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Cerebral Salt-Wasting Syndrome

INTRODUCTION
Background: First described by Peters et al in 1950, cerebral salt-wasting syndrome (CSWS) is defined by the development of excessive natriuresis and subsequent hyponatremic dehydration in patients with intracranial disease. Differentiation of this disorder from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), another common cause of hyponatremia in this setting, is critical to prescribing appropriate therapy.

Pathophysiology: The exact mechanism underlying renal salt wasting in this syndrome remains unclear. One hypothesis states that an exaggerated renal pressure-natriuresis response caused by increased activity of the sympathetic nervous system and dopamine release is responsible for urinary sodium loss. Another hypothesis involves the presence of circulating natriuretic factors, possibly including atrial natriuretic peptide, in patients with CSWS. Maesaka et al have identified a protein in the plasma of neurosurgical patients with hyponatremia, renal salt wasting, and hyperuricosuria that inhibits sodium reabsorption in the proximal tubule.

Frequency:

  • In the US: Exact incidence data for this disorder are not available. Approximately 60% of children with brain injuries or tumors develop hyponatremia during their hospital course. Some experts suggest that CSWS is responsible for hyponatremia at least as often as SIADH, particularly in neurosurgical patients.

Mortality/Morbidity: CSWS usually appears in the first week after brain injury and spontaneously resolves in 2-4 weeks. Death and complication rates for this syndrome are not available. Failure to distinguish CSWS from SIADH as the cause of hyponatremia will lead to improper therapy (ie, fluid restriction), thereby exacerbating intravascular volume depletion and potentially jeopardizing cerebral perfusion.
Age: CSWS can occur at any age. Published reports include patients aged 6 months to 65 years.

Age: CSWS can occur at any age. Published reports include patients aged 6 months to 65 years.

CLINICAL
History:

  • Hyponatremia
    • As the decline in serum sodium concentration reduces serum osmolality, a tonicity gradient develops across the blood-brain barrier that causes cerebral edema.
    • Symptoms include lethargy, agitation, headache, altered consciousness, seizures, and coma.
    • Severity of symptoms typically reflects the magnitude and rapidity of the decrease in serum sodium concentration.
  • Intravascular volume depletion: Historical features suggesting hypovolemia include thirst, abrupt weight loss, decreasing urinary frequency, and negative fluid balance.

Physical:

  • Physical signs include those associated with severe hyponatremia or intravascular volume depletion. Hyponatremia can be indicated by acute central nervous system (CNS) dysfunction such as altered mental status, seizures, and coma.
  • Unfortunately, no single physical finding can accurately and reproducibly measure effective circulating volume. Commonly used signs of hypovolemia include orthostatic tachycardia or hypotension, increased capillary refill time, increased skin turgor, dry mucous membranes, and sunken anterior fontanel. These signs usually appear only when the degree of dehydration is moderate to severe.

Causes:

  • CSWS occurs in the setting of acute CNS disease. Conditions include the following:
    • Head injury
    • Brain tumor
    • Intracranial surgery
    • Stroke
    • Intracerebral hemorrhage

       

    • Tuberculous meningitis
    • Tuberculous meningitis

WORKUP
 Lab Studies:

  • Serum sodium concentration: Patients with untreated CSWS are hyponatremic.
  • Serum osmolality: If measured serum osmolality exceeds twice the serum sodium concentration and azotemia is not present, suspect hyperglycemia or mannitol as the cause of hyponatremia.
  • Serum uric acid concentrations are low in SIADH but can be normal in CSWS.
  • Urine output: Urine is dilute and flow rate is often high in CSWS but is usually very concentrated, and flow rate is low in SIADH.
  • Urine sodium concentrations are typically elevated in both SIADH and CSWS (>40 mEq/L). However, urinary sodium excretion (urine sodium concentration [mEq/L] x urine volume [L/24 hr]) is high in CSWS and normal in SIADH. Therefore, net sodium balance (intake minus output) is negative in CSWS.
  • Fractional excretion of uric acid
    • Fractional excretion of uric acid (FEUA) is defined as the percentage of urate filtered by glomeruli that is excreted in urine. It is calculated by dividing the product of (urinary uric acid [mg/mL] x serum creatinine [mg/mL]) by the product of (serum uric acid [mg/mL] x urine creatinine [mg/mL]) and multiplying the result by 100.
    • Normal values are less than 10%. Patients with either CSWS or SIADH have elevated FEUA. However, after correction of hyponatremia, FEUA normalizes in SIADH but remains elevated in CSWS.
    • Maesaka et al have proposed that FEUA can be used to distinguish between CSWS and SIADH when the clinical picture is unclear.

TREATMENT
Medical Care:

  • Evaluation and treatment typically occurs in the inpatient setting because most patients are seriously ill with acute CNS disease.
  • Management centers on correction of intravascular volume depletion and hyponatremia as well as replacement of ongoing urinary sodium loss with intravenous isotonic or hypertonic saline solutions.
  • Once the patient is stabilized, enteral salt supplementation can be considered.

MEDICATION
 Drug Category: Mineralocorticoids -- Some clinicians have reported a favorable response to mineralocorticoid therapy in CSWS. Acts on fluid and electrolyte balance. Enhances sodium reabsorption in the kidney by direct action on renal tubule cell, resulting in expanded extracellular fluid volume. Increases renal excretion of potassium and hydrogen ion.

Drug Name
 		 Fludrocortisone (Florinef) -- Promotes increased reabsorption of sodium and loss of potassium renal distal tubules.
Adult Dose 0.05-0.2 mg/d PO
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; systemic fungal infections
Interactions Barbiturates, phenytoin, and rifampin can increase hepatic metabolism of fludrocortisone diminishing its effect; fludrocortisone-induced hypokalemia can enhance digoxin toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Adverse effects include hypertension, edema, congestive heart failure, and hypokalemic alkalosis; dose should be carefully titrated to level of patient tolerance and effectiveness; monitor for dizziness, severe or continuing headaches, swelling feet or lower legs, or unusual weight gain; administer with food to minimize GI adverse effects

FOLLOW-UP
Further Inpatient Care:

  • Children with CSWS usually are hospitalized for management of their underlying CNS disease.
  • Ongoing monitoring of body weight, fluid balance, and serum sodium concentration is essential during the hospital course.

Further Outpatient Care:

  • Patients whose neurologic insult has improved and who demonstrate normal intravascular volume and serum sodium concentrations on enteral salt supplements and/or fludrocortisone can be closely observed as outpatients until CSWS resolves.

In/Out Patient Meds:

  • Medications include sodium chloride tablets or solution (adjust based on serum and urine sodium levels) and fludrocortisone.

Complications:

  • Symptomatic hyponatremia
  • Dehydration

Prognosis:

  • CSWS usually develops in the first week following a brain insult. Its duration is usually brief (spontaneously resolves in 2-4 weeks), although it can last for several months.

MISCELLANEOUS
Medical/Legal Pitfalls:

  • Failure to distinguish CSWS from SIADH in a hyponatremic patient with brain injury will lead to inappropriate therapy and potentially exacerbate intravascular volume depletion.
 

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