> Table of Contents > Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Elise J. Barney, DO
image BASICS
DESCRIPTION
  • A syndrome of abnormal production of antidiuretic hormone (ADH), despite low serum osmolality, leading to hyponatremia and inappropriately elevated urine osmolality
    • Resulting abnormal urinary free water retention leads to dilutional hyponatremia (total body sodium levels may be normal or near normal, but the patient's total body water is increased).
    • Often secondary to medications but may be associated with an underlying disorder, such as neoplasm, pulmonary disorder, or CNS system disease
  • Synonym(s): syndrome of inappropriate secretion of ADH
EPIDEMIOLOGY
Incidence
  • Often found in the hospital setting, where incidence can be as high as 35%
  • Predominant age: elderly
  • Predominate sex: females > males
ETIOLOGY AND PATHOPHYSIOLOGY
  • Drugs:
    • Antidepressants (e.g., monoamine oxidase inhibitors [MAOIs], tricyclics, SSRIs)
    • Antineoplastic drugs (e.g., vincristine, vinblastine, cisplatin, cyclophosphamide)
    • Antipsychotic agents (e.g., phenothiazines, thioridazine, haloperidol)
    • Analgesics (e.g., NSAIDs)
    • Antiepileptics (e.g., carbamazepine, oxcarbazepine, valproic acid)
    • Oral hypoglycemics (e.g., chlorpropamide, metformin)
    • Others (e.g., vasopressin, DDAVP, oxytocin, ciprofloxacin, &agr;-interferon, ecstasy)
  • Neoplasms (ectopic ADH production):
    • Bronchogenic carcinoma
    • Hodgkin disease
    • Mesothelioma
    • Oat cell carcinoma of the lung
    • Pancreatic carcinoma
    • Small cell carcinoma of the lung
    • Thymoma
  • Pulmonary conditions:
    • Asthma/COPD
    • Atelectasis
    • Cystic fibrosis
    • Positive pressure mechanical ventilation
    • Pneumonia
    • Pulmonary tuberculosis (TB)
    • Sarcoidosis
  • Neurological causes:
    • Acute porphyria
    • CNS injury (i.e., SAH, trauma, stroke)
    • CNS lupus
    • Encephalitis
    • Epilepsy
    • Guillain-Barré syndrome
    • Meningitis
    • Multiple sclerosis
  • Other:
    • HIV infection
    • Hypothyroidism, myxedema
    • Rocky Mountain spotted fever
  • Idiopathic
Genetics
  • 10% of patients have X-linked mutation of V2R (1)
  • Polymorphisms in TPRV4 gene (2)
RISK FACTORS
  • Use of predisposing drugs
  • Advanced age
  • Postoperative status
  • Institutionalization
GENERAL PREVENTION
  • Search for cause, if unknown.
  • Reduce/change medications, if drug-induced.
  • Lifelong restriction of fluid intake
COMMONLY ASSOCIATED CONDITIONS
See “Etiology.”
image DIAGNOSIS
PHYSICAL EXAM
  • Euvolemic state
  • Mild/moderate hyponatremia (serum Na 125 to 135 mEq/L)
    • Slow cognition and reaction times
    • Hyporeflexia
    • Ataxia
  • Severe hyponatremia (serum Na <125 mEq/L) (3)
  • Altered mental status
  • Lethargy
  • Seizures
  • Psychosis
  • Coma
  • Death
DIFFERENTIAL DIAGNOSIS
  • Intravascular volume depletion and thiazide-induced
  • Appropriate ADH secretion secondary to decreased effective arterial blood volume (e.g., congestive heart failure [CHF], nephrotic syndrome, liver cirrhosis)
  • Low solute intake hyponatremia
    • “Tea and toast” diet
    • Beer potomania
  • Psychogenic polydipsia
    • Intake usually >10 L/day
    • Diuresis occurs when intake is stopped.
  • Endocrinopathies
    • Addison disease
    • Hypothyroidism
  • Translocational hyponatremia: caused by hyperglycemia, mannitol, sucrose, glycine
  • Pseudohyponatremia
    • Lab artifact caused by hyperlipidemia, paraproteinemias, administration of IVIG
    • Labs using flame photometry or indirect potentiometry susceptible
  • Postoperative complications:
    • Caused by nonosmotic release of ADH, probably mediated by pain afferents
    • ADH stimulated by pain, nausea, vomiting, and hypotension
  • Cerebral salt-wasting syndrome (hyponatremia, extracellular fluid depletion, CNS insult)
DIAGNOSTIC TESTS & INTERPRETATION
  • Serum Na level: low
  • Serum urea level: normal to low
  • Serum osmolality: low
  • Urine osmolality: high; urine osmolality >100 mOsm/kg H2O (4)
  • Urine Na concentration: high; urine Na >30 mEq/L (4)
  • Fractional excretion of Na >0.5 % (4)
  • Serum ADH level: high (not clinically useful)
  • Not usually required for diagnosis but to assess for other concerns:
    • Serum uric acid
    • Serum glucose; creatinine
    • Thyroid function
    • Morning cortisol
image TREATMENT
GENERAL MEASURES
  • Treatment of the underlying cause is essential.
  • Requires frequent monitoring (see “Patient Monitoring”)
  • Fluid restriction (<1,000 mL/day) is the main form of treatment (5)[C].
  • Mildly symptomatic (serum Na >125 mEq/L [>125 mmol/L]): Restrict fluid to <1,000 mL/day.
  • P.1009

  • Acute (<48 hours duration) or symptomatic (altered mental status, seizure, coma)
    • Hypertonic saline (3% normal saline) bolus
    • Diuresis with loop diuretics
    • Restrict oral free water intake.
    • Increase oral solute intake.
    • Calculate serum Na deficit (mEq Na deficit = [desired Na - actual Na] × 0.5 × body weight [kg]).
    • Increase serum Na slowly with hypertonic saline by 4 to 6 mEq/L over 4 to 6 hours (not to exceed 10 mEq/L in a 24-hour period) (3,6,7).
MEDICATION
  • If severe or neurological symptoms: IV 3% sodium chloride to increase serum Na cautiously (8)[B]:
    • If serum Na <120 mEq/L or severe neurologic symptoms; consider bolus of hypertonic saline to increase serum Na by 4 to 6 mEq/L over the first 4 to 6 hours.
  • Sodium chloride (NaCl) oral tablets
  • Oral urea is an option, but limited due to bitter taste.
  • Loop diuretics: furosemide (Lasix) + KCl replacement
  • Vasopressin-2 receptor antagonist (the vaptans: tolvaptan, conivaptan) (8),(9)[C]
    • Good efficacy and safety profiles in the treatment of moderate hyponatremia due to SIADH
    • Liberal fluid intake encouraged.
    • Must be initiated in hospital setting.
    • Cost may limit long-term use.
    • Avoid tolvaptan in patients with liver disease.
  • Demeclocycline (second line) (10)[C]
    • Blocks ADH at renal tubule; produces nephrogenic diabetes insipidus
    • Dosage for long-term management: 300 to 600 mg PO BID
    • Onset of action within 1 week; therefore, not best for acute management.
  • Contraindications: Avoid fluids in CHF, nephrotic syndrome, or cirrhosis. Avoid tolvaptan in patients with cirrhosis due to possible liver injury.
  • Precautions: Overly rapid correction (>10 mEq/L/day) can increase risk for osmotic demyelination syndrome:
    • Permanent CNS damage in pons leading to quadriplegia and pseudobulbar palsy.
    • Increased risk in women, alcoholics, malnutrition, hypoxia, and hypokalemia
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Careful continuous clinical and laboratory monitoring of hyponatremic state during acute phase:
    • Hourly urine output
    • Urine Na
    • Serum Na and potassium (K) every 4 to 6 hours if moderate/severe, then daily once stable
    • Goal sodium increase is <10 mEq/L in first 24-hour period, then 8 mEq/L in subsequent 24-hour periods until Na reaches 130 mEq/L (3)[C].
  • Chronic management: Treat underlying cause; continue fluid restriction and NaCl tablets as needed.
DIET
Increase protein/solute intake and decrease water intake.
PATIENT EDUCATION
Diet and fluid restrictions
PROGNOSIS
  • Depends on underlying cause; in general, higher morbidity and mortality in hospitalized patients with hyponatremia
  • If symptomatic (seizure, coma): high mortality due to cerebral edema if serum Na <120 mEq/L (<120 mmol/L)
REFERENCES
1. Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005;352(18):1884-1890.
2. Tian W, Fu Y, Garcia-Elias A, et al. A loss-offunction nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A. 2009;106(33):14034-14039.
3. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant. 2014;29(Suppl 2):i1-i39.
4. Decaux G, Musch W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clin J Am Soc Nephrol. 2008;3(4):1175-1184.
5. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-2072.
6. Adrogué HJ, Madias NE. The challenge of hyponatremia. J Am Soc Nephrol. 2012;23(7): 1140-1148.
7. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3): 282-299.
8. Esposito P, Piotti G, Bianzina S, et al. The syndrome of inappropriate antidiuresis: pathophysiology, clinical management and new therapeutic options. Nephron Clin Pract. 2011;119(1): c62-c73.
9. Friedman B, Cirulli J. Hyponatremia in critical care patients: frequency, outcome, characteristics, and treatment with the vasopressin V2-receptor antagonist tolvaptan. J Crit Care. 2013;28(2):219.e1-e12.
10. Sherlock M, Thompson CJ. The syndrome of inappropriate antidiuretic hormone: current and future management options. Eur J Endocrinol. 2010;162(Suppl 1):S13-S18.
11. Fleming JD, Babu S. Images in clinical medicine. Central pontine myelinolysis. N Engl J Med. 2008;359(23):e29.
12. Verbalis JG, Barsony J, Sugimura Y, et al. Hyponatremia-induced osteoporosis. J Bone Miner Res. 2010;25(3):554-563.
See Also
&NA;
Hyponatremia
Codes
&NA;
ICD10
E22.2 Syndrome of inappropriate secretion of antidiuretic hormone
Clinical Pearls
&NA;
  • Treatment of the underlying cause is a key. Review all medications for potential culprits.
  • Consultation is recommended in moderate to severe hyponatremia or if hypertonic saline indicated.
  • Fluid restriction is the mainstay of treatment in SIADH. Fluid restriction fails to correct hyponatremia and Na wasting in salt-losing renal disease.
  • Cerebral salt wasting is a controversial disease entity and is similar to SIADH. However, patients with SIADH are euvolemic, whereas patients with cerebral salt wasting are hypovolemic. The only real way to establish the diagnosis is through fluid restriction. Serum urate and fractional excretion of urate will be corrected with fluid restriction in SIADH, but will not correct in cerebral salt wasting.
  • CPM is a cerebral demyelination syndrome that causes quadriplegia, pseudobulbar palsy, seizures, coma, and death. It is caused by an overly rapid rate of Na correction.
  • Safe correction of hyponatremia is important. Online calculators are available: www.medcalc.com/sodium.html.