATPase and decrease solute extrusion from brain cells. Sequelae include hypothalamic and posterior pituitary infarction and occasionally osmotic demyelination syndrome or brain stem herniation.

Serum sodium may be low when severe hyperglycemia (or exogenously administered mannitol or glycerol) increases osmolality and water moves out of cells into the ECF. Serum sodium concentration falls about 1.6 mEq/L (1.6 mmol/L) for every 100-mg/dL (5.55-mmol/L) rise in the serum glucose concentration above normal. This condition is often called translocational hyponatremia because it is caused by translocation of water across cell membranes.

Pseudohyponatremia with normal serum osmolality may occur in severe hyperlipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol level that contributes to the development of atherosclerosis... read more

Identifying the cause of hyponatremia can be complex. The history sometimes suggests a cause (eg, significant fluid loss due to vomiting or diarrhea, renal disease, compulsive fluid ingestion, intake of drugs that stimulate vasopressin release or enhance vasopressin action).

• Overtly hypovolemic patients usually have an obvious source of fluid loss and typically have been treated with hypotonic fluid replacement.

• Overtly hypervolemic patients usually have a readily recognizable condition, such as heart failure or hepatic or renal disease.

• Euvolemic patients and patients with equivocal volume status require more laboratory testing to identify a cause.

Laboratory tests should include serum and urine osmolality and electrolytes. Euvolemic patients should also have thyroid and adrenal function tested. Hypo-osmolality in euvolemic patients should cause excretion of a large volume of dilute urine (eg, osmolality < 100 mOsm/kg [< 100 mmol/kg]) and specific gravity < 1.003). Serum sodium concentration and serum osmolality that are low and urine osmolality that is inappropriately high (120 to 150 mmol/L [120 to 150 mOsm/kg]) with respect to the low serum osmolality suggests volume overload, volume contraction, SIADH, or cerebral salt wasting. Volume overload Volume Overload Volume overload generally refers to expansion of the extracellular fluid (ECF) volume. ECF volume expansion typically occurs in heart failure, kidney failure, nephrotic syndrome, and cirrhosis... read more and volume contraction Volume Depletion Volume depletion, or extracellular fluid (ECF) volume contraction, occurs as a result of loss of total body sodium. Causes include vomiting, excessive sweating, diarrhea, burns, diuretic use... read more are differentiated clinically.

In patients with hypovolemia and normal renal function, sodium reabsorption results in a urine sodium of < 20 mEq/L (< 20 mmol/L). Urine sodium > 20 mEq/L (> 20 mmol/L) in hypovolemic patients suggests mineralocorticoid deficiency or salt-losing nephropathy. Hyperkalemia suggests adrenal insufficiency.

In patients with hyponatremia and a urine sodium of > 40 mEq/L (> 40 mmol/L) who have recent traumatic brain injury or CNS surgery , cerebral salt wasting should be considered.

Mild to moderate, asymptomatic hyponatremia (ie, serum sodium ≥ 121 and < 135 mEq/L [≥ 121 and < 135 mmol/L]) requires restraint because small adjustments are generally sufficient. In diuretic-induced hyponatremia, elimination of the diuretic may be enough; some patients need some sodium or potassium replacement. Similarly, when mild hyponatremia results from inappropriate hypotonic parenteral fluid administration in patients with impaired water excretion, merely altering fluid therapy may suffice.

In asymptomatic patients, severe hyponatremia (serum sodium < 121 mEq/L [< 121 mmol/L]; effective osmolality < 240 mOsm/kg [< 240 mmol/kg] ) can be treated safely with stringent restriction of water intake.

In patients with neurologic symptoms (eg, confusion, lethargy, seizures, coma), treatment is more controversial. The debate primarily concerns the rate and degree of hyponatremia correction. Many experts recommend that, in general, serum sodium be raised no faster than 1 mEq/L/hour (1 mmol/L/hour). However, replacement rates of up to 2 mEq/L/hour (2 mmol/L/hour) for the first 2 to 3 hours have been suggested for patients with seizures or significantly altered sensorium. Regardless, the rise should be ≤ 8 mEq/L (≤ 8 mmol/L) over the first 24 hours. More vigorous correction risks precipitating osmotic demyelination syndrome Osmotic demyelination syndrome Hyponatremia is decrease in serum sodium concentration 136 mEq/L ( 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure, liver... read more .

Acute hyponatremia with known rapid onset (ie, within < 24 hours) is a special case. Such rapid onset can occur with

• Acute psychogenic polydipsia

• Use of the recreational drug ecstasy (MDMA)

• Postoperative patients who received hypotonic fluid during surgery

• Marathon runners who replace sweat loss with hypotonic fluids

Rapid-onset hyponatremia is problematic because the cells of the central nervous system have not had time to remove some of the intracellular osmolar compounds used to balance intracellular and extracellular osmolality. Thus, the intracellular environment becomes relatively hypertonic compared to the serum, causing intracellular fluid shifts that can rapidly cause cerebral edema, potentially progressing to brain stem herniation and death. In these patients, rapid correction with hypertonic saline is indicated even when neurologic symptoms are mild (eg, forgetfulness). If more severe neurologic symptoms, including seizures, are present, rapid correction of sodium by 4 to 6 mEq/L (4 to 6 mmol/L) using hypertonic saline is indicated. The patient should be monitored in an intensive care unit and serum sodium levels monitored every 2 hours. After sodium level has increased by the initial target of 4 to 6 mEq/L, the rate of correction is slowed so that serum sodium level does not rise by > 8 mEq/L (> 8 mmol/L) in the first 24 hours.

Hypertonic (3%) saline (containing 513 mEq sodium/L [513 mmol/L]) use requires frequent (every 2 hours) electrolyte determinations. In some situations, hypertonic saline may be used with a loop diuretic. Equations are available to help predict the sodium response to a given amount of hypertonic saline, but these formulas are only rough guidelines and do not decrease the need to monitor electrolyte levels frequently. For instance, in hypovolemic hyponatremia the sodium level can normalize too quickly as volume is replaced and thus removes the hypovolemic stimulus for vasopressin secretion, causing the kidneys to excrete large amounts of water.

Another recommendation includes administration of desmopressin 1 to 2 mcg every 8 hours concurrently with hypertonic saline. The desmopressin prevents an unpredictable water diuresis that can follow the abrupt normalization of endogenous vasopressin that can occur as the underlying disorder causing hyponatremia is corrected. After the sodium has been corrected at the appropriate rate for 24 hours, desmopressin is stopped. Hypertonic saline can then be stopped, or, if required for continuing correction of hyponatremia, continued..

For patients with rapid-onset hyponatremia and neurologic symptoms, rapid correction is accomplished by giving 100 mL of hypertonic saline IV over 15 minutes. This dose can be repeated once if neurologic symptoms are still present.

For patients with seizures or coma but slower onset hyponatremia, ≤ 100 mL/hour of hypertonic saline may be administered over 4 to 6 hours in amounts sufficient to raise the serum sodium 4 to 6 mEq/L (4 to 6 mmol/L). This amount (in mEq OR mmol) may be calculated using the sodium deficit formula as

where TBW is 0.6 × body weight in kg in men and 0.5 × body weight in kg in women.

For example, the amount of sodium needed to raise the sodium level from 106 to 112 mEq/L in a 70-kg man can be calculated as follows:

Because there is 513 mEq (mmol) sodium/L in hypertonic saline, roughly 0.5 L of hypertonic saline is needed to raise the sodium level from 106 to 112 mEq/L (mmol/L). To result in a correction rate of 1 mEq/L/hour, this 0.5 L volume would be infused over about 6 hours.

Patients meeting the criteria for cerebral salt wasting should not be fluid restricted because fluid restriction can cause brain vessel vasospasm. Although isotonic saline should correct the cause of hyponatremia, use of hypertonic saline is recommended to prevent more severe hyponatremia if indeed SIADH is present.

The selective vasopressin (V2) receptor antagonists conivaptan (IV) and tolvaptan (oral) are treatment options for severe or resistant hyponatremia. These drugs are potentially dangerous because they may correct serum sodium concentration too rapidly; they are typically reserved for severe (< 121 mEq/L [< 121 mmol/L]) and/or symptomatic hyponatremia that is resistant to correction with fluid restriction. The same pace of correction as for fluid restriction, ≤ 8 mEq/L over 24 hours, is used. These drugs should not be used for hypovolemic hyponatremia or in patients with liver disease or advanced chronic kidney disease.

Conivaptan is indicated for treatment of hypervolemic and euvolemic hyponatremia. It requires close monitoring of patient status, fluid balance, and serum electrolytes and so its use is restricted to hospitalized patients. A loading dose is given followed by a continuous infusion over a maximum of 4 days. It is not recommended in patients with advanced chronic kidney disease (estimated glomerular filtration rate < 30 mL/minute) and should not be used if anuria is present. Caution is advised in moderate to severe cirrhosis.

Tolvaptan is a once daily tablet indicated for hypervolemic and euvolemic hyponatremia. Close monitoring is recommended especially during initiation and dosage changes. Tolvaptan use is limited to 30 days because of the risk of liver toxicity. Tolvaptan is not recommended for patients with advanced chronic kidney disease or liver disease. Its effectiveness can be limited by increased thirst. Tolvaptan use is also limited by high cost.

Both of these drugs are strong inhibitors of CYP3A (cytochrome P450, family 3, subfamily A) and as such have multiple drug interactions. Other strong CYP3A inhibitors (eg, ketoconazole, itraconazole, clarithromycin, retroviral protease inhibitors) should be avoided. Clinicians should review the other drugs the patient is taking for potentially dangerous interactions with V2 receptor antagonists before initiating a treatment trial.

Patients with SIADH need chronic treatment for hyponatremia. Fluid restriction alone is frequently not enough to prevent recurrence of hyponatremia. Oral salt (NaCl) tablets can be used with dosage adjusted to treat mild to moderate chronic hyponatremia in these patients.

Oral urea is a very effective treatment for hyponatremia, but it is tolerated poorly by patients due to its taste. A newer oral formulation of urea has been developed to enhance palatability.

Osmotic demyelination syndrome (previously called central pontine myelinolysis) may follow too-rapid correction of hyponatremia. Demyelination classically affects the pons, but other areas of the brain can also be affected. Lesions are more common among patients with alcohol use disorder Alcohol Use Disorders and Rehabilitation Alcohol use disorder involves a pattern of alcohol use that typically includes craving and manifestations of tolerance and/or withdrawal along with adverse psychosocial consequences. Alcoholism... read more , undernutrition Overview of Undernutrition Undernutrition is a form of malnutrition. (Malnutrition also includes overnutrition.) Undernutrition can result from inadequate ingestion of nutrients, malabsorption, impaired metabolism, loss... read more , or other chronic debilitating illness. Flaccid paralysis, dysarthria, and dysphagia can evolve over a few days or weeks after a hyponatremic episode. The classic pontine lesion may extend dorsally to involve sensory tracts and leave patients with a "locked-in" syndrome (an awake and sentient state in which patients, because of generalized motor paralysis, cannot communicate, except by vertical eye movements controlled above the pons). Damage often is permanent. When sodium is replaced too rapidly (eg, > 14 mEq/L/8 hour [> 14 mmol/L/8 hours]) and neurologic symptoms start to develop, it is critical to prevent further serum sodium increases by stopping hypertonic fluids. In such cases, inducing hyponatremia with hypotonic fluid may mitigate the development of permanent neurologic damage.