AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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

INTRODUCTION

Section 2 of 11  

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

Background

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) consists of hyponatremia, inappropriately elevated urine osmolality (>200 mOsm/kg), excessive urine sodium excretion (UNa >30 mEq/L), and decreased serum osmolality. These findings occur in the absence of diuretic therapy; in the presence of euvolemia without edema; and in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function. The key to the pathophysiology, signs, symptoms, and eventual treatment of SIADH is an understanding that the hyponatremia is a result of excess water and not a sodium deficiency.
 
Inappropriate secretion of the antidiuretic hormone (ADH), also known as vasopressin, due to any cause interferes with renal excretion of water and results in production of concentrated urine and hyponatremia.

Pathophysiology

The serum sodium concentration is normally regulated by the balance of water intake, renal excretion of sodium, and ADH-mediated water conservation by the distal renal tubule. These processes are mediated by stimulation of thirst, secretion of ADH, feedback mechanisms of the renin-angiotensin-aldosterone system, and variation of renal handling of filtered sodium. Disorders in any one of these components of sodium balance can result in hyponatremia.¹ 

ADH is secreted by the posterior pituitary gland. Its effect in the kidney is mediated via the vasopressin V2 receptor on the basolateral surface of the principal cells of the collecting duct, cyclic AMP, protein kinase A, and a molecular dynein motor. The key action of ADH in the kidney is the insertion of water channels into the principal cells of the collecting duct, thus increasing the permeability of water. These channels include aquaporin-2, which is located at the apical membrane, and aquaporin-3, which is located at the basolateral membrane. These channels allow free water to be reabsorbed from the collecting duct within the hypertonic renal medulla. In SIADH, the inappropriately elevated level of vasopressin enhances the reabsorption of water, thereby leading to production of concentrated urine, inability to excrete water, and consequently hyponatremia.
 
Two scenarios exist in which vasopressin secretion will be sustained or increased despite hypoosmolality. An appropriate increase in ADH secretion occurs when the vascular baroreceptors sense a decrease in the effective circulatory volume associated with cirrhosis, nephrotic syndrome, congestive heart failure, and plasma volume depletion. In these cases, the stimulus brought about by hypovolemia for ADH secretion overrides osmotic signals and results in hyponatremia.² Inappropriate ADH secretion occurs when there is dysregulation of cells secreting vasopressin. The posterior pituitary is not always the source of ADH secretion. A variety of ADH-secreting tumors has been associated with SIADH, as well as various CNS disorders, pulmonary disorders, and drugs.

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%.³ In one study, the prevalence of hyponatremia in hospitalized patients, defined as plasma sodium concentration of less than 130 mEq/L, was 2.5%. Two thirds of these patients had hospital-acquired hyponatremia. Remarkably, non-osmotic secretion of vasopressin was found in 97% of all patients with hyponatremia.⁴ 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%.⁵ Although a number of potential causes of hyponatremia exist, ADH dysregulation is the most common.⁴

Mortality/Morbidity

The fatality rate of patients with hyponatremia (when defined by a sodium concentration of <130 mEq/L) is 60-fold compared to that of patients without documented hyponatremia. Morbidity and mortality rates are higher in hospitalized patients and those with acute onset or severe hyponatremia.⁴

Race

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

Sex

In one study,⁵ acute symptomatic hyponatremia was found more often in female emergency department patients than in male emergency department patients. Another study reported a higher prevalence of symptomatic hyponatremia among female geriatric patients than among male geriatric patients (4.6% vs 2.6%).⁶

Age

Studies suggest that the very old and very young develop symptoms with lesser decreases in serum sodium levels than adults.⁷

CLINICAL

Section 3 of 11  

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

History

Signs and symptoms of hyponatremia are primarily related to the dysfunction of the central nervous system and correlate with severity and rapidity of development of 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 result in cerebral edema and increased intracranial pressure. Whereas most patients with serum sodium concentration above 125 mEq/L are asymptomatic, those with lower levels typically have symptoms, especially in the setting of a rapid decrease. When sodium concentration drops below 105 mEq/L, life-threatening complications are likely to occur.⁸
 
Helpful historical details in identifying the responsible mechanism for hyponatremia include diet, fluid intake, gastrointestinal losses, amount of urinary output, and medications.  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. These include congestive heart failure, hepatic dysfunction, adrenal insufficiency, renal failure, and thyroid diseases.

Physical

On physical examination, evaluation of volume status is important. SIADH is characterized by euvolemic hyponatremia. Edema in a hyponatremic patient should lead to the consideration of conditions other than SIADH, such as the hypervolemic hyponatremic states (CHF, cirrhosis, and nephrotic syndrome). Other findings consistent with euvolemia include normal blood pressure, absence of orthostatic instability, moist mucous membranes, and normal skin turgor. 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, and coma.

Causes

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


• Surgery - Postoperative


• Idiopathic (most common)

DIFFERENTIALS

Section 4 of 11  

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

Other Problems to Be Considered

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

WORKUP

Section 5 of 11  

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

Lab Studies

• Serum electrolytes, BUN, creatinine, and glucose levels

• Hyponatremia (sodium <135 mEq/L)

• BUN and serum uric acid levels tend to fall because of plasma dilution and increased excretion of nitrogenous products.

• Serum potassium and bicarbonate levels are normal in SIADH; hypokalemia and metabolic alkalosis suggest diuretic therapy or vomiting, which can be surreptitious.

• 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.

• Low serum osmolality (<280 mOsm/kg)

• Urine

• Elevated urinary sodium level (>20 mmol/L)

• 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.

TREATMENT

Section 6 of 11  

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

Prehospital Care

Prehospital treatment 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. Typical features are disorders of upper motor neurons including spastic quadriparesis and pseudobulbar palsy, and mental disorders ranging from confusion to coma.⁹ The risk is increased in persons with hepatic failure, potassium depletion, large burns, and malnutrition.⁸

The total rate of correction should not exceed 12 mEq/L in the first 24 hours to minimize the risk of CPM. However, in the presence of risk factors for CPM, correction should be restricted to 10 mEq/L per 24 hours.

Formulas for the dose and rate of hypertonic saline are based on a sodium deficit and have not been prospectively studied. These formulas should only be used as a guideline, requiring frequent retesting of serum sodium level. Administration of 3% NaCl should only be required in patients with severely symptomatic hyponatremia (eg, seizures) or potentially in patients with serum sodium level of less than 110 mEq/L. Acute hyponatremia can be corrected at a rate of up to 1-2 mEq/L per hour. In general, sodium levels should not be corrected to above 120 mEq/L or increase by more than 12 mEq/L per day. However, if necessary, as with a patient with hyponatremia-induced seizure or agitated confusion, the initial rate of correction can be rapid, provided that the final rate of correction does not exceed 15 mEq/L per 24 hours.¹⁰    

The approximate sodium deficit can be estimated by using the following formula:

Na Deficit = (Desired Na – Measured Na) X 0.6 X (Weight in Kilograms)

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

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

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

Monitor serum and urine electrolyte levels. Initially, recheck them in 2 hours, then at least every 4 hours until the patient's levels are stabilized.

Consultations

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

MEDICATION

Section 7 of 11  

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

Reserve pharmacologic therapy for patients with 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.

Drug Category: Tetracyclines

The tetracycline antibiotic demeclocycline has been used successfully to treat chronic SIADH that is refractory to water restriction or in patients who are noncompliant with water restriction. This therapy rarely is instituted in the ED and generally is instituted by (or in consultation with) a nephrologist or primary care physician.

Drug Category: Osmotic diuretic

These agents induce diuresis by elevating the osmolarity of the glomerular filtrate, thereby hindering the tubular reabsorption of water (concomitantly, sodium and chloride excretion also increase but to a lesser extent than water excretion).

Drug Category: Loop diuretic

These agents are used in the treatment of hypervolemic hyponatremia and, in conjunction with normal saline, in euvolemic hyponatremia for maintenance of euvolemia.

Drug Category: Vasopressin receptor antagonists

Tolvaptan,^{11, 12} lixivaptan,^{13, 12} and satavaptan¹³ are new selective oral vasopressin V2 receptor antagonists and conivaptan¹³ is an intravenous dual V1a/V2 antagonist; these have all been shown to improve hyponatremia and to increase aquaresis, free water diuresis without natriuresis or kaliuresis, in patients with SIADH. Their advantages include the predictability of their effect, rapid onset of action, and limited urinary electrolyte excretion. Conivaptan is currently the only vasopressin receptor antagonist that is commercially available in the US and FDA-approved for the treatment of euvolemia in hospitalized patients.

FOLLOW-UP

Section 8 of 11  

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

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.

• Demeclocycline, 300-600 mg PO bid

• Oral urea, 0.5-1 g/kg PO qd

• Furosemide, 40 mg PO qd - Maintain a high-sodium diet or provide sodium and potassium supplementation when using furosemide for treatment of chronic SIADH.

In/Out Patient Meds

• Conivaptan, for inpatient therapy, 20 mg IV loading dose over 30 minutes followed by 20 mg IV over 24 hours.

Transfer

• Transfer is only indicated when the underlying pathology cannot be managed adequately at the treating facility.

Complications

• Central pontine myelinolysis (CPM) is the most feared complication of excessive, overly rapid correction of hyponatremia.
  
  
  • 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, also may 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 1-2 days after correction, despite initial clinical improvement.

Prognosis

• Ultimately, 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.


• Similarly, successful treatment of pulmonary or CNS infection can lead to correction of SIADH. 

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

Section 9 of 11  

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

Medical/Legal 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.


• Do not neglect to consider laboratory error as a cause of hyponatremia.

ACKNOWLEDGMENTS

Section 10 of 11  

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

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, James Foster, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

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

1. McPhee S, Ganong W, Lingappa VR. Pathophysiology of Disease: An Introduction to Clinical Medicine. 5^th ed. Lange; 2005.
2. 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].
3. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. Jul 2006;17(7):1820-32. [Medline].
4. Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med. Feb 1985;102(2):164-8. [Medline].
5. 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].
6. Terzian C, Frye EB, Piotrowski ZH. Admission hyponatremia in the elderly: factors influencing prognosis. J Gen Intern Med. Feb 1994;9(2):89-91. [Medline].
7. Brenner BM. Pathophysiology of water metabolism. In: Brenner & Rector's The Kidney. 7^th ed. Saunders; 2004:chap 19.
8. Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. May 25 2000;342(21):1581-9. [Medline].
9. Laureno R, Karp BI. Myelinolysis after correction of hyponatremia. Ann Intern Med. Jan 1 1997;126(1):57-62. [Medline].
10. Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol. Sep 1996;46(3):149-69. [Medline].
11. 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].
12. Yeates KE, Morton AR. Vasopressin antagonists: role in the management of hyponatremia. Am J Nephrol. 2006;26(4):348-55. [Medline].
13. Verbalis JG. AVP receptor antagonists as aquaretics: review and assessment of clinical data. Cleve Clin J Med. Sep 2006;73 Suppl 3:S24-33. [Medline].

Article Last Updated: May 22, 2007