Classification:

Pathophysiology:

Aldosterone, synthesized by the adrenal cortex, is regulated primarily by serum potassium but also is released in response to hypovolemia through the renin-angiotensin-aldosterone axis. Aldosterone causes absorption of sodium at the distal renal tubule. Sodium retention obligates free water retention, helping to correct the hypovolemic state.

The healthy kidney regulates sodium balance independently of ADH or aldosterone by varying the degree of sodium absorption at the distal tubule. Hypovolemic states, such as hemorrhage or dehydration, prompt increases in sodium absorption in the proximal tubule. Increases in vascular volume suppress tubular sodium reabsorption, resulting in natriuresis and helping to restore normal vascular volume.

Generally, disorders of sodium balance can be traced to a disturbance in thirst or water acquisition, ADH, aldosterone, or renal sodium transport. Hyponatremia is physiologically significant when it indicates a state of extracellular hypo- osmolarity and a tendency for free water to shift from the vascular space to the intracellular space. Although cellular edema is well tolerated by most tissues, it is not well tolerated within the skull. Therefore, clinical manifestations of hyponatremia are related primarily to cerebral edema.

The rate of development of hyponatremia plays a critical role in its pathophysiology. When serum sodium falls slowly, over a period of several days or weeks, the brain is capable of compensating by extrusion of solutes and fluid to the extracellular space. Compensatory extrusion of solutes reduces the flow of free water into the intracellular space, and symptoms are much milder for a given degree of hyponatremia. When serum sodium falls rapidly, over a period of 24-48 hours, this compensatory mechanism is overwhelmed and severe cerebral edema may ensue, resulting in brainstem herniation and death.

Frequency/Mortality/Morbidity:

Patients with acute hyponatremia (developing over 48 hours or less) are subject to more severe degrees of cerebral edema for a given level of serum sodium. The primary cause of morbidity and death is brainstem herniation and mechanical compression of vital midbrain structures. Rapid identification and correction of serum sodium is necessary in patients with severe acute hyponatremia to avert brainstem herniation and death.

Patients with chronic hyponatremia (developing over more than 48 hours) experience milder degrees of cerebral edema for a given level of serum sodium. Brainstem herniation has not been observed in this group of patients. The principal causes of morbidity and death are status epilepticus (when chronic hyponatremia reaches levels of 110 mEq/L or less) and cerebral pontine myelinolysis (an unusual demyelination syndrome that occurs when chronic hyponatremia is corrected too quickly). The distinction between acute and chronic hyponatremia has critical implications in terms of morbidity and mortality and in terms of proper corrective therapy.

History:

Symptoms may be limited to mild anorexia, headache, or muscle cramps, or the patient may present with obtundation, coma, or status epilepticus. Hyponatremia is often seen in association with pulmonary/mediastinal disease or CNS disorders. There should be an increased index of suspicion of hyponatremia in patients with pneumonia; active tuberculosis; pulmonary abscess; neoplasm; asthma; or in patients with CNS infection, trauma, or neoplasm. Patients with carcinoma of the nasopharynx, duodenum, stomach, pancreas, ureter, prostate, or uterus also have an increased risk. A history of hypothyroidism or adrenal insufficiency should be sought because each is associated with hypo-osmolar hyponatremia.

Hyponatremia is associated with numerous medications. The patient's medication list should be examined for drugs known to cause hyponatremia. Hyponatremia has been noted in patients with poor dietary intake who consume large amounts of beer (called beer potomania) and after use of the recreational drug N-methyl-3,4-methylenedioxyamphetamine (i.e.: MDMA or ecstasy).

Patients with clinically significant hyponatremia present with nonspecific symptoms attributable to cerebral edema. These symptoms, especially when coupled with a recent history of altered fluid balance, should suggest the possibility of hyponatremia. Those symptoms include anorexia, vomiting, confusion, lethargy, agitation, headache and seizures.

Physical:

Causes:

Excess fluid losses (e.g.: vomiting, diarrhea, excessive sweating, GI fistulas or drainage tubes, pancreatitis, burns) that have been replaced primarily by hypotonic fluids is a common cause of hyponatremia. Acute or chronic renal insufficiency in which patient may be unable to excrete adequate amounts of free water is another cause. Salt- wasting syndromes can also produce hyponatremia. These occur in patients with traumatic brain injury, aneurysmal subarachnoid hemorrhage, and intracranial surgery. Prolonged exercise in a hot environment, especially in patients who hydrate aggressively with hyposmolar fluids during exertion can result in hyponatremia. (Severe symptomatic hyponatremia has been reported in marathon runners and in recreational hikers in the Grand Canyon.)

Other causes include hepatic cirrhosis, congestive heart failure, or nephrotic syndrome, in which patients are subject to insidious increases in total body sodium and free water stores; uncorrected hypothyroidism or cortisol deficiency; SIADH (syndrome of inappropriate ADH secretion), and psychogenic over-drinking of clear liquids.

Hyponatremia can be caused by many medications. Known offenders include acetazolamide, amiloride, amphotericin, atovaquone, thiazide diuretics, amiodarone, basiliximab, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, carbamazepine, carboplatin, carvedilol, celecoxib, cyclophosphamide, clofibrate, desmopressin, donepezil, eplerenone, gabapentin, haloperidol, heparin, hydroxyurea, indomethacin, ketorolac, loop diuretics, mitoxantrone, nimodipine, oxcarbazepine, opiates, oxytocin, pimozide, propafenone, proton pump inhibitors, sirolimus, ticlopidine, vincristine, selective serotonin reuptake inhibitors, sulfonylureas, trazodone, tolbutamide, zalcitabine, and zonisamide.

Treatment:

Acute hyponatremia is less common than chronic hyponatremia and typically is seen in patients with a history of sudden free water loading (e.g.: patients with psychogenic polydipsia, infants fed tap water for 1-2 days, patients given hypotonic fluids in the postoperative period). The therapeutic goal is to increase serum sodium rapidly by 4-6 mEq/L over the first 1-2 hours. Patients with seizures, severe confusion, coma, or signs of brainstem herniation should receive hypertonic (3%) saline to rapidly correct serum sodium toward normal, but only enough to arrest the progression of symptoms. An increase in serum sodium of 4-6 mEq/L is generally sufficient.

Chronic hyponatremia is more common than acute hyponatremia. Patients with mild symptoms and serum sodium of 125 mEq/L or less often have chronic hyponatremia. These patients lack any history of sudden free water loading. Chronic hyponatremia must be managed with extreme care.

A rapid increase in serum sodium once compensatory mechanisms are in place can lead to cerebral pontine myelinolysis (CPM). CPM is a poorly understood entity characterized by focal demyelination in the pons and extrapontine areas. Symptoms (e.g.: dysarthria, dysphagia, seizures, altered mental status, quadriparesis, hypotension) begin 1-3 days after overly rapid correction of serum sodium. The condition is often irreversible; slow, cautious correction of serum sodium in these patients is important. The risk of CPM appears to be minimal in patients whose chronic hyponatremia is corrected at a rate of less than 0.5 mEq/L/hour or 12 mEq/L/day.

Patients with chronic hyponatremia and severe symptoms (e.g.: severe confusion, coma, seizures) should receive hypertonic saline but only enough to raise the serum sodium by 4-6 mEq/L and to arrest seizure activity. Further correction should proceed at an overall rate that is no greater than 0.5 mEq/L/hour or 12 mEq/L/day.

Hypovolemic hyponatremia: Patients have decreased total body sodium stores. If symptoms are mild to moderately severe, treat with isotonic saline; monitor serum sodium levels frequently to ensure that serum sodium increases no faster than 0.5 mEq/L/hour or 12 mEq/L/day.

Hypervolemic hyponatremia: Patients have increased total body sodium stores. Treatment consists of sodium and water restriction and attention to the underlying cause.

Euvolemic hyponatremia: This implies normal sodium stores and a total body excess of free water. Treatment consists of free water restriction and correction of the underlying condition.

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