Approach
The mainstay of treatment for SIADH is to remedy hyponatremia with salt administration and/or water restriction. The inappropriate activation of the V2-receptor, causing excessive free water absorption in the collecting duct, has been targeted with the introduction of the vasopressin receptor antagonists (also known as vaptans). Although vasopressin receptor antagonists are a logical therapy for hyponatremic patients with excess vasopressin, evidence of potential harms, such as overcorrection and liver toxicity, has restricted their use to certain patient groups.[4][7][21]
Acute hyponatremia (≤48 hours' duration) with severe symptoms
Patients are evaluated for severe symptoms of hyponatremia (mental status changes, seizure, and coma). Acute hyponatremia often occurs while a patient is hospitalized. As this is not of chronic duration, brain cells have not had time to compensate by releasing electrolytes and brain osmolytes. Therefore, patients with acute hyponatremia are more susceptible to symptoms at higher serum sodium levels.
Intravenous hypertonic saline (3% sodium chloride solution) is administered and serum sodium levels checked every 2 hours, with a goal of increasing serum sodium by 1 to 2 mEq/L/hour until neurologic symptoms resolve.[5] Subsequently, correction is slowed to elevate serum sodium by no more than 8 to 10 mEq/L in a 24-hour period thereafter.[16]
There is less risk of central pontine myelinolysis (osmotic demyelination syndrome) in patients who develop hyponatremia in ≤48 hours as compared with those with chronic hyponatremia. Therefore, more rapid correction, although not ideal, is less dangerous in patients with acute hyponatremia.
Furosemide may be used in addition to hypertonic saline, especially if the patient is at risk for volume overload. Furosemide helps to correct hyponatremia by increasing free water excretion. If furosemide is used in addition to intravenous hypertonic saline, infusion rates may need to be reduced, so as to avoid overcorrection of hyponatremia. Hypokalemia is monitored and corrected with intravenous potassium replacement.
Investigation for an underlying disorder (e.g., malignancy, infection, pain, nausea, stress, SIADH-associated medication, or administration of hypotonic fluid) is required. These disorders are treated and any causative medications discontinued. All hypotonic fluids are also stopped.
Acute hyponatremia, once corrected and any cause of SIADH removed, may be self-limited. It may be necessary to continue free fluid restriction (of 1-1.5 L/day) after hypertonic saline therapy is discontinued. Serum sodium is monitored daily until it stabilizes.
Chronic hyponatremia (>48 hours or unknown duration) with severe symptoms
These patients are also treated with intravenous hypertonic saline.[2] There is an increased risk of central pontine myelinolysis (osmotic demyelination syndrome) in chronically hyponatremic patients, so careful monitoring is of utmost importance. Central pontine myelinolysis occurs with overcorrection of hyponatremia where solute-poor cerebral cells are subject to shrinkage. It is characterized by demyelination of pontine, basal ganglion, and cerebellar regions, with resultant neurologic symptoms, including behavior disturbances, lethargy, dysarthria, dysphagia, paraparesis or quadriparesis, and coma. Seizures may also be seen but are less common.[22] Malnutrition, potassium depletion, and hepatic failure increase the risk of developing central pontine myelinolysis.[22][23] One large multicenter study in 2023 found a high incidence of overcorrection of sodium in hospitalized hyponatremic patients, but a relatively low incidence of osmotic demyelination syndrome. While this is an interesting finding, it does not downplay the importance of slow correction of sodium in the chronic hyponatremic patient.[24]
Furosemide may also be used in addition to hypertonic saline, especially if the patient is at risk for volume overload, and hypokalemia is corrected if necessary with intravenous potassium replacement.
Investigation and management of any underlying disorder is also undertaken and any causative medication discontinued.
Following successful therapy with intravenous hypertonic saline, a vasopressin receptor antagonist is used. Vasopressin receptor antagonists compete with arginine vasopressin (AVP) for binding at the V2 receptor on the basolateral side of the principal cell and inhibit water channel insertion and free water absorption.
Conivaptan is a nonselective vasopressin receptor antagonist that affects both V1 and V2 receptors. It is currently available as an intravenous formulation for inpatient administration only.[25]
The oral vasopressin receptor antagonist tolvaptan is recommended for the treatment of hyponatremia secondary to SIADH.[26][27] However, due to reports of potentially fatal liver injury in patients with autosomal dominant polycystic kidney disease, tolvaptan should not be used for more than 30 days, and it should be avoided in patients with underlying liver disease including cirrhosis. The drug should be discontinued immediately in patients with signs or symptoms of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice, elevated LFTs). FDA Drug Safety Communication: FDA limits duration and usage of Samsca (tolvaptan) due to possible liver injury leading to organ transplant or death Opens in new window Patients receiving tolvaptan should discontinue any previous fluid restriction and drink fluids freely though not excessively.[2]
Close monitoring, especially in the first 24 hours of oral therapy, is required. The concern is overcorrection of serum sodium (>12 mEq/24 hours), which occasionally occurs with these medications. Long-term studies have been promising in terms of sustained improved serum sodium with these agents.[28] Vasopressin receptor antagonists interact with the cytochrome P450 3A4 system, and use with other potent inhibitors is contraindicated.[29][30]
All other patients
Mild to moderate symptoms include nausea, vomiting, or headache. In acute SIADH patients, treatment is with fluid restriction of 1 to 1.5 L/day. Vasopressin receptor antagonists are used initially for chronic SIADH patients. In both cases, investigation and management of any underlying disorder is also undertaken and any causative medication discontinued.
Asymptomatic patients are managed with fluid restriction of 1 to 1.5 L/day and investigation and management of any underlying cause.
Persistent chronic SIADH
SIADH can persist if the underlying cause is irreversible. Fluid restriction of 1 to 1.5 L/day has been the mainstay of therapy for chronic SIADH outpatient therapy. Compliance with fluid restriction often limits this therapeutic option.
Management of any underlying disorder should continue.
If patients are intolerant to fluid restriction, tolvaptan may be used. Tolvaptan has been demonstrated to be well tolerated, with most commonly reported side effects of dry mouth (4.2% to 23%), thirst (7.7% to 40.3%), and polyuria (0.6% to 31.7%) coinciding with the mechanism of action of the medication. High cost may limit the use of tolvaptan.[30] Due to reports of potentially fatal liver injury, tolvaptan should not be used for more than 30 days, and it should be avoided in patients with underlying liver disease including cirrhosis. However, in select patients with persistent chronic SIADH, tolvaptan may be continued beyond 30 days (for longer-term treatment) at the lowest effective dose with very close monitoring, although there is limited data to support this approach.[31] Patients receiving tolvaptan should discontinue any previous fluid restriction and drink fluids freely though not excessively.[2]
Sodium chloride tablets may be administered, which can increase urine output and modestly improve serum sodium levels. This is heightened by co-administration of diuretics, which lower urine osmolality and improve water excretion. Serum potassium will need to be monitored closely.[32]
Demeclocycline, a bacteriostatic antibiotic, causes diminished responsiveness of the collecting tubule to AVP. Similar to tolvaptan, demeclocycline is used without fluid restriction. Side effects such as skin photosensitivity and nephrotoxicity limit its use.
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