Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

For further information, see CMDT Part 21-02: Hyponatremia

Essentials of Diagnosis

• Euvolemic hypotonic hyponatremia, particularly among hospitalized patients

• Serum sodium concentration < 130 mEq/L (< 130 mmol/L)

• Urine sodium > 20 mEq/L, urine osmolality usually > 300 mOsm/kg

• Risk of osmotic demyelination syndrome from overly rapid correction of serum sodium

General Considerations

• Nonphysiologic ADH secretion: water is inappropriately retained leading to relatively concentrated urine (Uosm is usually > 300 mOsm/kg)

• Urinary solute handling remains preserved, thus, urine sodium is generally not low (U_Na > 20 mEq/L), though it does depend on dietary ingestion of sodium

• Hyponatremia after exercise, especially endurance events such as triathlons and marathons, is generally thought to be a combination of excessive hypotonic fluid intake and inappropriate ADH secretion

• Specific universal recommendations for fluid replacement rates are not possible given the variability of sweat production, renal water excretion, and environmental conditions

Symptoms and Signs

• Frequently asymptomatic; symptoms depend on severity and acuity of the hyponatremia

• Symptoms mainly relate to brain edema: nausea, malaise, headache, lethargy, disorientation

• Most serious symptoms: seizures, coma, brainstem herniation, death

Differential Diagnosis

• Severe hypothyroidism and glucocorticoid insufficiency can cause hyponatremia that cannot be differentiated from SIADH by urine or serum electrolytes alone

• Hypovolemic or hypervolemic hyponatremia

• Clinical in a euvolemic patient

• Characterized by

  • Hypotonic hyponatremia

  • Absence of heart, kidney, or liver disease

  • Normal thyroid and adrenal function

  • Urine sodium usually > 20 mEq/L, urine osm usually > 300 mOsm/kg

• In clinical practice, ADH levels are not measured

• Low blood urea nitrogen (BUN) (< 5–10 mg/dL) and hypouricemia (< 4 mg/dL) may be present

• Acute (< 24–48 hours, eg, postoperatively) hyponatremia

  • Generally, the 24-hour correction goal rate of 4–6 mEq/L/h (for chronic hyponatremia) is still recommended for acute hyponatremia, so after a brief period of rapid correction, no further correction may be needed until the next day

  • Monitor serum sodium every 2–8 hours, depending on severity, and hourly urinary output

  • High urinary output suggests that serum sodium will rise quickly unless oral intake is relatively high

  • Severe acute symptomatic hyponatremia (seizures or other life-threatening symptoms)

    • Give 100 mL of 3% hypertonic saline infused over 10 minutes (repeated twice as necessary) aiming to reverse symptoms

  • Mild to moderate acute symptomatic hyponatremia

    • Can give 3% hypertonic saline at an initial rate of 0.5–2 mL/kg/h

• Chronic hyponatremia

  • Goal is correction of 4–6 mEq/L in 24 hours to prevent osmotic demyelination syndrome (ODS) or brain herniation

  • Severe chronic symptomatic hyponatremia (seizures or other life-threatening symptoms)

    • Give 100 mL of 3% hypertonic saline infused over 10 minutes (repeated twice as necessary) aiming to reverse symptoms

  • Severe chronic symptomatic hyponatremia but without seizures or other life-threatening symptoms

    • May give 3% hypertonic saline at an initial rate of 0.5–2 mL/kg/h; titrate rate to achieve a correction rate of 4–6 mEq/L/24 h

    • Frequent monitoring of serum sodium (initially every 1–2 hours) is needed

  • Mild to moderate chronic hyponatremia without severe symptoms

    • Often responds to fluid restriction and withholding offending medications or treating pain and nausea

    • Among inpatients, 2 g of sodium chloride orally twice or three times daily is often a reasonable dose

    • May be challenging to correct with fluid restriction and salt tablets alone, particularly if the sum of the spot urine potassium and urine sodium is greater than the serum sodium (U_K + U_Na > S_Na)

    • Loop diuretics (for example, furosemide, 10–20 mg orally twice daily) can be added to increase water clearance in patients who have substantially concentrated urine and are assuredly not hypovolemic

    • Oral urea is an evidence-based therapy but is an infrequent choice in the United States because it is challenging to obtain

    • Demeclocycline

      • Second- or third-line choice

      • Induces diabetes insipidus

• Vasopressin 2 (V₂) receptors

  • Mediate the diuretic effect of ADH

  • Consider vasopressin 2 (V₂)–receptor antagonists for patients with a sodium < 125 mEq/L or milder hyponatremia that is symptomatic and resistant to fluid restriction

  • Do not use concomitantly with 3% hypertonic saline

  • Tolvaptan

    • Starting dose: 15 mg/daily orally

    • Can be increased to 30 mg/daily and 60 mg/daily at 24-h intervals if hyponatremia persists or if the increase in serum sodium concentration is < 4–6 mEq/L over the preceding 24 hours

    • Approved for up to 30 days

  • Conivaptan

    • Given as an intravenous loading dose of 20 mg delivered over 30 minutes, then as 20 mg continuously over 24 hours

    • Subsequent infusions may be administered for an additional 1–3 days at 20–40 mg/day by continuous infusion

    • Approved for up to 4 days

    • Contraindicated in liver disease

• Over correction of chronic hyponatremia

  • Patients with chronic hyponatremia at high risk for ODS who are corrected too quickly may need treatment with desmopressin (DDAVP) and intravenous dextrose 5% to re-lower the serum sodium; nephrology consultation is strongly recommended

Follow-Up

• Meticulous monitoring of the urinary output and serum sodium is necessary

  • For severe hyponatremia

  • When starting V₂-receptor antagonist therapy

  • High hourly urinary output is the first sign that their water diuresis is excessive (with attendant risk for overcorrection)

Complications

• Cerebral ODS

  • Can be caused by overly rapid correction of hypotonic hyponatremia, particularly severe chronic hypotonic hyponatremia

  • May occur outside the brainstem

  • Classic presentation

    • Altered mental status

    • Quadriparesis

    • Pseudobulbar symptoms

  • Risk factors for ODS include serum sodium < 120 mEq/L, malnourishment, or hepatic disease

  • Symptoms may be reversible or permanent

  • Diagnosis can be confirmed with MRI

Prognosis

• Depends on underlying cause of SIADH

When to Refer

• Nephrology or endocrinology consultation should be considered in severe, symptomatic, refractory, or complicated cases of hyponatremia

• Aggressive therapies with hypertonic saline, V₂-receptor antagonists, DDAVP and dextrose 5%, or dialysis mandate specialist consultation

When to Admit

• Symptomatic or severe hyponatremia

• Aggressive therapies requiring close monitoring and frequent laboratory testing

• Initiation of V₂-receptor antagonists