Syndrome of Inappropriate Antidiuretic Hormone Secretion

SIADH is characterized by hyponatremia, an inappropriately concentrated urine (>100 mOsm/kg), normal or slightly elevated plasma volume, normal-to-high urine sodium, and low serum uric acid. SIADH is uncommon in children, and most cases result from excessive administration of vasopressin in the treatment of central diabetes insipidus. It can also occur with encephalitis, brain tumors, head trauma, psychiatric disease, prolonged nausea, pneumonia, tuberculous meningitis, and AIDS and in the postictal phase following generalized seizures. SIADH is the cause of the hyponatremic second phase of the triphasic response seen after hypothalamic-pituitary surgery (Chapter 552). It is found in up to 35% of patients 1 wk after surgery and can result from retrograde neuronal degeneration with cell death and vasopressin release. Common drugs that have been shown to increase vasopressin secretion or mimic vasopressin action, resulting in hyponatremia, include oxcarbazepine, carbamazepine, oxcarbazepine, chlorpropamide, vinblastine, vincristine, and tricyclic antidepressants.

Nephrogenic Syndrome of Inappropriate Antidiuresis

Gain-of-function mutations in the V₂ vasopressin receptor gene have been described in male infants presenting with an SIADH-like clinical picture with undetectable vasopressin levels. Activating mutations in the aquaporin-2 gene might also give rise to the same syndrome but have not yet been described.

Systemic Dehydration

The initial manifestation of systemic dehydration is often hypernatremia and hyperosmolality, which subsequently lead to the activation of vasopressin secretion and a decrease in water excretion. As dehydration progresses, hypovolemia and/or hypotension becomes a major stimulus for vasopressin release, further decreasing free water clearance. Excessive free water intake with ongoing salt loss can also produce hyponatremia. Urinary sodium excretion is low (usually <10 mEq/L) owing to a low glomerular filtration rate and concomitant activation of the renin-angiotensin-aldosterone system, unless primary renal disease or diuretic therapy is present.

Primary Salt Loss

Hyponatremia can result from the primary loss of sodium chloride as seen in specific disorders of the kidney (congenital polycystic kidney disease, acute interstitial nephritis, chronic renal failure), gastrointestinal tract (gastroenteritis), and sweat glands (cystic fibrosis). The hyponatremia is not solely due to the salt loss, because the latter also causes hypovolemia, leading to an increase in vasopressin. Mineralocorticoid deficiency, pseudohypoaldosteronism (sometimes seen in children with urinary tract obstruction or infection), and diuretics can also result in loss of sodium chloride.

Decreased Effective Plasma Volume

Hyponatremia can result from decreased effective plasma volume, as found in congestive heart failure, cirrhosis, nephrotic syndrome, positive pressure mechanical ventilation, severe burns, bronchopulmonary dysplasia in neonates, cystic fibrosis with obstruction, and severe asthma. The resulting decrease in cardiac output leads to reduced water and salt excretion, as with systemic dehydration, and an increase in vasopressin secretion. In patients with impaired cardiac output and elevated atrial volume (congestive heart failure, lung disease), atrial natriuretic peptide concentrations are elevated further, leading to hyponatremia by promoting natriuresis. However, owing to the marked elevation of aldosterone in these patients, their urine sodium remains low (<20 mEq/L) despite this. Unlike dehydrated patients, these patients also have excess total body sodium from activation of the renin-angiotensin-aldosterone system and can demonstrate peripheral edema as well.

Primary Polydipsia (Increased Water Ingestion)

In patients with normal renal function, the kidney can excrete dilute urine with an osmolality as low as 50 mOsm/kg. To excrete a daily solute load of 500 mOsm/m², the kidney must produce 10 L/m² of urine per day. Therefore, to avoid hyponatremia, the maximum amount of water a person with normal renal function can consume is 10 L/m². Neonates, however, cannot dilute their urine to this degree, putting them at risk for water intoxication if water intake exceeds 4 L/m²/day (approximately 60 mL/h in a newborn). Many infants develop transient but symptomatic hyponatremic seizures after being fed pure water without electrolytes rather than breast milk or formula.

Decreased Free Water Clearance

Hyponatremia due to decreased renal free water clearance, even in the absence of an increase in vasopressin secretion, can result from adrenal insufficiency or thyroid deficiency or can be related to a direct effect of drugs on the kidney. Both mineralocorticoids and glucocorticoids are required for normal free water clearance in a vasopressin-independent manner. In patients with unexplained hyponatremia, adrenal and thyroid insufficiency should be considered. In addition, patients with coexisting adrenal failure and diabetes insipidus might have no symptoms of the latter until glucocorticoid therapy unmasks the need for vasopressin replacement. Certain drugs can inhibit renal water excretion through direct effects on the nephron, thus causing hyponatremia; these drugs include high-dose cyclophosphamide, vinblastine, cisplatinum, carbamazepine, and oxcarbazepine.

Cerebral Salt Wasting

Cerebral salt wasting appears to be the result of hypersecretion of atrial natriuretic peptide and is seen primarily with central nervous system disorders including brain tumors, head trauma, hydrocephalus, neurosurgery, cerebrovascular accidents, and brain death. Hyponatremia is accompanied by elevated urinary sodium excretion (often >150 mEq/L), excessive urine output, hypovolemia, normal or high uric acid, suppressed vasopressin, and elevated atrial natriuretic peptide concentrations (>20 pmol/L). Thus, it is distinguished from SIADH, in which normal or decreased urine output, euvolemia, only modestly elevated urine sodium concentration, and an elevated vasopressin level occur. The distinction between cerebral salt wasting and SIADH is important because the treatment of the two disorders differs markedly. However, its existence has been questioned, because few patients with the suspected syndrome have documented hypovolemia and thus might truly have SIADH.

Runners’ Hyponatremia

Excess fluid ingestion during long-distance running (e.g., marathon running) can result in severe hyponatremia due to hypovolemia-induced activation of AVP secretion coupled with excessive water ingestion and is correlated with weight gain, long racing time, and extremes of body mass index.

Pseudohyponatremia and Other Causes of Hyponatremia

Pseudohyponatremia can result from hypertriglyceridemia (Chapter 52). Elevated lipid levels result in a relative decrease in serum water content. As electrolytes are dissolved in the aqueous phase of the serum, they appear low when expressed as a fraction of the total serum volume. As a fraction of serum water, however, electrolyte content is normal. Modern laboratory methods that measure sodium concentration directly, independent of sample volume, do not cause this anomaly. Factitious hyponatremia can result from obtaining a blood sample proximal to the site of intravenous hypotonic fluid infusion.

Hyponatremia is also associated with hyperglycemia, which causes the influx of water into the intravascular space. Serum sodium decreases by 1.6 mEq/L for every 100 mg/dL increment in blood glucose >100 mg/dL. Glucose is not ordinarily an osmotically active agent and does not stimulate vasopressin release, probably because it can equilibrate freely across plasma membranes. In the presence of insulin deficiency and hyperglycemia, however, glucose acts as an osmotic agent, presumably because its normal intracellular access to osmosensor sites is prevented. Under these circumstances, an osmotic gradient exists, stimulating vasopressin release.

Emergency Treatment of Hyponatremia

The development of acute hyponatremia (onset <12 hr) or a serum sodium concentration <120 mEq/L may be associated with lethargy, psychosis, coma, or generalized seizures, especially in younger children. Acute hyponatremia can cause cell swelling and lead to neuronal dysfunction or to cerebral herniation. The emergency treatment of cerebral dysfunction resulting from acute hyponatremia includes water restriction and can require rapid correction with hypertonic 3% sodium chloride. If hypertonic saline treatment is undertaken, the serum sodium should be raised only high enough to cause an improvement in mental status, and in no case faster than 0.5 mEq/L/hr or 12 mEq/L/24 hr.

Treatment of SIADH

Chronic SIADH is best treated by oral fluid restriction. With full antidiuresis (urine osmolality of 1,000 mOsm/kg), a normal daily obligate renal solute load of 500 mOsm/m² would be excreted in 500 mL/m² water. This, plus a daily nonrenal water loss of 500 mL/m², would require that oral fluid intake be limited to 1,000 mL/m²/24 hr to avoid hyponatremia. In young children, this degree of fluid restriction might not provide adequate calories for growth. In this situation, the creation of nephrogenic diabetes insipidus using demeclocycline therapy may be indicated to allow sufficient fluid intake for normal growth. Urea has also been safely used to induce an osmotic diuresis in infants and children.

Treatment of Cerebral Salt Wasting

Treatment of patients with cerebral salt wasting consists of restoring intravascular volume with sodium chloride and water, as for the treatment of other causes of systemic dehydration. The underlying cause of the disorder, which is usually due to acute brain injury, should also be treated if possible. Treatment involves the ongoing replacement of urine sodium losses volume for volume.