eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic

Syndrome of Inappropriate Antidiuretic Hormone Secretion

Keenan Bora, MD, Fellow, Medical Toxicology, Detroit Medical Center; Attending Physician, Medical Center Emergency Services, Detroit
Meher Chaudhry, MD, Chief Resident, Department of Emergency Medicine, Detroit Receiving Hospital, University Health Center

Updated: Oct 20, 2009

Introduction

Background

The serum sodium concentration is regulated by the balance of water intake, renal filtration and reabsorption of sodium, and antidiuretic hormone (ADH) – mediated water conservation by the collecting duct. Water balance is normally mediated by thirst, the secretion of antidiuretic hormone (also known as vasopressin), the feedback mechanisms of the renin-angiotensin-aldosterone system, and renal handling of filtered sodium and water. Disorders in any one of these components of sodium balance can result in hyponatremia.¹

ADH is secreted by supraoptic and paraventricular nuclei in the hypothalamus and transmitted via the neuronal axons to the posterior pituitary where it is secreted.² It is released when a decrease in the effective circulatory volume is sensed by vascular baroreceptors primarily located in the large arterial vessels. The key action of ADH in the kidney is to trigger the insertion of aquaporin-2 into the principal cells of the collecting duct. Aquaporins' selective permeability allows water reabsorption and consequently urine concentration.²

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was initially described by Leaf and Mamby. They demonstrated a direct relationship between excessive vasopressin and fall in serum sodium concentration without any change in urine osmolality or flow rate.³

Pathophysiology

The key to the pathophysiology, signs, symptoms, and treatment of SIADH is to understand that the hyponatremia is a result of excess water and not a serum sodium deficiency. SIADH consists of hyponatremia, inappropriately elevated urine osmolality (>200 mOsm/kg), excessive urine sodium (UNa >30 mEq/L), and decreased serum osmolality. These findings occur in the absence of diuretic therapy; in the presence of euvolemia without edema; in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function; and in absence of factors known to stimulate ADH secretion such as severe pain, hypotension, and stress.

In SIADH, the inappropriately elevated level of vasopressin enhances the reabsorption of water, thus concentrating the urine. It is the excess free water absorption that causes hyponatremia.

Two scenarios can occur in which vasopressin secretion will be not be correlated with the serum osmolality. First, a decrease in the effective circulatory volume may be falsely sensed by the large arterial baroreceptors in conditions such as cirrhosis, nephrotic syndrome, and congestive heart failure. In these cases, the stimulus for ADH secretion overrides osmotic signals, which are conveying a hypoosmotic state. ADH secretion ensues despite hypoosmolality resulting in hyponatremia.⁴ In contrast to patients with SIADH, these patients appear hypervolemic.

Second, inappropriate ADH secretion occurs when there is dysregulation of cells secreting vasopressin or in the feedback mechanisms responsible for its release. A variety of ADH-secreting tumors both inside and outside the pituitary have been associated with SIADH, as well as certain CNS disorders, pulmonary disorders, and medications (see Differentials).

A distinction should be made between the SIADH and the clinical syndrome of euvolemic hyponatremia. A mutation of the ADH receptor can make it more responsive to ADH and can result in the same clinical picture of hyponatremia, concentrated urine output, and decreased serum osmolality but with normal ADH secretion.⁵

Frequency

United States

Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. When defined as plasma sodium concentration of less than 135 mEq/L, the prevalence of hyponatremia in hospitalized patients may be as high as 15-30%.^6,7 The prevalence of hyponatremia in hospitalized patients has been reported in different studies as being between 2.5 and 16%.^8,6 In a majority of cases, the hyponatremia was found to be hospital acquired. In another study among emergency department patients, the prevalence of hyponatremia, defined as serum sodium concentration of less than 130 mEq/L, was 2.9%. Additionally, the prevalence of acute hyponatremia was 0.8%.⁹ Although a number of potential causes of hyponatremia exist, ADH dysregulation is the most common.⁸

Mortality/Morbidity

The fatality rate of patients with hyponatremia (sodium <130 mEq/L) is 60-fold compared to that of patients without documented hyponatremia, though the mortality is typically related to comorbid conditions rather than the hyponatremia itself. Predictors for higher morbidity and mortality rates include being hospitalized, acute onset, and severe hyponatremia.⁸

Previously, mild hyponatremia was considered relatively asymptomatic. However, recent evidence suggests that even mild hyponatremia can cause significant impairment such as unsteady gait and lead to frequent falls. This effect may be greater in elderly persons who are more sensitive to changes their sodium.¹⁰

Race

No evidence for race predilection was found in studies of SIADH.

Sex

Studies reveal variable evidence between gender and hyponatremia. Studies showing that females are at increased risk for hyponatremia failed to take body mass into account. Men appear to be more likely to get mild or moderate but not severe hyponatremia.¹¹

Age

Increasing age is a strong risk factor for hyponatremia; although, again, this may be confounded by body mass.¹¹ The very old and very young develop symptoms with smaller changes in serum sodium levels than adults.^12,2

Clinical

History

Signs and symptoms of hyponatremia are primarily related to the central nervous system dysfunction and correlate with severity and acuity of the hyponatremia. Anorexia, nausea, and malaise are the earliest findings, followed by headache, irritability, confusion, muscle cramps, weakness, obtundation, seizures, and coma. These occur as osmotic fluid shifts resulting in cerebral edema and increased intracranial pressure. Those with rapidly decreasing sodium levels manifest more pronounced symptoms. Patients with moderate chronic hyponatremia may have decreased reaction times, cognitive slowing, and ataxia resulting in frequent falls.¹⁰ When sodium concentration drops below 105 mEq/L, life-threatening complications are likely to occur.¹³

Helpful historical details in identifying the responsible mechanism for hyponatremia include diet, fluid intake, gastrointestinal losses, amount of urinary output, medications, and weight loss. Historical information can give important clues in deciding whether the hyponatremia is from an acute or chronic condition. This may help the physician in correlating the degree of hyponatremia with the patient's neurologic condition and influence the rate of sodium correction.

Prior to establishing a diagnosis of SIADH, a detailed history should be obtained in order to exclude the numerous disorders capable of causing hyponatremia (see Causes).

Physical

On physical examination, evaluation of volume status is important. SIADH is characterized by euvolemic hyponatremia. Edema in a hyponatremic patient is inconsistent with SIADH and may represent another hyponatremic states such as CHF, cirrhosis, or nephrotic syndrome. Prominent physical examination findings may be seen only in severe or rapid-onset hyponatremia and include confusion, lethargy, weakness, myoclonus, asterixis, depressed reflexes, generalized seizures, ataxia, nystagmus, tremor, dysarthria, dysphagia, and coma.

Causes

Causes of syndrome of inappropriate antidiuretic hormone secretion (SIADH) vary widely. The syndrome was first described in patients with bronchogenic carcinoma. SIADH may be a marker for occult malignancy such as head and neck cancers. SIADH may also be manifested in cases of hypothyroidism and is corrected when thyroid hormone is replaced.

Many therapeutic agents can induce SIADH. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin E₂, which modulates vasopressin action and can result in decreased water excretion.⁵ SIADH has been reported as an adverse effect of multiple psychotropic medications.^14,15 While the exact mechanism of action is unknown, it has been proposed that serotonin and serotonergic medications cause increased ADH secretion via the 5-HT_1C and 5-HT₂ receptors.¹⁵

SIADH should be differentiated from hospital-acquired hyponatremia often seen secondary to overzealous administration of hypotonic IV fluids.⁶

Some of the causes of SIADH are listed below:

• Central nervous system disease - Tumor, trauma, infection, cerebrovascular accident, subarachnoid hemorrhage, Guillain-Barré syndrome, delirium tremens, multiple sclerosis
• Pulmonary disease - Tumor, pneumonia, chronic obstructive pulmonary disease, lung abscess, tuberculosis, cystis fibrosis, positive-pressure ventilation
• Carcinoma -Lung, pancreas, thymoma, ovary, lymphoma
• Drugs - Exogenous vasopressin, nonsteroidal anti-inflammatory drugs, nicotine, diuretics, chlorpropamide, carbamazepine, tricyclic antidepressants, SSRIs, vincristine, thioridazine, cyclophosphamide, clofibrate, bromocriptine, haloperidol, thiothixene, exogenous oxytocin, MAOIs
• Surgery - Postoperative
• Idiopathic

Differential Diagnoses

Other Problems to Be Considered

CHF
Liver cirrhosis
Nephrotic syndrome
Hypothyroidism
Addison disease
Hypopituitarism
Primary polydipsia
Compulsive water drinking

Workup

Laboratory Studies

• Serum: Electrolytes, BUN, creatinine, glucose levels, and osmolality
  • Hyponatremia (sodium <135 mEq/L): Serum potassium and bicarbonate levels are normal in SIADH. Hypokalemia and metabolic alkalosis suggest diuretic therapy or vomiting.
  • BUN and serum uric acid levels tend to fall because of plasma dilution and increased excretion of nitrogenous products.
  • Low serum osmolality (<280 mOsm/kg)
  • Hyperkalemia and metabolic acidosis coexisting with hyponatremia suggest adrenal insufficiency.
  • Elevated glucose levels decrease the measured serum sodium levels by 1.6 mEq/L for every 100 mg/dL increase in glucose. This results from the osmotic effect of glucose drawing water into the intravascular space. The serum sodium level rises as hyperglycemia is corrected.
• Urine: Electrolytes and osmolality (specific gravity is nonspecific but sensitive)
  • Elevated urinary sodium level (>20 mmol/L). It would be preferable to check urine electrolytes at the same time as the serum electrolytes to determine the fractional excretion of sodium or FeNa.
  • Urine osmolality generally >100 mOsm/L
• Plasma cortisol level may be obtained to exclude adrenal insufficiency.
• Pseudohyponatremia occurs with severe hyperlipidemia and with hyperproteinemia (levels >10 g/dL, as seen in multiple myeloma).

Imaging Studies

• Chest radiographs may reveal an underlying cause (eg, pulmonary disease, lung carcinoma).
• CT scan of the head may be appropriate in selected cases.
  
  
  • CT scan may show evidence of cerebral edema (eg, narrowing of the ventricles) or may identify a CNS disorder responsible for SIADH (eg, brain tumor).
  • CT helps rule out other potential causes of acute changes in neurologic status.

Other Tests

• Serum ADH levels tend to not be available on a stat basis.
• Isolated hyponatremia has no consistent effect on ECG.

Treatment

Prehospital Care

Prehospital treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is directed toward treatment of symptoms (eg, seizures, arrhythmias) in severely symptomatic patients; the underlying hyponatremia is unlikely to be recognized prior to evaluation in the ED.

Emergency Department Care

Aggressive treatment of hyponatremia should always be weighed against the risk of inducing osmotic central pontine myelinolysis (CMP). Although rare, osmotic myelinolysis is a serious complication and can develop one to several days after aggressive treatment of hyponatremia. Management of acute, severe, and symptomatic hyponatremia varies widely from that of insidious chronic hyponatremia.

Emergent aggressive management of hyponatremia is indicated in patients with severe symptoms such as seizures or mental status changes and those with extremely low levels of sodium (less than 110 mEq/L). Administration of 3% hypertonic saline should be restricted to these emergent circumstances. It is recommended that the total serum sodium be corrected at a rate of 0.5-2 mEq/L/h.¹⁶ Correction of hyponatremia-induced neurologic symptoms can be rapid, provided that the final correction does not exceed 15 mEq/L in 24 hours.¹
 
Formulas for the dose and rate of hypertonic saline have been proposed based on a sodium deficit to calculate the rate of administration of hypertonic fluids. However, they have not been prospectively studied. Despite the correct use of sodium correction formulas, hyponatremia is often corrected too rapidly. Therefore, these formulas should serve only as guidelines. Patients will still require frequent retesting of their serum sodium concentration.¹⁷

The approximate sodium deficit can be estimated by using the following formula (consider 0.5 L/kg for females):

Na⁺ Deficit (mEq) = (Desired Na⁺ – Measured Na⁺) X 0.6 L/kg X Weight (kg)

The volume of hypertonic saline needed to correct that deficit can be calculated as follows:

Volume of 3% Saline = (Na⁺ Deficit) / 513 mEq/L Na⁺

Time Needed for Correction = (Desired Na⁺ – Measured Na⁺) / 0.5 mEq/L per hour

Rate = (Volume of 3% Saline)/(Time Needed for Correction)

Consultations

For severe symptomatic hyponatremia, consult an internist or a nephrologist for admission.

Medication

Reserve pharmacologic therapy for patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) who have chronic hyponatremia (serum sodium concentration <125 mEq/L) or who are unable to comply with water restriction or in whom the condition is refractory to water restriction.

Vasopressin receptor antagonists

Many nonpeptide vasopressin antagonists have been discovered in the past decade. Relcovaptan is a V_1a selective antagonist, and nelivaptan is a V_1b selective antagonist. Tolvaptan, mozivaptan, lixivaptan, and satavaptan are selective oral vasopressin V₂ receptor antagonists, and conivaptan is an intravenous dual V_1a/V₂ antagonist.^18,1 The potential benefits to these drugs include the predictability of their effect, rapid onset of action, and limited urinary electrolyte excretion. Conivaptan and tolvaptan are currently the only vasopressin receptor antagonists that are commercially available in the United States and FDA-approved for the treatment of euvolemic-hyponatremia in hospitalized patients. These medications should be initiated in a closely monitored setting to prevent rapid correction of serum sodium, which can result in central pontine myelinolysis.¹⁹

Conivaptan (Vaprisol)

Vasopressin receptor antagonist used for treatment of euvolemic hyponatremia in hospitalized patients.

Dosing

Adult

20 mg IV loading dose over 30 min; follow by 20 mg IV over 24 h; continue IV therapy for 1-3 d; may increase dose to 40 mg IV over 24 h if serum Na level does not rise at desired rate

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; CHF, impaired renal function, impaired liver function; 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 antidiuretic hormone secretion. 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

CYP 3A substrate, P-gp inhibitor, and weak CYP 3A inhibitor; CYP 3A inhibitors (see Contraindications) may lead to marked increase in serum concentrations; avoid coadministration with moderate CYP 3A inhibitors (eg, erythromycin, fluconazole, aprepitant, diltiazem, verapamil); also avoid coadministration with CYP 3A 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, or 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

Loop diuretic

These agents are often used in the treatment of hypervolemic hyponatremia. In SIADH patients with euvolemic hyponatremia, diuretics are usually used in conjunction with normal saline to replenish the sodium excreted with the diuresis.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system that, in turn, results in inhibition of sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Its action on distal tubule is independent of any inhibitory effect it may have on either carbonic anhydrase or aldosterone.
Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after previous dose, until desired diuresis occurs.
When treating infants, titrate with 1-mg/kg/dose increments until satisfactory effect achieved. In children, if diuretic response after initial dose is not satisfactory, increase dosage by 1 mg/kg, no sooner than 2 h after previous dose, until desired effect obtained. Doses >6 mg/kg not recommended.

Dosing

Adult

40 mg IV over 1-2 min initial; if response not satisfactory, increase to 80 mg IV (administered over 1-2 min) or 20-80 mg/d PO qd maintenance

Pediatric

1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg

Interactions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; aminoglycosides increase risk of auditory toxicity (hearing loss of varying degrees may occur); may enhance anticoagulant activity of warfarin; may increase plasma lithium levels and toxicity

Contraindications

Documented hypersensitivity; hepatic coma; anuria; severe electrolyte depletion

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

Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Osmotic Diuretic

These agents induce diuresis by elevating the osmolarity of the glomerular filtrate, thereby hindering the tubular reabsorption of water. The overall effect is increase in free water excretion by the kidneys. Concomitantly, sodium and chloride excretion also increase but to a lesser extent than water excretion.

Urea (Ureaphil, Aquacare)

For treatment of SIADH refractory to or in patients noncompliant with alternative therapies. Isosmotic concentration of dextrose or invert sugar is coadministered with urea to prevent hemolysis produced by pure solutions of urea.

Dosing

Adult

1-1.5 g/kg (0.45-0.68 g/lb) as 3% solution; by slow IV infusion; not to exceed rate of 4 mL/min or dose of 120 g/d

Pediatric

<2 years: 0.1 g/kg IV may be adequate
>2 years: 0.5-1.5 g/kg IV

Interactions

May decrease effects of lithium

Contraindications

Documented hypersensitivity; severely impaired renal function; active intracranial bleeding; marked dehydration; frank liver failure
Infusion into veins of lower extremities in elderly persons may cause phlebitis and thrombosis

Precautions

Pregnancy

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

Precautions

Do not use if intracranial bleeding present, unless prior to surgical intervention to control hemorrhage (reduction of brain edema by urea may result in reactivation of intracranial bleeding); may increase risk of venous thrombosis and hemoglobinuria in hypothermic patients; caution in renal impairment

Tetracyclines

Demeclocycline is an older tetracycline. One of its adverse effects is nephrogenic diabetes insipidus and polyuria, which can correct the excess of water seen in SIADH. This therapy rarely is instituted in the ED and generally is instituted by (or in consultation with) a nephrologist or a primary care physician. In addition, it is no longer available in most countries and may be nephrotoxic in patients with liver failure.¹⁹

Demeclocycline (Declomycin)

A tetracycline derivative that induces drug-induced diabetes insipidus by impairing generation and action of cyclic AMP. Onset of action may be delayed by over a week; thus, not indicated for emergency management of symptomatic hyponatremia.

Dosing

Adult

300-600 mg PO bid

Pediatric

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

Interactions

Antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate may increase bioavailability; may increase hypoprothrombinemic effects of anticoagulants (monitor prothrombin activity); 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; if used 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

Further Inpatient Care

• Inpatient care is indicated for severe symptomatic hyponatremia or for treatment of the underlying disease.

Further Outpatient Care

• Water restriction is the mainstay of treatment. Patients with sodium levels of more than 125 mEq/L can be managed with water restriction of 500 mL per day and close follow-up.
• For refractory cases of SIADH, consider pharmacologic therapy.

Inpatient & Outpatient Medications

• See Medications.

Complications

• Central pontine myelinolysis (CPM) is the most feared complication of excessive, overly rapid correction of hyponatremia. Typical features are disorders of upper motor neurons including spastic quadriparesis and pseudobulbar palsy, and mental disorders ranging from confusion to coma.²⁰ The risk is increased in persons with hepatic failure, potassium depletion, large burns, and malnutrition.¹³ Once central pontine myelinolysis occurs as a complication, there is no proven treatment.
  • Patients with cerebral disease or underlying metabolic disorders (eg, alcoholism, liver disease, malnutrition, hypokalemia, large burns) are at increased risk for CPM. Premenopausal patients undergoing surgery, especially gynecologic or related procedures, may also have an increased risk.
  • CPM is more likely in patients with long-standing, severe hyponatremia that is corrected too rapidly.
  • Risk is minimal if hyponatremia develops over less than 48 hours, even with rapid correction.
  • Onset of CPM may be delayed, manifesting days after correction, despite initial clinical improvement.

Prognosis

• The prognosis of SIADH best correlates to the underlying cause.
• Rapid and complete recovery tends to be the rule for recovery from drug-induced SIADH when the offending agent is withdrawn.
• Successful treatment of pulmonary or CNS infection can lead to correction of SIADH. 
• Patients who present with neurologic symptoms, cerebral edema, or severe hyponatremia may develop permanent neurologic impairment.

Patient Education

• Emphasize the importance of compliance with fluid restriction.
  
  
  • Patients must understand that a typical diet may contain 750-1000 mL of water before accounting for free water intake.
  • Voluntary fluid intake may have to be limited to 250-500 mL (ie, 1-2 glasses) per day.

Miscellaneous

Medicolegal Pitfalls

• Correcting hyponatremia too rapidly may result in CPM with permanent neurologic deficits.
• Given the strong association with small cell carcinoma of the lung, aggressive workup for occult small cell carcinoma in patients without an alternative explanation for their SIADH may be warranted.
• Attributing low sodium to laboratory error is a pitfall.

References

1. Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet. May 10 2008;371(9624):1624-32. [Medline].

2. Verbalis JG, Berl T. Disorders of water balance. In: Brenner BM. Brenner & Rector's The Kidney. Vol 1. 8^th ed. Saunders; 2007:459-491.

3. Leaf A, Mamby AR. An antidiuretic mechanism not regulated by extracellular fluid tonicity. J Clin Invest. Jan 1952;31(1):60-71. [Medline].

4. Rai A, Whaley-Connell A, McFarlane S, Sowers JR. Hyponatremia, arginine vasopressin dysregulation, and vasopressin receptor antagonism. Am J Nephrol. 2006;26(6):579-89. [Medline].

5. Decker BC. Disorders of Water Excess: Hyponatremia. In: Dale DC, Federman DD, eds. ACP Medicine. Vol 1. BC Decker; 2007.

6. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol Dial Transplant. Jan 2006;21(1):70-6. [Medline].

7. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. Jul 2006;17(7):1820-32. [Medline].

8. Stelfox HT, Ahmed SB, Khandwala F, Zygun D, Shahpori R, Laupland K. The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units. Crit Care. 2008;12(6):R162. [Medline].

9. Hsu YJ, Chiu JS, Lu KC, Chau T, Lin SH. Biochemical and etiological characteristics of acute hyponatremia in the emergency department. J Emerg Med. Nov 2005;29(4):369-74. [Medline].

10. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. Jan 2006;119(1):71.e1-8. [Medline].

11. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. Jul 2006;119(7 Suppl 1):S30-5. [Medline].

12. Chua M, Hoyle GE, Soiza RL. Prognostic implications of hyponatremia in elderly hospitalized patients. Arch Gerontol Geriatr. Nov-Dec 2007;45(3):253-8. [Medline].

13. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. May 25 2000;342(21):1581-9. [Medline].

14. Kohen I, Voelker S, Manu P. Antipsychotic-induced hyponatremia: case report and literature review. Am J Ther. Sep-Oct 2008;15(5):492-4. [Medline].

15. Agrawal NK, Rastogi A, Goyal R, Singh SK. Sertraline-induced hyponatremia in the elderly. CJEM. Nov 2007;9(6):415. [Medline].

16. Morris JE. Fluid, Electrolyte, & Acid-Base Emergencies. In: Stone CK, Humphries RL, eds. Current Diagnosis & Treatment: Emergency Medicine. 6^th ed. McGraw-Hill Professional; 2007:814-818.

17. Mohmand HK, Issa D, Ahmad Z, Cappuccio JD, Kouides RW, Sterns RH. Hypertonic saline for hyponatremia: risk of inadvertent overcorrection. Clin J Am Soc Nephrol. Nov 2007;2(6):1110-7. [Medline].

18. [Best Evidence] Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. Nov 16 2006;355(20):2099-112. [Medline].

19. Gross P. Treatment of hyponatremia. Intern Med. 2008;47(10):885-91. [Medline].

20. Kumar S, Fowler M, Gonzalez-Toledo E, Jaffe SL. Central pontine myelinolysis, an update. Neurol Res. Apr 2006;28(3):360-6. [Medline].

Keywords

SIADH, antidiuretic hormone, ADH, vasopressin, syndrome of inappropriate antidiuretic hormone secretion, hyponatremia, elevated urine osmolality, excessive sodium excretion, renal excretion of water, concentrated urine, ADH dysregulation, exercise-induced hyponatremia, osmolarity, cerebral salt wasting, reset osmostat

Contributor Information and Disclosures

Author

Keenan Bora, MD, Fellow, Medical Toxicology, Detroit Medical Center; Attending Physician, Medical Center Emergency Services, Detroit
Keenan Bora, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Meher Chaudhry, MD, Chief Resident, Department of Emergency Medicine, Detroit Receiving Hospital, University Health Center
Disclosure: Nothing to disclose.

Medical Editor

Erik D Schraga, MD, Consulting Staff, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Howard A Bessen, MD, Professor of Medicine, Department of Emergency Medicine, UCLA School of Medicine; Program Director, Harbor-UCLA Medical Center
Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Erik D Schraga, MD, Consulting Staff, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara Medical Center
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Alexandr Rafailov, MD, Richard H Sinert, DO, and James Foster, MD, to the development and writing of this article.

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