Key Points

• Laboratory evaluation of plasma osmolality, urine osmolality, and urine sodium concentration assist in determining the cause of hyponatremia.

• Water restriction and salt replacement are the most important treatments in hyponatremia. The underlying cause should be identified and treated, when possible.

• Vasopressin antagonists are currently indicated for the treatment of euvolemic and hypervolemic hyponatremia.

Syndrome of inappropriate secretion of antidiuretic hormone

(SIADH) is associated with plasma ADH concentrations that are inappropriately high for the plasma osmolality. Laboratory and clinical features of SIADH include (1) euvolemic hyponatremia; (2) decreased measured plasma osmolality (<275 mOsm/kg); (3) urine osmolality >100 mOsm/kg; (4) urine sodium usually >40 mEq/L; (5) normal acid-base and potassium balance; (6) blood urea nitrogen (BUN) <10 mg/dL; (7) hypouricemia <4 mg/dL; (8) normal thyroid and adrenal function; and (9) absence of advanced cardiac, renal, or liver disease (Reddy and Mooradian, 2009). Conditions or factors associated with SIADH include CNS trauma and infections, tumors, drugs, major surgery, pulmonary disease (e.g., TB), hormone administration, human immunodeficiency virus (HIV) infection, hereditary SIADH, idiopathic causes, and cerebral salt wasting (Box 35-1).

In some cases it is difficult to differentiate SIADH from mild to moderate depletional hyponatremia. The response of urinary and plasma sodium concentration to an infusion of 1 to 2 L of 0.9% (isotonic) saline may help in the differential diagnosis. In the patient with SIADH who is at equilibrium, the saline will be excreted, and therefore urinary sodium will increase while plasma sodium concentration will either not change or decrease slightly. If the patient has depletional hypo-natremia from renal losses, sodium from the administered saline is retained and the excess water excreted. Urinary sodium decreases, whereas plasma sodium concentration increases.

Box 35-1 Select Causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Nonosmotic stimuli

Increased intrathoracic pressure

Nausea, pain, stress

Mediastinal tumors (thymoma, sarcoma)

Human immunodeficiency virus (HIV)

Positive-pressure ventilation

Acute psychosis

Infections (pneumonia, TB, aspergillosis, lung abscess)


Bronchogenic carcinoma, mesothelioma

Pregnancy (physiologic)

Bronchiectasis, empyema


Chronic obstructive pulmonary disease

Congestive heart failure exacerbation


Central nervous system lesions

Drug induced

Tumors (neuroblastoma)


Cerebrovascular accident (stroke)


Meningitis, encephalitis




Guillain-Barre syndrome



Pituitary stalk lesion


Delirium tremens


Demyelinating disease

Carbamazepine, oxcarbazepine

Acute porphyria

Sodium valproate


Analgesics and recreational drugs

Lymphoma, leukemia, Hodgkin's disease

Morphine (high doses)

Carcinoma of uterus


Ureteral, prostate, and bladder carcinoma

MDMA ("ecstasy")

Carcinoma of duodenum and pancreas

Nonsteroidal anti-Inflammatory drugs

Ectopic production of vasopressin by tumors (small cell lung

Colchicine, venlafaxine

carcinoma, carcinoids)

Duloxetine (Cymbalta)

Cancers of head and neck and nasopharynx

Renal cell carcinoma



Box 35-1 Select Causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)—cont'd

Cardiac drugs

Cisplatin, hydroxyurea

Thiazides, clonidine


ACE inhibitors, aldosterone antagonists Amiloride, loop diuretics Methyldopa, amlodipine Amiodarone, lorcainide Propafenone, theophylline, terlipressin


Tacrolimus, methotrexate Interferon a and y, levamisole Monoclonal antibodies


Azithromycin, ciprofloxacin Trimethoprim-sulfamethoxazole Cefoperazone/sulbactam, rifabutin

Unfractionated heparin (aldosterone antagonist) Antidiabetic drugs

Chlorpropamide Tolbutamide, glipizide

Lipid-lowering agent


Modified from Reddy P, Mooradian AD. Diagnosis and management of hyponatremia in hospitalized patients. Int J Clin Pract 2009;63:1494-1508.

TB, Tuberculosis; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic anti

Antineoplastic agents


depressants; MAOIs, monoamine oxidase inhibitors; ACE, angiotensin-converting enzyme; MDMA, 3,4-methylenedioxymethamphetamine.

Vincristine, vinblastine

A reset osmostat may be suspected when mild hyponatremia persists despite changes in fluid and salt intake. A reset osmostat may be confirmed by giving the patient a fluid bolus of 10 to 15 ml/kg. Normal patients, or those with a reset osmostat, should excrete 80% of this bolus in 4 hours, which does not occur with SIADH. Cerebral salt wasting induces SIADH-like symptoms. Salt wasting, followed by volume depletion, occurs in some patients with cerebral disease. This leads to a secondary rise in ADH levels. The mechanism underlying cerebral salt wasting is unclear.

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