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Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), Emergency Medicine

Basics

Description

- Most common cause of hyponatremia in hospitalized patients (and doubles inpatient mortality in some studies) - A water balance problem more than 1 of sodium (Na) balance - Normal regulation of water balance: - Antidiuretic hormone (ADH): - Integral controller of water balance - Increases water permeability of the collecting tubules, resulting in free water reabsorption - Synthesized by hypothalamus but secreted by posterior pituitary

- Water deprivation (increased plasma osmolality) stimulates secretion as sensed by: - Osmoreceptors/atrial stretch receptors - Carotid baroreceptors - Aortic arch/pulmonary veins

- Hyponatremia: - Mild: Serum sodium <135 mEq/L - Moderate: Serum sodium <130 mEq/L - Severe: Serum sodium <125 mEq/L - Excess extracellular water relative to Na - Depletional hyponatremia: - Sodium depletion can be caused by diet, GI losses, diuretic use, and renal or adrenal disease. - Often accompanied by extracellular fluid volume depletion - Hyponatremia associated with clinical signs of hypovolemia - Increased Hct, BUN, Cr - Urinary sodium excretion <20 mEq/L

- Dilutional hyponatremia: - Increased extracellular water in presence of normal or increased total body sodium - Can be caused by increased fluid intake (oral, IV), drugs, or medical conditions - Euvolemia with edema - Normal or decreased Hct, BUN, Cr - Urinary sodium excretion >20 mEq/L - Inappropriate ADH secretion is a form of dilutional hyponatremia.

- Supplemental features: - Plasma uric acid <4 mg/dL - BUN <10 mg/dL - FENa >1% - Failure to correct hyponatremia after an infusion of normal saline (NS) 0.9% - Abnormal water load test (inability to excrete ≥90% of a 20 mL/kg water load in 4 hr)

- Pulmonary disorders: - Pneumonia - TB - Lung abscess - COPD

- Transient: - Endurance exercise - General anesthesia - Pain - Stress

- Other: - Hereditary - Positive-pressure ventilation - HIV/AIDS - Idiopathic

- Serum sodium <135 mEq/L: - Serum sodium <130 mEq/L: - Weakness/lethargy - Weight gain - Headache - Anorexia

- Normal extracellular fluid (dilutional hyponatremia): - SIADH - Myxedema - Sheehan syndrome (postpartum hypopituitarism) - Reset osmostat syndromes (dilute urine at lower than normal sodium levels)

- 3rd-space sequestration - Diuretic use - Aldosterone deficiency: - Salt-losing nephropathies:

  • Most common cause of hyponatremia in hospitalized patients (and doubles inpatient mortality in some studies)
  • A water balance problem more than 1 of sodium (Na) balance
  • Normal regulation of water balance:Antidiuretic hormone (ADH):Integral controller of water balanceIncreases water permeability of the collecting tubules, resulting in free water reabsorptionSynthesized by hypothalamus but secreted by posterior pituitaryWater deprivation (increased plasma osmolality) stimulates secretion as sensed by:Osmoreceptors/atrial stretch receptorsCarotid baroreceptorsAortic arch/pulmonary veins
  • Hyponatremia:Mild: Serum sodium <135 mEq/LModerate: Serum sodium <130 mEq/LSevere: Serum sodium <125 mEq/LExcess extracellular water relative to NaDepletional hyponatremia:Sodium depletion can be caused by diet, GI losses, diuretic use, and renal or adrenal disease.Often accompanied by extracellular fluid volume depletionHyponatremia associated with clinical signs of hypovolemiaIncreased Hct, BUN, CrUrinary sodium excretion <20 mEq/LDilutional hyponatremia:Increased extracellular water in presence of normal or increased total body sodiumCan be caused by increased fluid intake (oral, IV), drugs, or medical conditionsEuvolemia with edemaNormal or decreased Hct, BUN, CrUrinary sodium excretion >20 mEq/LInappropriate ADH secretion is a form of dilutional hyponatremia.
  • Definition of SIADH:ADH secretion in absence of hyperosmolality or hypovolemia
  • Criteria for definition:Essential features:Hyponatremia " despite correction for hyperglycemia, hyperproteinemia, or hyperlipidemiaEuvolemia " no clinical signs of volume depletion (orthostasis, tachycardia) or volume overload (edema, ascites)Hyposmolality of the plasma " <275 mOsm/kg of waterNormal renal, adrenal, and thyroid functionNo recent diuretic useUrine Osm >100 mOsm/kg of waterSupplemental features:Plasma uric acid <4 mg/dLBUN <10 mg/dLFENa >1%Failure to correct hyponatremia after an infusion of normal saline (NS) 0.9%Abnormal water load test (inability to excrete ≥90% of a 20 mL/kg water load in 4 hr)

Etiology

  • Malignant disorders:ADH-producing tumorsCancer (Small-cell lung, pancreatic, prostate)Pituitary tumorsThymomaLymphoma
  • Pulmonary disorders:PneumoniaTBLung abscessCOPD
  • CNS disorders:Meningitis/encephalitisCVAHead injury
  • Medications:ThiazidesChlorpropamideVincristineAnticonvulsants (carbamazepine)Antidepressants (tricyclics, SSRIs)AntipsychoticsNSAIDsEcstasy (MDMA)Vasopressin analogs (DDAVP, oxytocin, vasopressin)
  • Transient:Endurance exerciseGeneral anesthesiaPainStress
  • Other:HereditaryPositive-pressure ventilationHIV/AIDSIdiopathic

Cerebral salt-wasting syndrome (CSWS) can mimic SIADH.

  • Seen in patients with cerebral tumors or subarachnoid hemorrhage and in neurosurgical patients
  • Etiology unclear
  • Represents appropriate water resorption in the face of salt wasting (urine Na >30 " 40 mmol/L)
  • Fluid restriction can help differentiate the 2:In SIADH: Hypouricemia will correctIn CSWS: Hypouricemia will persist
  • Treatment of CSWS may differ from that of SIADH:Infusion of NSMay benefit from fludrocortisones therapy

Diagnosis

Signs and Symptoms

  • Serum sodium <135 mEq/L:
  • Serum sodium <130 mEq/L:Weakness/lethargyWeight gainHeadacheAnorexia
  • Sodium serum <120 mEq/L:Altered mental statusSeizure/coma
  • Chronic hyponatremia: 50% asymptomatic
  • High mortality in acute hyponatremia

History

  • Thorough medication history
  • Course of illness (acute, subacute, or chronic)

Physical Exam

  • Volume status
  • Mental status
  • Stigmata of malignancy

Essential Workup

  • Diagnosis is 1 of exclusion, need to evaluate for other causes of:Depletional or dilutional hyponatremia
  • Electrolytes, BUN, Cr, glucose, protein, lipids:Hyponatremia (serum Na <135 mmol/L)Serum hyposmolality (serum Osm <275 mOsm/kg)
  • Urine osmolality:Inability to excrete dilute urineUrine osmolality >100 mOsm/kg
  • Urine sodium:Continued urinary excretion of sodiumUrinary sodium >20 mEq/L

Diagnosis Tests & Interpretation

Lab

  • Serum protein levels
  • Lipid levels
  • Glucose levels
  • Serum osmolality
  • LFT and thyroid function test
  • Morning cortisol level

Imaging

Consider imaging (CXR, CT head) to screen for pathology causing SIADH (tumors/masses)

Differential Diagnosis

Causes of Hyponatremia

  • See etiologies above
  • Increased extracellular fluid (dilutional hyponatremia):Renal failure/insufficiencyCHFEnd-stage liver disease
  • Normal extracellular fluid (dilutional hyponatremia):SIADHMyxedemaSheehan syndrome (postpartum hypopituitarism)Reset osmostat syndromes (dilute urine at lower than normal sodium levels)
  • Decreased extracellular fluid (depletional hyponatremia):Increased losses:Excessive sweating (endurance sports)GI losses (vomiting, diarrhea)3rd-space sequestrationDiuretic useAldosterone deficiency:Salt-losing nephropathies:
  • Pseudohyponatremia (seen in hyperglycemia, hyperproteinemia, hyperlipidemia)

Treatment

Pre-Hospital

  • In patients with altered mental status, maintenance and protection of the airway are paramount.
  • When hypovolemia is suspected, appropriate fluid resuscitation should be initiated.
  • Rapid patient evaluation and transport are essential.

Initial Stabilization/Therapy

  • Severe symptomatic hyponatremia with CNS manifestations
  • Endotracheal intubation for patients in need of airway protection
  • Identify/treat other causes of altered mental status
  • Treat seizures with benzodiazepines
  • Proceed to hyponatremia treatment

Ed Treatment/Procedures

  • Most effective treatment of SIADH is successful eradication of the underlying cause.
  • Initial treatment of hyponatremia caused by SIADH is the same for all causes of euvolemic/hypervolemic hyponatremia.

Mildly Symptomatic Hyponatremia, Chronic Hyponatremia with Minimal Symptoms, Asymptomatic Hyponatremia

  • Serum sodium usually >125 mEq/L
  • Fluid restriction 800 " 1,000 mL/day alone or in conjunction with:0.9% NS infusion and/or IV furosemide
  • Correct serum sodium by no more than 0.5 mEq/L/hr (5 " 6 mEq/day):Too rapid correction of serum sodium levels can induce central pontine myelinolysis, associated with development of bulbar palsy, quadriplegia, seizures, coma, and death.

Severe Hyponatremia

  • Symptomatic patient, serum sodium <125 mEq/L
  • Increase serum sodium by no more than 12 mEq/L in 1st 24 hr at a rate of 1 mEq/L/hr (8 " 12 mEq/day when serum sodium below 125 mEq/L and slow to 5 " 6 mEq/day when serum sodium rises to 125 mEq/L).
  • Target level: 125 mEq/L
  • Treat patients with significant neurologic symptoms with 3% saline solution.
  • Serum sodium lab testing every 1 " 2 hr

Acute Life-threatening Hyponatremia

  • Serum sodium usually <120 mEq/L
  • Associated with seizures or coma
  • Clinical goal: Stop seizure and improve neurologic status
  • Therapeutic goal: Same as for severe hyponatremia
  • Administer hypertonic saline solution (3%)
  • Stop hypertonic saline when symptoms (i.e., seizures) resolve and transition to NS.
  • IV furosemide to promote diuresis and induce a negative fluid balance.
  • Once serum sodium = 125 mEq/L, further IV fluid should be in the form of 0.9% saline solution.
  • Restoration of serum sodium to normal levels should take place over ≥48 hr.
  • Drugs that inhibit the secretion/effects of ADH:Indicated when SIADH not self-limited and cause cannot be removedDemeclocycline (blocks effect of ADH)

Medication

  • Conivaptan 20 mg IV over 30 min (for severe hyponatremia in concert with admitting physician)
  • Demeclocycline: 300 mg PO BID " QID
  • Hypertonic saline solution (3% NaCl): 250 " 500 mL (max. initial dose 5 mL/kg):25 " 100 mL/hrLimit rate in rise of serum sodium to 0.5 " 1 mEq/L/h.Discontinue when seizure resolves or serum sodium of 125 mEq/L is reached.Rise in serum sodium by 4 " 6 mEq/L is usually sufficient to stop seizures.
  • 0.9% NS: Maintenance rates
  • Lasix: 1 mg/kg up to 20 " 40 mg IV

Follow-Up

Disposition

Admission Criteria

  • Severe life-threatening hyponatremia
  • Symptomatic hyponatremia
  • Serum sodium <125 mEq/L regardless of symptoms
  • New-onset SIADH in which underlying cause or complications must be diagnosed and treated
  • Patients compliance an issue

Discharge Criteria

  • Asymptomatic chronic hyponatremia
  • Serum sodium >125 mEq/L
  • No unstable comorbid factors
  • Known diagnosis of SIADH

Followup Recommendations

All patients with hyponatremia that meet discharge criteria still require follow-up to check for resolution, monitoring, and/or diagnosis of the underlying cause of the SIADH/hyponatremia.

Pearls and Pitfalls

  • SIADH is a diagnosis of exclusion.
  • Must evaluate for other causes as well as renal, thyroid, adrenal, cardiac, and hepatic dysfunction.
  • Take a thorough medication history.

Additional Reading

  • Balasubramanian A, Flareau B, Sourberr J. Syndrome of inappropriate antidiuretic hormone secretion. Hospital Physician. 2007;39:33 " 36.
  • Brimioulle S, Orellana-Jimenez C, Aminian A, et al. Hyponatremia in neurological patients: Cerebral salt wasting versus inappropriate antidiuretic hormone secretion. Intensive Care Med. 2008;34:125 " 131.
  • Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064 " 2072.
  • Gross P. Clinical management of SIADH. Ther Adv Endocrinol Metab. 2012;3(2):61 " 73.
  • Verbalis JG. Managing hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion. J Hosp Med. 2010;5(suppl 3):S18 " S26.

See Also (Topic, Algorithm, Electronic Media Element)

Hyponatremia

The author gratefully acknowledges the contribution of Arunachalam Einstein on previous editions of this chapter.

Codes

ICD9

  • 253.6 Other disorders of neurohypophysis
  • 276.1 Hyposmolality and/or hyponatremia

ICD10

  • E22.2 Syndrome of inappropriate secretion of antidiuretic hormone
  • E87.1 Hypo-osmolality and hyponatremia

SNOMED

  • 55004003 Syndrome of inappropriate vasopressin secretion (disorder)
  • 89627008 Hyponatremia (disorder)