Syndrome Inappropriate ADH Secretion

Aka: Syndrome Inappropriate ADH Secretion, Syndrome of Inappropriate Antidiuretic Hormone, Inappropriate ADH Syndrome, SIADH, Medication Causes of SIADH

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II. Pathophysiology

  1. Isovolemic Hypoosmolar Hyponatremia due to excessive Antidiuretic Hormone

III. Causes: General

  1. Malignancy (Paraneoplastic Syndromes)
    1. Small Cell Lung Cancer (most common ectopic ADH source)
    2. Duodenal Cancer
    3. Pancreatic Cancer
    4. Head and neck cancers
  2. Lung disease
    1. Bacterial Pneumonia
    2. Empyema
    3. Legionella pneumonia
    4. Pulmonary Tuberculosis
    5. Acute Respiratory Distress Syndrome (ARDS) or other Acute Respiratory Failure
  3. Neurologic disorders
    1. Brain Abscess
    2. Brain Tumor
    3. Bacterial Meningitis
    4. Subarachnoid Hemorrhage
    5. Subdural Hematoma
    6. Cerebrovascular Accident
    7. Head Injury
    8. Multiple Sclerosis
    9. Guillain-Barre Syndrome
  4. Miscellaneous causes
    1. Psychiatric illness
    2. Rocky Mountain Spotted Fever
      1. Hyponatremia is common in this uncommon Tick Borne Illness
    3. Post-operative period
      1. Young women have postoperative ADH levels 40x higher than postmenopausal women
      2. Young women are at higher risk of postoperative hyponatremic encephalopathy

IV. Causes: Medications

  1. Cardiovascular agents
    1. Amiodarone
    2. Clofibrate
    3. Thiazide Diuretics (e.g. Hydrochlorothiazide)
  2. Neuropsychiatric agents
    1. Barbiturates
    2. Carbamazepine (Tegretol)
    3. Chlorpromazine (Thorazine)
    4. Clozapine (Clozaril)
    5. Haloperidol
    6. Selective Serotonin Reuptake Inhibitors
    7. Tricyclic Antidepressants (e.g. Amitriptyline)
    8. Thiothixene
    9. Thioridazine
  3. Analgesics
    1. Morphine Sulfate and other Opioids
    2. NSAIDs
  4. Chemotherapeutic agents
    1. Vinca Alkaloids (e.g. Vincristine)
    2. Platinum Chemotherapy (e.g. Cisplatin)
    3. Other Alkylating Agents (e.g. Cyclophosphamide)
  5. Endocrine Agents
    1. Desmopressin
    2. Oxytocin
  6. Miscellaneous agents
    1. Nicotine
    2. Theophylline
  7. Sulfonylureas
    1. Chlorpropamide
    2. Tolbutamide

V. Differential Diagnosis

  1. SIADH is a diagnosis of exclusion
  2. Isovolemic Hypoosmolar Hyponatremia
  3. Non-osmotic causes for ADH secretion
    1. Hypovolemic Hypoosmolar Hyponatremia
  4. Causes of Decreased urine diluting capacity

VI. Symptoms

  1. Nausea or Vomiting
  2. Constipation
  3. Muscle Weakness
  4. Headaches
  5. Altered Level of Consciousness with severe Hyponatremia (confusion to coma)
  6. Seizures with severe Hyponatremia

VII. Labs

  1. Core SIADH findings (see Barrter and Schwartz criteria below)
    1. Hyponatremia
      1. See Isovolemic Hypoosmolar Hyponatremia
    2. Urine Osmolality > 100 mOsm/kg water
      1. Dilution not maximized despite serum hypoosmolality
    3. Urine Sodium > 20-30 mEq/L
    4. Serum Osmolality decreased <275 to 280 mOsm
  2. Other supportive features of SIDH diagnosis
    1. Hypouricemia (Serum Uric Acid <4 mg/dl)
    2. Fractional Excretion of Uric Acid >10%
    3. Antidiuretic Hormone (ADH) inappropriately elevated (despite low Serum Osmolality)

VIII. Diagnosis: Barrter and Schwartz SIADH Criteria (defined in 1957)

  1. Isovolemic Hypoosmolar Hyponatremia (Serum Osmolality <275 mOsm/kg)
  2. Urine is NOT maximally dilute (Urine Osmolality >100 mOsm)
  3. Urine Sodium excretion elevated (>20 to 30 mEq/L), lacking avid Sodium retention
  4. Other causes absent
    1. No advanced Kidney disease, Cirrhosis or Congestive Heart Failure
    2. No uncorrected Hypothyroidism or Adrenal Insufficiency
    3. No Diuretic use

IX. Management

  1. Treating underlying cause is key in SIADH
    1. Example: Treat underlying Bronchogenic Carcinoma
    2. Relevant Consultation (e.g. oncology, nephrology)
  2. Overall strategy
    1. See Isovolemic Hypoosmolar Hyponatremia
    2. Fluid restriction (<1000 to 1500 ml/day)
    3. Diuretics
      1. Furosemide (Lasix)
      2. Potassium-Sparing Diuretics
    4. Slow Serum Sodium correction
      1. See Hyponatremia Management
      2. Serum Sodium >125 mEq/L
        1. Limit correction to <10-12 mEq/L in 24 hours or 18 mEq/L in 48 hours
      3. Severe, symptomatic Hyponatremia (Serum Sodium <125 mEq/L)
        1. Limit correction to <6-8 mEq/L in first 24 hours
    5. Avoid Normal Saline infusion
      1. May worsen Hyponatremia with Fluid Shifts intravascularly
  3. SIADH refractory to above measures
    1. Induce Nephrogenic Diabetes Insipidus
    2. Demeclocycline (600-1200 mg/day)
    3. Lithium Carbonate 300 mg PO tid
    4. Tolvaptan (Samsca)
      1. Selective Vasopressin (V2) receptor Antagonist
      2. Increases free water excretion
      3. Vaptan use is typically discouraged due to limited evidence of benefit and associated risk
      4. If used, started in hospital setting and NOT combined with water restriction
      5. Adverse effects: Hepatotoxicity, Hypernatremia, Cerebral Demyelination Syndrome

X. References

  1. Le and Drogell (2015) Crit Dec Emerg Med 29(11): 13-19
  2. Kone in Tisher (1993) Nephrology, p. 87-100
  3. Levinsky in Wilson (1991) Harrison's IM, p. 281-84
  4. Preston (2011) Acid-Base, Fluids and Electrolytes, Medmaster, Miami
  5. Rose (1989) Acid-Base and Electrolytes, p. 601-38
  6. Goh (2004) Am Fam Physician 69:2387-94 [PubMed]
  7. Higdon (2018) Am Fam Physician 97(11):741-8 [PubMed]
  8. Braun (2015) Am Fam Physician 91(5): 299-307 [PubMed]
  9. Miller (2023) Am Fam Physician 108(5): 476-86 [PubMed]

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