eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic
Syndrome of Inappropriate Antidiuretic Hormone Secretion: Treatment & Medication
Updated: Oct 20, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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+
The rate of correction of chronic hyponatremia should not exceed 0.5 mEq/L per hour. Therefore, the amount of time needed to correct a given degree of hyponatremia is as follows:Time Needed for Correction = (Desired Na+ – Measured Na+) / 0.5 mEq/L per hour
The rate of infusion of hypertonic saline is as follows:Rate = (Volume of 3% Saline)/(Time Needed for Correction)
Attention should be paid to the prevention of severe hypokalemia in conjunction with treatment of hyponatremia.Furosemide increases excretion of free water and has been used along with isotonic or hypertonic saline in severe cases.
Therapy should be stopped if serum sodium concentration is increasing faster than 2 mEq/h or by greater than 15 mEq/L in 24 hours or less or if there is resolution of symptoms. Special attention should be paid on the correction of chronic hyponatremia or those with risk factors for central pontine myelinolysis (eg, patients with burns, hypokalemia, malnutrition, alcoholism, liver disease).13
The management of acute symptomatic versus chronic hyponatremia is markedly different. Patients with chronic hyponatremia usually develop fewer symptoms and require slow correction. Many treatment strategies have been proposed in patients with chronic hyponatremia secondary to SIADH. These primarily focus on reducing the total body water.
Fluid restriction to less than 0.8 L/d has been proposed. The aim is to create a negative fluid balance and a slow increase in serum sodium level.11 This is often a challenging regimen, and noncompliance is common, especially in the emergency department.
Pharmacologic agents may be useful in the management of hyponatremia in SIADH, but use of any specific agent should be selected after an assessment of the patient's ability to comply with treatment.
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 V1a selective antagonist, and nelivaptan is a V1b selective antagonist. Tolvaptan, mozivaptan, lixivaptan, and satavaptan are selective oral vasopressin V2 receptor antagonists, and conivaptan is an intravenous dual V1a/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.
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
Sensitive CYP3A4 substrate and potent CYP3A4 inhibitor; coadministration with potent CYP3A4 inhibitors significantly increases Cmax and AUC; coadministration with CYP3A4 substrates (eg, midazolam, simvastatin, amlodipine) may increase substrate's toxicity; significantly decreases digoxin clearance
Documented hypersensitivity; hypovolemic hyponatremia; CHF, impaired renal function, impaired liver function; coadministration with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir)
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.
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
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)
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
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.
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
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
Documented hypersensitivity; hepatic coma; anuria; severe electrolyte depletion
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.
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
May decrease effects of lithium
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
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.
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
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
Documented hypersensitivity
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
More on Syndrome of Inappropriate Antidiuretic Hormone Secretion |
| Overview: Syndrome of Inappropriate Antidiuretic Hormone Secretion |
| Differential Diagnoses & Workup: Syndrome of Inappropriate Antidiuretic Hormone Secretion |
 Treatment & Medication: Syndrome of Inappropriate Antidiuretic Hormone Secretion |
| Follow-up: Syndrome of Inappropriate Antidiuretic Hormone Secretion |
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References
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Further Reading
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
