Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

BASICS

Definition: Impaired water excretion (concentrated urine) due to inappropriate/abnormal ADH production despite low serum osmolality.
Effect: Dilutional hyponatremia (total body sodium may be normal/near-normal, but total body water is increased).
Synonyms: SIADH, syndrome of inappropriate antidiuresis
Common cause of hyponatremia in hospitalized patients

EPIDEMIOLOGY

Incidence: Up to 35% in perioperative hospital patients
Demographics: Elderly; females > males

ETIOLOGY AND PATHOPHYSIOLOGY

Drugs:
Antidepressants (SSRIs, tricyclics, MAOIs)
Antineoplastics (vincristine, cisplatin, cyclophosphamide)
Antipsychotics (risperidone, quetiapine, phenothiazines, haloperidol)
Analgesics (duloxetine, pregabalin, tramadol, NSAIDs)
Anticonvulsants (carbamazepine, valproic acid, phenytoin)
Vasopressin, DDAVP, oxytocin, ciprofloxacin, α-interferon, ecstasy
Malignancies (ectopic ADH):
Small cell lung cancer, lymphoma, mesothelioma, pancreatic/thymic tumors
Pulmonary:
Asthma, COPD, pneumonia, TB, sarcoidosis, positive pressure ventilation
CNS/Neurologic:
Tumor, trauma, stroke, hemorrhage, encephalitis, epilepsy, MS, Guillain-Barré, SLE, porphyria, HIV, Rocky Mountain spotted fever
Genetics:
10% X-linked V2 receptor mutation; TRPV4 polymorphisms

RISK FACTORS

Advanced age
Recent surgery/postoperative status
Institutionalization
Predisposing drug use

GENERAL PREVENTION

Avoid high-risk drugs if possible.

COMMONLY ASSOCIATED CONDITIONS

Pulmonary and CNS disorders, drug exposure, malignancy

DIAGNOSIS

Diagnostic Criteria (Bartter & Schwartz):

↓ Serum osmolality (<275 mOsm/kg) with inappropriately concentrated urine (>100 mOsm/kg)
Euvolemia (no clinical evidence of volume depletion or overload)
Symptoms: Depend on acuity/severity of hyponatremia/cerebral edema

History

Symptoms: Fatigue, lethargy, anorexia, nausea, vomiting, thirst, headache, vision changes, ataxia, weakness, confusion, seizures, coma

Physical Exam

Mild: Slow cognition, hyporeflexia, ataxia (Na 125–135)
Severe: AMS, coma, seizures, psychosis (Na <125)

Differential Diagnosis

Volume depletion/hypovolemia
CHF, nephrotic syndrome, cirrhosis (↓effective arterial volume)
Low solute intake (“tea & toast,” beer potomania)
Psychogenic polydipsia
Endocrinopathies (adrenal insufficiency, hypothyroidism)
Translocational/pseudohyponatremia

Diagnostic Tests

Serum Na: Low
Serum osmolality: Low
Urine osmolality: High (>100 mOsm/kg)
Urine Na: High (>30 mEq/L)
Fractional excretion Na: >0.5%
Serum urea: Normal/low
Additional: Serum uric acid, glucose, creatinine, TSH, AM cortisol
Imaging: Chest x-ray (evaluate for pulmonary cause), Head CT (neurologic symptoms)

TREATMENT

General Measures

Treat underlying cause/stop offending agent
Fluid restriction (<1,000 mL/day)
Correct hypokalemia
Avoid isotonic saline (may worsen hyponatremia)

By Severity

Mild/asymptomatic (Na >125): Fluid restriction, treat cause
Moderate (Na 120–125): Fluid restriction, ↑oral solute intake; calculate urine/plasma [Na+K]/[serum Na+K] ratio to assess response
Severe/neurologic symptoms:
Hypertonic (3%) saline: Bolus to increase Na by 4–6 mEq/L over 4–6 hr (do not exceed 8 mEq/L in 24 hr)
Goal: Chronic (≥48 hr): 6–8 mEq/L/24 hr; Acute (<48 hr): same 24 hr goal

Medications

IV 3% NaCl (severe/neurologic symptoms)
NaCl oral tablets
Oral urea (rare, poor palatability)
Loop diuretics (with K+ replacement)
Vaptans (V2 antagonists): Tolvaptan, conivaptan (hospital only; avoid in cirrhosis/renal impairment)
Demeclocycline: Chronic SIADH; onset 1 week; limited by GI/nephrotoxicity

ALERT

Correct Na slowly! Max ↑8 mEq/L/24 hr to avoid ODS (osmotic demyelination syndrome).

ISSUES FOR REFERRAL

Nephrology for severe hyponatremia

ADMISSION, INPATIENT, NURSING

Neurologic exam and vitals for symptomatic/moderate/severe cases

ONGOING CARE

Monitoring: Hourly urine output; check urine/serum Na, K, osmolality; serial chemistry every 4–8 hr if moderate/severe
Goal: Na rise <8 mEq/L/24 hr until Na reaches 130
Chronic: Continue cause treatment, fluid restriction, NaCl tabs as needed

DIET

Increase protein/solute intake; restrict water/fluid

PATIENT EDUCATION

Diet and fluid restrictions

PROGNOSIS

Hyponatremia: ↑ICU admission, ↑30-day readmission risk
Na <120 with symptoms: High mortality from cerebral edema

COMPLICATIONS

Falls, hip fractures
Cerebral edema (acute, severe cases)
Osmotic demyelination syndrome (overcorrection: central pontine/extrapontine myelinolysis)
Chronic hyponatremia: ↑risk osteoporosis

REFERENCES

Decaux G, Musch W. Clin J Am Soc Nephrol. 2008;3(4):1175-1184.
Furst H, Hallows KR, Post J, et al. Am J Med Sci. 2000;319(4):240-244.
Adrogué HJ, Madias NE. J Am Soc Nephrol. 2012;23(7):1140-1148.
Esposito P, Piotti G, Bianzina S, et al. Nephron Clin Pract. 2011;119(1):c62-c73.
Usala RL, Fernandez SJ, Mete M, et al. J Clin Endocrinol Metab. 2015;100(8):3021-3031.

ICD-10

E22.2 Syndrome of inappropriate secretion of antidiuretic hormone

CLINICAL PEARLS

Always treat the underlying cause; review all drugs.
ODS (osmotic demyelination): Can cause quadriplegia, pseudobulbar palsy, seizures, coma, death. Prevent by slow correction (<8 mEq/L/24 hr).
Safe correction: Use calculators (see: mdcalc sodium correction calculator).
Chronic hyponatremia: Increased risk for osteoporosis and fractures.