AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Water balance is an important regulatory function involving the hypothalamus and the kidneys (among other organs). Various hormones are also involved, of which the antidiuretic hormone (ADH) arginine vasopressin is most important.

The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the nonphysiologic release of ADH, resulting in impaired water excretion with normal sodium excretion.

SIADH was first described by Schwartz and associates in 2 patients with bronchogenic carcinoma and was later further characterized by Bartter and Schwartz.

Pathophysiology

ADH is a polypeptide synthesized in the supraoptic and paraventricular nuclei in the hypothalamus and is released in response to a number of stimuli. ADH is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.

In the kidneys, ADH acts on the principal cells of the cortical and medullary collecting tubules to increase water permeability. Other renal actions include local production of prostaglandins in a variety of renal cells, including the glomerulus and the thick ascending limb of the loop of Henle. Elsewhere, ADH causes vasoconstriction in a number of vascular beds and releases factor VIII and von Willebrand factor from vascular endothelium.

Three known receptors bind ADH at the cell membrane: V1a, V1b (also known as V3), and V2. The vasopressin (AVP, ADH) receptor subtypes belong to the G protein–coupled receptor superfamily. The V1a and V1b receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates protein kinase C.

V1a subtype is ubiquitous and found on cells, such as vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. V1b receptors are found predominantly in the anterior pituitary.

V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly in the principal cells of the renal collecting duct, where they mediate antidiuretic response. V2 receptors are also found in endothelial cells and induce the secretion of von Willebrand factor.

ADH activates the V2 receptor on the basolateral membrane of the principal cells of the renal collecting duct. This activates cyclic adenosine monophosphate through heterotrimeric G proteins, which results in insertion of aquaporin-2 water channels in the luminal membrane, thus making it more permeable to water.

The major stimuli to ADH are hyperosmolality and effective circulating volume depletion. Normally, ADH secretion ceases when plasma osmolality falls below 275 mOsm/kg. This fall causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. In addition to the hypothalamic osmoreceptors, hypothalamic neurons secreting ADH also receive input from baroreceptors in the great vessels and the atria. This results in nonosmotic release of ADH. Other stimuli for ADH secretion include pain and nausea.

In general, the plasma sodium concentration is the primary osmotic determinant of ADH release. However, in persons with SIADH, a nonphysiologic secretion of ADH results in enhanced water reabsorption, leading to dilutional hyponatremia. Sodium excretion is intact, and the amount of sodium excreted in the urine varies with diet. Ingestion of water is an essential prerequisite to the development of dilutional hyponatremia; regardless of cause, hyponatremia does not occur if water is restricted.

The continued presence of ADH with water intake causes retention of ingested water. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and peptides (eg, atrial natriuretic peptide) are secreted, which causes natriuresis with some degree of accompanying kaliuresis and diuresis. Thus, these patients are euvolemic or are slightly volume-expanded.

If water and sodium intake remain constant, a steady state is reached and sodium excretion equals sodium intake. Experimental evidence indicates that several days after ADH-induced water retention, escape from its effect occurs. This results in the establishment of a water balance and a newer, stable (although lower) sodium concentration. This is thought to be mediated via pressure-induced natriuresis and diuresis. Other authorities attribute this escape phenomenon to a decrease in the aquaporin-2 channel expression in the renal collecting duct.

In addition to the inappropriate ADH secretion, persons with this syndrome also may have an inappropriate thirst sensation, which leads to an intake of water that is in excess of the free water excreted. This increase in water ingested may then contribute to the maintenance of hyponatremia.

Before the diagnosis of SIADH is made, other causes for a decreased diluting capacity (eg, renal, pituitary, adrenal, thyroid, cardiac, or hepatic disease) must be excluded. In addition, nonosmotic stimuli for arginine vasopressin release, particularly hemodynamic derangements (eg, due to hypotension, nausea, uncontrolled pain, or drugs) must be excluded.

Frequency

United States

SIADH is usually observed in patients in hospital settings, and the frequency may be as high as 35%.

Mortality/Morbidity

The mortality rate for acute symptomatic hyponatremia has been noted to be as high as 55% and as low as 5%, depending on the reference source. The mortality rate associated with chronic hyponatremia has been reported to be 14-27%.

In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had a significantly higher mortality rate. The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization. The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum sodium in the patients.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

SIADH is usually detected based on the results of laboratory testing.

• Two important considerations related to the history include the following:
• • Note symptoms that may suggest increased secretion of ADH, such as chronic pain, CNS or pulmonary tumors (eg, hemoptysis, chronic headaches), head injury, and drug use.
  • Determine if the patient has had excessive fluid intake because of inappropriate thirst or psychogenic polydipsia or because intravenous fluids were administered by health care providers.

• Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms. In general, slowly progressive hyponatremia is associated with fewer symptoms than a rapid drop of serum sodium to the same value. A recent paper by Decaux evaluating mild chronic hyponatremia suggests that it contributes to an increased rate of falls.
• When the serum sodium level is less than 125 mEq/L, mild CNS symptoms, such as lethargy, fatigue, anorexia, nausea, and muscle cramps, may develop. A further decrease in the serum sodium level can lead to drowsiness, confusion, seizures, and coma.

Physical

After the identification of hyponatremia, the approach to the patient depends on the clinically assessed volume status. In SIADH, the patient is typically euvolemic and hypertension, peripheral and pulmonary edema, dry mucous membranes, reduced skin turgor, and orthostatic hypotension are usually absent.

• Neurologic signs may be present if hyponatremia is severe or if it develops rapidly.
• • These signs include Cheyne-Stokes respiration, drowsiness, disorientation, delirium, seizures, and coma.
  • Neurologic complications occur as a result of the brain's adaptation to changes in osmolality. Hyponatremia and hypoosmolality lead to acute edema of the brain cells. An increase in brain water content of more than 5-10% is incompatible with life. The rigid calvarium prevents expansion of brain volume beyond a certain point, after which the brain cells must adapt to persistent hypoosmolality.
  • In response to a decrease in osmolality, the brain rapidly loses electrolytes (eg, sodium and chloride from interstitial fluid in minutes, potassium from intracellular space within 2-3 h) and intracellular organic osmolytes (eg, amino acids, such as glutamate, glutamine, taurine, polyhydric alcohol, myoinositol, methylamine, and creatinine). This occurs concurrently to prevent excessive brain swelling.
  • Quantitative brain osmolyte modifications have recently been studied in humans in vivo (by proton magnetic resonance spectroscopy), and results showed profound decreases in myoinositol.

• Following correction of hyponatremia, the adaptive process does not match the extrusion kinetics.
• • Electrolytes rapidly reaccumulate within 24 hours, resulting in a significant overshoot above normal brain contents within the first 48 hours after correction.
  • Organic osmolytes return to normal brain content very slowly over 5-7 days. Electrolyte brain content returns to normal levels by the fifth day after correction, when organic osmolytes return to normal.

• Irreversible neurologic damage and death may occur when the rate of correction of sodium exceeds 0.5 mEq/L/h for patients with severe hyponatremia. At this rate of correction, the osmolytes that have been lost in defense against brain edema during the development of hyponatremia cannot be restored as rapidly. The brain cells are thus subject to osmotic injury. This condition is called osmotic demyelination. Certain conditions, such as female sex (menstruating women), young age, and hypoxia, predispose patients to worse outcomes.

Causes

In most patients, the defect in urinary dilution is caused by ectopic production, exogenous administration, or osmotically inappropriate neurohypophyseal secretion of ADH. The causes of SIADH are as follows:

• Increased hypothalamic production
• • Neuropsychiatric
    • Infections - Meningitis, encephalitis, abscess

    • Vascular - Thrombosis, subarachnoid or subdural hemorrhage

    • Neoplasms

    • Other - HIV, Guillain-Barré syndrome, acute intermittent porphyria, autonomic neuropathy, post–pituitary surgery, multiple sclerosis, psychosis
  • Drugs
    • Chemotherapeutic - Cyclophosphamide, vincristine, vinblastine

    • Antipsychotic - Thiothixene, thioridazine, haloperidol

    • Antidepressants - Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors

    • Miscellaneous – Bromocriptine

• Pulmonary diseases
• • Pneumonia

  • Tuberculosis

  • Acute respiratory failure

  • Positive pressure ventilation

  • Asthma

  • Atelectasis

• Postoperative complications

• Severe nausea, pain

• Ectopic production of ADH
• • Oat cell of lung

  • Bronchogenic carcinoma

  • Carcinoma of duodenum, pancreas, or thymus

  • Olfactory neuroblastoma

• Potentiation of ADH effect
• • Chlorpropamide
  • Tolbutamide
  • Carbamazepine
  • Intravenous cyclophosphamide

• Exogenous administration of ADH
• Idiopathic

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The differential diagnoses include conditions that can cause impairment in water excretion and hyponatremia. These can be further divided into those that cause a renal impairment in water excretion and those in which renal handling of water is normal.

• Disorders in which renal water handling is impaired
• • Effective circulating volume depletion - GI losses (eg, diarrhea, vomiting), renal (eg, diuretic therapy, renal salt wasting, skin losses, edematous disorders)
  
  
  • Diuretics
  
  
  • Renal failure
  
  
  • States of ADH excess - SIADH, cortisol deficiency, hypothyroidism, exogenous ADH (eg, deamino-D-arginine-vasopressin, vasopressin, oxytocin)
  
  
  • Decreased solute intake
  
  
  • Cerebral salt wasting


• Disorders with normal water excretion
• • Primary polydipsia
  
  
  • Reset osmostat

• Plasma triglycerides (g/L) X 0.002 = mEq/L decrease in sodium


• Plasma protein level - 8 (g/L) X 0.025 = mEq/L decrease in sodium

Cerebral salt wasting

The term cerebral salt wasting (CSW) was introduced by Peters et al in 1950. They hypothesized that cerebral disorders can cause the kidneys to be unable to conserve salt, thus eliciting salt wasting and fluid loss. Therefore, CSW is defined as the renal loss of sodium during intracranial disease, which leads to hyponatremia and a decrease in extracellular fluid volume.

Over the years, much debate has been focused on the existence of this entity. The evidence in favor of CSW rests on the following points: (1) the presence of a negative salt balance, (2) the development of volume contraction (by definition, patients with SIADH are euvolemic), and (3) the fact that patients with CSW respond to salt and volume replacement rather than to fluid restriction.

Various mechanisms have been postulated, including the roles of natriuretic peptides and neural regulatory mechanisms. The measurement of ADH or atrial natriuretic peptide levels provides no clues because they have been known to vary even in persons with SIADH.

The treatment of CSW is, in fact, the opposite of that for SIADH and (besides treating the inciting event) involves fluid and salt replacement.

Sodium administration in persons with CSW corrects both the hyponatremia and the fluid loss; however, in those with SIADH, the effect is temporary. The mineralocorticoid fludrocortisone has been used as part of the treatment of CSW. Remember the adverse effects of hypokalemia, pulmonary edema, and hypertension when using this drug.

Adrenal insufficiency

Cortisol has a negative feedback effect on ADH and corticotropin-releasing hormone. The absence of cortisol thus removes this inhibitory effect, increasing the release of ADH.

Reset osmostat

Persons with this entity have a normal response to changes in osmolality, but their threshold for ADH release is reduced. Therefore, they have a lower but stable plasma sodium concentration. Reset osmostat has also been observed in pregnant women. Increased human chorionic gonadotropin levels have been implicated to play a role in this condition. The serum sodium concentration falls by approximately 5 mEq/L in the first 2 months of pregnancy and remains stable until after delivery, when it returns to normal levels. Recognizing this entity is important because it does not require treatment.

Psychogenic polydipsia

This condition is characterized by an increase in water intake attributed to a defect in the thirst mechanism. In some patients, the osmotic threshold for thirst is reset below the reset for release of ADH. This disorder is mostly observed in patients with psychosis and has been associated with an increase in water intake.

Water excretion is normal in these patients, and water restriction corrects the hyponatremia. In a patient on a normal diet and an average solute (protein and salts) intake, a substantial amount of water must be imbibed for hyponatremia to develop. Consider an individual who has 700 mOsm (primarily consisting of urea, sodium, potassium, and chloride) to excrete per day. Ordinarily, this person can vary his or her urine osmolality between 50 and 1400 mOsm/L and thus can excrete the osmotic load in a minimum of 500 mL and a maximum of 14 L. As long as his or her fluid intake is between these extremes, he or she adjusts urine osmolality to excrete the load. To become hyponatremic, such an individual must drink more than 14 L/d.

Decreased solute intake (beer potomania)

This disorder is observed in persons who drink hyponatremic fluids without adequate food intake. The condition is described in individuals who drink beer and thrive on little else and thus have substantially reduced protein and salt intake. The daily solute intake directly influences the osmotic load to be excreted. With poor nutritional intake, the osmotic load may be as little as 200 mOsm; in this situation, it can be excreted in a maximum of 4 L. Ingestion of a larger quantity of solute-free fluids (typically beer) without other avenues for water loss can result in the development of hyponatremia.

Thiazides and hyponatremia

Diuretics can cause mild hyponatremia. Thiazide diuretics cause hyponatremia more often than loop diuretics. This is related to the different sites of action of these agents.

Loop diuretics act in the medullary thick ascending limb and prevent sodium absorption in the medullary thick ascending limb. This interferes with the concentrating ability and the ability of ADH-induced water reabsorption because of diminished medullary osmolality. The sodium can be reabsorbed once it reaches the distal tubule.

In contrast, the thiazide diuretics prevent sodium absorption in the distal tubule and do not interfere with the medullary concentrating ability or the effect of ADH. Therefore, sodium is lost but water reabsorption is still possible, leading to hyponatremia. In patients who are susceptible to this effect, hyponatremia is usually observed within 2 weeks. After the first few weeks, a new steady state is reached and further changes in sodium occur, with added insults, such as vomiting and diarrhea.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Order tests for the following:
• • Serum sodium, potassium, chloride, and bicarbonate
  
  
  • Serum osmolality
  
  
  • Serum creatinine
  
  
  • Serum urea nitrogen
  
  
  • Serum uric acid
  
  
  • Urine osmolality
  
  
  • Urine sodium
  
  
  • Serum cortisol
  
  
  • Thyroid-stimulating hormone


• Consider the following scenarios:
• • Hyponatremia combined with high serum osmolality: This indicates the presence of an osmotically active substance, such as mannitol, or an elevated blood glucose concentration.
  
  
  • Hyponatremia with normal serum osmolality: This indicates pseudohyponatremia (see Pseudohyponatremia).
  
  
  • Hyponatremia with serum hypoosmolality: If urine osmolality is higher than plasma osmolality, this finding excludes primary polydipsia and reset osmostat. In both these conditions, the body is able to appropriately dilute the urine to rid itself of excess free water.


• Assess volume status, as follows:
• • Hypovolemia
    
    
    • The patient should be assessed clinically to help rule out the presence of hypovolemia. Clues from the physical examination include hypotension with or without orthostasis, dry mucosae, cold peripheries, reduced skin turgor, and low central venous pressures (if central venous pressure or pulmonary capillary wedge pressure measurements are available).
    
    
    • In persons with hypovolemic hyponatremia, the urine sodium concentration is usually less than 25 mEq/L. Thus, if the urine sodium concentration is less than 25 mEq/L, volume depletion from extrarenal volume loss should be excluded.
    
    
    • Volume depletion causes an appropriate (nonosmotic) secretion of ADH and leads to hyponatremia if hypotonic fluid is used to replace isotonic fluid losses. Typically, a volume-depleted person responds to this thirst by drinking free water. Replacing isotonic losses (lost from the extracellular compartment) with water or hypotonic fluids makes a patient hyponatremic.
    
    
    • Hypovolemia can also be associated with a urine sodium concentration of more than 25 mEq/L if the source of volume loss is the kidney. Thus, diuretic use, mineralocorticoid deficiency, and salt-losing nephropathy can lead to hyponatremia with a high urine sodium concentration.
  
  
  • Hypervolemia: The presence of edema with elevated jugular venous pressure indicates increased volume, such as in heart failure and cirrhosis (with other signs of liver failure).
  
  
  • Euvolemia
    
    
    • In euvolemic states, before attributing the hyponatremia to SIADH, renal disease and endocrine disorders (especially states of thyroid, pituitary, and adrenal insufficiency) should be excluded.
    
    
    • In persons with SIADH, serum osmolality is generally lower than urine osmolality. In the setting of serum hypoosmolality, ADH secretion is usually suppressed to allow the excess water to be excreted, thus moving the plasma osmolality toward normal. If ADH secretion is shut down completely, urine should have an osmolality of less than 100 mOsm. Therefore, urine osmolality of more than 100 mOsm in the context of plasma hypoosmolality is sufficient to confirm the diagnosis of SIADH, although classic SIADH is associated with urine osmolality greater than the serum osmolality. Inappropriate water retention causes the dilutional hyponatremia.
    
    
    • Urine sodium concentration in persons with SIADH is usually more than 40 mEq/L because, in SIADH, sodium handling is not abnormal and the urine sodium concentration reflects sodium intake, which is generally more than 40 mEq per day (usually 50-100 mEq/d). However, the urine sodium concentration in persons with SIADH can be modulated by dietary sodium intake. On a low-sodium diet, patients with SIADH may have a urine sodium level of less than 40 mEq/L.
    
    
    • Other conditions associated with an increased urinary sodium concentration include reset osmostat, renal sodium-wasting conditions (eg, diuretic therapy), renal disease, and adrenal insufficiency.


• In SIADH, hypouricemia (ie, serum uric acid lower than 4 mg/dL) is common and is usually associated with increased fractional excretion of uric acid, usually greater than 9%. Hypouricemia may be helpful in distinguishing SIADH from hyponatremias seen in hypovolemic individuals. In hypovolemia, the serum uric acid level is usually increased and fractional excretion of uric acid is increased. Hypouricemia and the associated increase in urinary excretion of uric acid return to normal after the correction of hyponatremia.

Imaging Studies

• The diagnosis of SIADH is made based on clinical and laboratory results. Imaging studies are not usually required unless they are required for the diagnosis of an underlying disease process. For example, head CT scanning may be necessary for a possible subarachnoid hemorrhage or chest radiography may be needed to help diagnose a lung tumor.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of SIADH and the rapidity of correction of hyponatremia depend on whether the patient is symptomatic or asymptomatic from the hyponatremia and whether it is an acute or chronic condition. The mainstay of treatment of acute and chronic SIADH is water restriction. The urine osmolality and creatinine clearance also must be considered when choosing the type of therapy.

If no history is available to determine the duration of hyponatremia and if the patient is asymptomatic, presuming that the condition is chronic is reasonable. However, extreme hyponatremia and an inappropriate approach to treatment can have disastrous consequences, and consultation with a nephrologist should be sought early in difficult cases.

• Acute setting (ie, <48 h since onset and usually with symptoms): Administer sodium chloride, hypertonic saline, and loop diuretics, and initiate water restriction (see Chronic setting).
• • The goal is to correct hyponatremia at a rate that does not cause neurologic complications. The objective is to raise serum sodium levels by 0.5-1 mEq/h, or not more than 10-12 mEq in the first 24 hours, to bring the sodium value to a maximum level of 125 mEq/L.
  
  
  • Depending on the rate of development of hyponatremia, the approach to correction varies. If an acute onset and neurologic symptoms have occurred, the use of hypertonic saline may be warranted. Three percent normal saline has 513 mEq/L each of sodium and chloride and has an osmolality of 1026 mOsm/L.
  
  
  • Hypertonic saline is usually combined with furosemide to limit treatment-induced volume expansion. The diuresis induced by furosemide has a solute concentration roughly equivalent to half-normal saline, thus excretion of free water occurs. Electrolyte free water intake is restricted. Check serum sodium and osmolality and urine osmolality frequently to follow the change in serum sodium values and to prevent overcorrection.
  
  
  • The recommended rate of correction initially equals 1-2 mEq/L/h in severely symptomatic patients, until symptoms resolve (or for the first 3-4 h). Total correction in the first 24 hours must not exceed 10 mEq. Osmotic demyelination has been reported in cases in which the initial correction exceeded 12 mEq and even in cases in which the correction was 9-10 mEq/24 h. Some authors have recommended a lower target of 8 mEq in 24 hours.
  
  
  • The change in serum sodium per liter of infused saline can be calculated as follows:

    [infusate sodium (mEq/L) - initial serum sodium (mEq/L)] / [total body water + 1 (L)]*

    
    
    
    • *Where total body water is 0.6 multiplied by body weight for men and 0.5 multiplied by body weight for women. This formula calculates the change in the serum sodium concentration after infusion of 1 L of sodium chloride solution. The infusate sodium is the sodium in the replacement fluid of choice. The initial serum sodium level is the patient's sodium value at presentation.
    
    
    • Normal saline (3%): Infusate sodium is 513 mEq/L.
    
    
    • Normal saline (0.9%): Infusate sodium is 154 mEq/L.
    
    
    • Normal saline (0.45%): Infusate sodium is 77 mEq/L.
    
    
    • For example, if the patient's serum sodium level is 115 mEq/L and total body water level is 35, then substituting in the above equation produces (513-115)/(35+1) = 11. This means that 1 L of 3% normal saline increases the serum sodium by 11 mEq. If the rate at which the correction must be made is known (not >10 mEq/24 h), the rate of infusion can be calculated.
  
  
  • The patient's serum sodium level and clinical status must be monitored often to determine the need for continued aggressive therapy.



• Chronic setting: Institute water restriction, a high-sodium and high-protein diet, loop diuretics, demeclocycline, lithium, urea, and V2 receptor antagonists.
• • Water restriction
  • • Water restriction to about 500 mL/d (or even lower in some cases) is prescribed. Although easy to maintain in the hospital setting, this becomes difficult for patients to follow in an outpatient setting.
    
    
    • One of the functions of the kidneys is to excrete solutes in varying amounts of water. In persons with SIADH, urine osmolality is fixed at a certain value; for the kidneys to eliminate an "X" amount of solutes, a certain volume of water must be excreted. If water intake is lowered below total obligatory fluid losses (insensible losses + volume of urine required to excrete the osmolar load), then serum osmolality rises because a net loss of water occurs.
    
    
    • For example, consider a patient who has a net solute load of 900 mOsm/kg/d that must be excreted, and, because of SIADH, his or her urine osmolality is fixed at 600 mOsm/kg. This patient then excretes the solute load in 1.5 L of urine. On the other hand, if the urine osmolarity is fixed at 300 mOsm/kg, then 3 L of urine is required to excrete the same osmolar load. When water intake is restricted, the body mobilizes the free water already present to excrete this load. Thus, if urine output exceeds water intake, a net water loss occurs and the serum sodium level returns to normal. The insensible losses of relatively hypotonic fluids also contribute to net water loss. The key is sufficient restriction of water intake so that the excretion of free water from all sources is in excess of that taken in.
  
  
  • Urea
  • • Urea is a solute that must be excreted by the kidneys. Because urine osmolality is fixed in persons with SIADH, the obligatory urine volume can be increased by increasing the osmotic or solute load. Increased urinary loss of water decreases free water retention. Urea is a relatively nontoxic compound and, as opposed to sodium chloride treatment, does not cause edema or increase body weight.
    
    
    • Urea can be administered on a long-term basis without major adverse effects. (A case report of a 5-year treatment has been noted.) Urea is available as a powder, which is dissolved in water and taken orally during or after meals. To avoid gastric upset, it can be taken with an antacid. Urea can also be used continuously in patients with cerebral hemorrhage via a gastric tube or intravenously to prevent a rapid fall in intracranial pressure.
    
    
    • The dose is calculated based on body weight (0.5 g/kg body weight). This amounts to approximately 30 g of urea in a 60-kg adult. The osmolar load of 30 g of urea is 500 mOsm. The usual dose is approximately 30 g/d but can range from 30-90 g/d. This therapy can be used in both chronic and acute settings if the urine osmolality is low. This treatment can increase the serum sodium level by as much as 5 mEq/L/d.
    
    
    • After the oral administration of urea, a slight and transient (3-4 h) increase in diuresis and osmolar free water excretion occurs. This helps move excess free water and helps relieve brain edema.
    
    
    • Exercise caution because urea should be used with great care in patients with levels of serum creatinine of more than 2 mg/dL, BUN of more than 80 mg/dL, or bilirubin of more than 2 mg/dL to avoid progressive azotemia, hyperammonemia, and/or hepatic encephalopathy. Hypernatremia and dehydration may occur if the patient does not have free access to water.
    
    
    • Adverse effects may include (1) hypersensitivity, (2) azotemia, (3) active intracranial bleeding, (4) marked dehydration, (5) frank liver failure, and (6) phlebitis and thrombosis (if infused into veins of the lower extremities, especially in elderly patients).


• Newer modalities
• • Vasopressin receptor antagonists were first designed in the 1970s by Manning and Sawyer. These were peptide antagonists that were limited by their poor bioavailability and short biological half-life. In 1992, Yamamura et al characterized the first nonpeptide V2 receptor antagonist, OPC-31260. Since then, several new nonpeptide antagonists have been synthesized. Some examples are SR-121463A, WAY-VPA-985, OPC-41061, VPA-343, and YM-087. Some of these V2 receptor antagonists are now in clinical development.
  
  
  • Inhibition of the V2 receptor reduces the number of aquaporin-2 water channels in the renal collecting duct and decreases the water permeability of the collecting duct. Collectively, agents that increase water excretion are called aquaretics, and they should prove useful in the treatment of SIADH by competitively blocking ADH action. The term "vaptan" has been coined to officially name all the members of this new class of drugs.
  
  
  • Studies in humans are ongoing. Phase I studies with OPC-31260 demonstrated safety in humans. Phase II trials have also documented human safety and efficacy in such conditions as SIADH, cirrhosis, and congestive heart failure. Together, these studies demonstrate that nonpeptide vasopressin antagonists can be given orally or parenterally, and they have a purely dose-dependent aquaretic (water diuresis) effect, as opposed to a natriuretic/saluretic effect.
  
  
  • Conivaptan is a nonpeptide dual AVP V1a and V2 receptor antagonist. The FDA approved this drug for parenteral use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia.
  
  
  • Trials are ongoing for orally active selective V2 receptor antagonists, such as lixivaptan (VPA-985), satavaptan (SR-121463), and tolvaptan (OPC-41061). Concerns do exist with using these agents in a clinical setting, and they should only be used by physicians who are experienced in the management of hyponatremia.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antibiotics

Agents that inhibit the action of ADH may be used.

Drug Category: Arginine vasopressin antagonists

Treats hyponatremia through V2 antagonism of AVP in the renal collecting ducts. This effect results in aquaresis (excretion of free water).

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Patient Education

• For excellent patient education resources, visit eMedicine's Endocrine System Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education article Anatomy of the Endocrine System.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Consult a nephrologist to help with the management of patients presenting with hyponatremia and mental status changes.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 7, 2007