eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Sonali Deshmukh, MBBS, Consulting Staff, Omaha Nephrology, Nebraska
Christie P Thomas, MB, BS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Hospitals and Clinics; Director of Transplantation Services, Veterans Affairs Medical Center

Updated: May 28, 2009

Introduction

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.¹

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.² 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

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.³
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 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

Differential Diagnoses

Acute Renal Failure
Addison Disease
Chronic Renal Failure
Hypopituitarism (Panhypopituitarism)
Hypothyroidism

Workup

Laboratory 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 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

Medical Care

The treatment of SIADH and the rapidity of correction of hyponatremia depend on whether the patient is symptomatic or asymptomatic from 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. Diagnosis and treatment of the underlying cause of SIADH (if known) is also important.

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 below).
- 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
- Newer modalities include water restriction; a high-sodium, high-protein diet; loop diuretics; urea; and V2 receptor antagonists. Demeclocycline is rarely used, and lithium is not used anymore.
- 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 plus 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).
- Vasopressin receptor antagonists
  - 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.
  - Tolvaptan (OPC-41061) was approved by the US Food and Drug Administration (FDA) in May 2009 in hospitalized patients.⁴ Trials with other orally active, selective V2-receptor antagonists, such as lixivaptan (VPA-985) and satavaptan (SR-121463), are ongoing. Concerns exist with the employment of these agents in a clinical setting, and they should be used only by physicians who are experienced in the management of hyponatremia.

Medication

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

Arginine vasopressin antagonists

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

Conivaptan (Vaprisol)

Arginine vasopressin antagonist (V1A, V2) indicated for euvolemic (dilutional) and hypervolemic hyponatremia. Increases urine output of mostly free water, with little electrolyte loss.

Dosing

Adult

20 mg IV loading dose (infuse over 30 min), followed by 20 mg via continuous IV infusion over 24 h; continue treatment for additional 1-3 d as a 20-mg/d continuous IV infusion; may titrate up to 40 mg/d if necessary

Pediatric

Not established

Interactions

Sensitive CYP3A4 substrate and potent CYP3A4 inhibitor; coadministration with potent CYP3A4 inhibitors significantly increases C_max and AUC; coadministration with CYP3A4 substrates (eg, midazolam, simvastatin, amlodipine) may increase substrate's toxicity; significantly decreases digoxin clearance

Contraindications

Documented hypersensitivity; hypovolemic hyponatremia; coadministration with potent CYP3A4 inhibitors (eg ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Rapid correction of serum sodium level may result in serious sequelae (eg, osmotic demyelination); may cause infusion site reactions, hypokalemia, headache, thirst, and vomiting; caution with hepatic impairment; limited data available in CHF and hepatic or renal impairment

Tolvaptan (Samsca)

Selective vasopressin V2-receptor antagonist. Indicated for hypervolemic and euvolemic hyponatremia (ie, serum sodium level <125 mEq/L) or less-marked hyponatremia that is symptomatic and has resisted correction with fluid restriction. Used for hyponatremia associated with congestive heart failure, liver cirrhosis, and syndrome of inappropriate secretion of antidiuretic hormone. Initiate or reinitiate in hospital environment only.

Dosing

Adult

15 mg PO qd initially; may increase at 24-h intervals to 30 mg/d; not to exceed 60 mg/d

Pediatric

Not established

Interactions

CYP3A substrate, P-gp inhibitor, and weak CYP3A inhibitor; CYP3A inhibitors (see Contraindications) may lead to marked increase in serum concentrations; avoid coadministration with moderate CYP3A inhibitors (eg, erythromycin, fluconazole, aprepitant, diltiazem, verapamil); also avoid coadministration with CYP3A inducers (eg, rifampin, rifabutin, rifapentine, barbiturates, phenytoin, carbamazepine, St. John's wort), as these may decrease tolvaptan serum levels by up to 85% and thereby decrease effectiveness; coadministration with grapefruit juice results in a 1.8-fold increase of serum levels; dose reduction may be required when coadministered with P-gp inhibitors (eg, cyclosporine)
May increase risk for hyperkalemia when administered with drugs known to increase serum potassium levels (eg, ACE inhibitors, potassium-sparing diuretics); may increase serum levels of P-gp substrates (eg, digoxin)

Contraindications

Documented hypersensitivity; urgent correction of hypovolemia; individuals unable to sense or respond to thirst; hypovolemic hyponatremia; strong CYP 3A inhibitors (eg, ketoconazole, clarithromycin, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, telithromycin); anuria

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Initiate only in hospital setting, since serum sodium levels and volume status require close monitoring; rapid rise in sodium levels may cause osmotic demyelination syndrome, resulting in serious neurologic sequelae, including dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death; use caution with cirrhosis, since may increase risk for GI bleeding; may cause hyperkalemia and other electrolyte concentration abnormalities; common adverse effects include thirst, xerostomia, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia

Antibiotics

Agents that inhibit the action of ADH may be used.

Demeclocycline (Declomycin)

Indicated for SIADH. Interferes with action of vasopressin (ADH) at renal collecting duct by impairing generation and action of cAMP. This results in a state similar to nephrogenic diabetes insipidus. Onset of action may be delayed by >1 week; therefore, not indicated for emergent management of symptomatic hyponatremia.

Dosing

Adult

150 mg PO qid or 300 mg bid

Pediatric

<8 years: Not recommended
>8 years: 3-6 mg/lb (6-12 mg/kg) PO divided bid/qid, depending on severity of disease

Interactions

Bioavailability may decrease with coadministration of antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; may increase hypoprothrombinemic effects of anticoagulants (monitor prothrombin activity); coadministration with oral contraceptives may decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Follow-up

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

Medicolegal Pitfalls

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

References

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Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM. Aug 2006;99(8):505-11. [Medline].
Decaux G. Is asymptomatic hyponatremia really asymptomatic?. Am J Med. Jul 2006;119(7 Suppl 1):S79-82. [Medline].
Wong F, Blei AT, Blendis LM, et al. A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial. Hepatology. Jan 2003;37(1):182-91. [Medline].
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Keywords

syndrome of inappropriate secretion of antidiuretic hormone, syndrome of inappropriate secretion of ADH, SIADH, ADH, antidiuretic hormone, antidiuretic hormone disorder, arginine vasopressin, AVP, hyponatremia, low serum osmolality, expanded extracellular volume, water balance, impaired water excretion, dilutional hyponatremia

Contributor Information and Disclosures

Author

Sonali Deshmukh, MBBS, Consulting Staff, Omaha Nephrology, Nebraska
Sonali Deshmukh, MBBS is a member of the following medical societies: American Society of Nephrology
Disclosure: Nothing to disclose.

Coauthor(s)

Christie P Thomas, MB, BS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Hospitals and Clinics; Director of Transplantation Services, Veterans Affairs Medical Center
Christie P Thomas, MB, BS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Heart Association, American Society of Nephrology, American Society of Transplantation, American Thoracic Society, International Society of Nephrology, and Royal College of Physicians
Disclosure: Genzyme Grant/research funds Other

Medical Editor

Chike Magnus Nzerue, MD, Associate Dean for Clinical Affairs, Meharry Medical College
Chike Magnus Nzerue, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Society of Nephrology, and National Kidney Foundation
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine, Director of Nephrology Training Program, Kidney Disease Program, University of Louisville School of Medicine; Director, Metabolic Stone Clinic
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

Further Reading

eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Introduction

Background

Pathophysiology

Frequency

United States

Mortality/Morbidity

Clinical

History

Physical

Causes

Differential Diagnoses

Other Problems to Be Considered

Workup

Laboratory Studies

Imaging Studies

Treatment

Medical Care

Medication

Arginine vasopressin antagonists

Conivaptan (Vaprisol)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Tolvaptan (Samsca)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Antibiotics

Demeclocycline (Declomycin)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Follow-up

Patient Education

Miscellaneous

Medicolegal Pitfalls

References

Keywords

Contributor Information and Disclosures

Author

Coauthor(s)

Medical Editor

Pharmacy Editor

Managing Editor

CME Editor

Chief Editor