Chronic hyponatremia
The distinction between acute and chronic hyponatremia is somewhat arbitrary. Commonly, hyponatremia is considered chronic when it has evolved over the course of 48 hours or more.11,12,26 Although the precise duration of an electrolyte disturbance cannot be known when it develops outside the hospital (except for psychotic water drinkers, marathon runners, and users of ecstasy), outpatients can be assumed to have chronic hyponatremia.33 Prolonged hyponatremia cannot occur unless there is a sustained defect in water excretion. Except for patients with renal failure, virtually all chronically hyponatremic patients have some abnormality in vasopressin secretion.
Etiology
Advanced renal failure A low glomerular filtration rate limits the ability to excrete electrolyte-free water. Many patients with advanced renal failure excrete urine that has the same os-molality as plasma regardless of physiologic conditions (fixed isosthenuria). In acute oliguric renal failure, the ability to excrete free water is virtually nil; administration of hypotonic fluids must be scrupulously avoided to avoid hyponatremia.
Diuretics Thiazide diuretics are commonly the sole cause or a major contributing factor of hyponatremia requiring hospital admission.33,34 For unknown reasons, severe hyponatremia caused by thiazides affects elderly women much more often than other groups. By blocking the reabsorption of sodium and chloride in the distal tubule, thiazides and metolazone prevent the generation of maximally dilute urine.35 Because sodium re-absorption in the ascending limb of the loop of Henle is left unaffected by these agents, they permit excretion of maximally concentrated, hypertonic urine and can lead to simultaneous retention of water and depletion of sodium and potassium. Extraordinarily severe hyponatremia can result from thiazides, with plasma sodium levels as low as 100 mEq/L. Vasopressin levels are usually elevated in patients who present with thiazide-in-duced hyponatremia, sometimes because of diuretic-induced volume depletion but more often because of the stress of minor intercurrent illnesses. Patients with thiazide-induced hypona-tremia do not usually appear clinically volume depleted, presumably because retained water partially sustains extracellular fluid volume. Patients who have become hyponatremic on thi-azides should not be given these agents again; recurrent episodes of severe hyponatremia are common.
Hypovolemia Hypovolemic hyponatremia is most often associated with gastrointestinal fluid losses caused by vomiting, diarrhea, or laxative abuse. Surprisingly, particularly in alcoholics, patients who continue to drink while vomiting repeatedly can still absorb enough ingested water to become hypona-tremic. Electrolyte losses in the vomitus, combined with urinary sodium and potassium losses that result from metabolic alkalo-sis, lower the plasma sodium concentration.
Beer potomania Patients who subsist on beer (a practice known as beer potomania) are susceptible to hyponatremia because of their low rates of solute excretion (beer contains little protein or electrolyte). Reduced delivery of the glomerular filtrate to distal diluting sites limits the amount of water that can be excreted. Nonosmotic stimuli to vasopressin secretion caused by nausea or gastrointestinal fluid losses or by treatment with thiazide diuretics are often contributing factors.
Edematous conditions Any disease that can cause edema also predisposes to water retention and hyponatremia. The same hemodynamic factors that promote sodium retention are nonosmotic stimuli for vasopressin release.8,16-18 Elevated vaso-pressin levels have been reported in hyponatremic patients with congestive heart failure, cirrhosis, and nephrotic syndrome. In heart failure, hyponatremia is associated with a low cardiac output and a poor prognosis.
SIADH Nonosmotic release of vasopressin that has no hemodynamic explanation is termed inappropriate [see Table 5].12,19 A number of tumors (most commonly small cell carcinoma of the lung) ectopically synthesize and secrete vasopressin.36 Unexplained, persistent hyponatremia should be considered a marker for an underlying malignancy.
SIADH may also complicate the course of a wide variety of conditions in which there is damage to or inflammation of the central nervous system.8,12 In patients with subarachnoid hemorrhage, natriuretic peptides released by the brain may directly promote urinary sodium loss, regardless of extracellular volume (cerebral salt wasting).37,38 Urinary salt losses combined with vasopressin-induced water retention are responsible for hy-ponatremia. SIADH is a common complication of chest infection. Antidiuretic activity has been demonstrated by bioassay in patients with tuberculous lung tissue, and tuberculosis causes SIADH.11 In pneumonia, vasopressin levels are increased during the acute phase of the disease and return to baseline within a few days. Isolated glucocorticoid deficiency caused by anterior pituitary dysfunction also causes hyponatremia; patients with hypopituitarism develop SIADH but, unlike patients with Ad-dison disease, have normal levels of mineralocorticoid and do not become hypovolemic or hyperkalemic. Hyponatremia caused by glucocorticoid deficiency promptly resolves when cortisol is replaced. Hypothyroidism also causes SIADH; hy-ponatremia gradually resolves when thyroid hormone replacement is given.
Table 5 Causes of the Syndrome of Inappropriate Antidiuretic Hormone
|
Tumors |
Bronchogenic (small cell) |
|
Pancreatic |
|
|
Duodenal |
|
|
Urethral |
|
|
Nasopharyngeal |
|
|
Leukemia |
|
|
Hodgkin disease |
|
|
Thymoma |
|
|
Neurologic disorders |
Psychosis |
|
Trauma |
|
|
Neoplasms (primary and metastatic) |
|
|
Vascular (hemorrhage, infarction, and vasculitis) |
|
|
Infection (meningitis, brain abscess, and encephalitis) |
|
|
Miscellaneous (Guillain-Barre syndrome, multiple sclerosis, hydrocephalus, Shy-Drager syndrome) |
|
|
Pulmonary disorders |
Infectious (bacterial, viral, and fungal pneumonia and tuberculosis) |
|
Functional (asthma, acute respiratory failure, and mechanical ventilation) |
|
|
Endocrine diseases |
Glucocorticoid deficiency (hypopituitarism) Hypothyroidism |
|
Drugs |
Antidiuretic hormones (vasopressin, DDAVP, and oxytocin) |
|
Psychotropic agents (tricyclic antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, and carbamazepine) |
|
|
Ecstasy (MDMA) Antineoplastic agents (cyclophosphamide, vincristine, and vinblastine) |
|
|
Nonsteroidal anti-inflammatory drugs |
|
|
Diabetic agents (chlorpropamide and tolbutamide) |
|
|
Miscellaneous (bromocriptine and nicotine) |
|
|
Other causes |
Postoperative stress |
|
Alcohol withdrawal |
|
|
AIDS |
|
|
Nausea |
DDAVP—1-desamino-8-D-arginine vasopressin
A number of therapeutic agents can induce SIADH.12,40 Non-steroidal anti-inflammatory drugs (NSAIDs) decrease water excretion because they inhibit formation of prostaglandin E2, which modulates vasopressin action.8 Rare cases of hypona-tremia solely attributable to NSAIDs have been reported, but these commonly used agents may exacerbate other causes of hyponatremia.
Hyponatremia in AIDS Hyponatremia is an extremely common finding in AIDS patients.41 Many AIDS patients have features of SIADH associated with opportunistic infections that cause pneumonia and meningitis. Others have clinical signs of volume depletion without low urine sodium values, a finding that may indicate coexistent renal disease or adrenal insufficien-cy.42 Hyponatremia often occurs when antibiotics are administered in hypotonic intravenous solutions.
Diagnosis
Hyponatremia should be approached in a systematic fashion. First, the various disorders that can lower the plasma sodium concentration without causing hypotonicity should be excluded [see Differential Diagnosis for Hyponatremia, above]. Once it has been established that hypotonic hyponatremia is present, the mechanism for impaired water excretion is identified (hypo-volemia versus an edematous condition versus SIADH), and the differential diagnosis that applies to that mechanism is considered. The most challenging goals of the diagnostic process are to determine whether chronic SIADH is present and, if it is, to define the specific disease responsible for the syndrome.
Clinical manifestations Because cerebral edema is usually not severe, the symptoms of chronic hyponatremia are much more subtle, vague, and nonspecific than those of acute water intoxication12,26; indeed, patients with chronic hyponatremia are often asymptomatic at sodium levels that may be lethal to a patient with acute water intoxication. As the plasma sodium concentration falls below 115 to 120 mEq/L, patients often experience anorexia, nausea, vomiting, muscle weakness, and muscle cramps. They may be irritable and show personality changes, becoming uncooperative, confused, hostile, or simply slow to respond. At plasma sodium concentrations below 110 mEq/L, gait disturbances, falling, stupor, tremulousness, and, more rarely, seizures may occur.
Chronic hyponatremia itself is rarely, if ever, fatal. However, chronically hyponatremic patients may develop life-threatening acute hyponatremia if they rapidly drink water or are infused with a large volume of hypotonic fluid. Because hyponatremia can be a marker for severe underlying illness, hospitalized patients with hyponatremia often have a high mortality, dying with but not of chronic hyponatremia. There is little evidence that chronic hyponatremia itself leads to permanent sequelae, even when the plasma sodium concentration falls below 105 mEq/L.33,43 However, patients with prolonged, severe hypona-tremia are susceptible to iatrogenic injury if their electrolyte disturbance is corrected too rapidly [see Treatment, below].
History and physical examination The history in patients with chronic hyponatremia should include information about diet, fluid intake, gastrointestinal fluid losses, and use of diuretics, antidepressants, or other antidiuretic drugs. During the physical examination, physicians should look for clinical signs of volume depletion or an edematous condition. Evidence of volume depletion may not always be definitive, however. For example, vomiting may be a symptom rather than the cause of hyponatremia; extreme hyponatremia may occasionally impair baroreceptor reflexes, causing postural hypotension and a false impression of volume depletion; and retained water may mask underlying volume depletion. When the distinction between hy-ponatremia caused by hypovolemia and hyponatremia caused by SIADH is not obvious, laboratory clues may helpful.
Laboratory tests Measurement of the urinary sodium concentration, chloride concentration, or both is often the most helpful test.44 Water retention caused by hypovolemia or by an ede-matous condition is usually associated with a urinary sodium concentration lower than 20 mEq/L in a spot sample. Hypov-olemia caused by upper gastrointestinal fluid losses is an important exception. Loss of gastric fluid causes a metabolic alkalosis that may increase urinary sodium excretion despite volume depletion; the diagnosis can be made by measuring the urine chloride concentration, which is reduced in this condition. In SIADH, urinary sodium matches intake; because the urine is usually concentrated, the urinary sodium concentration exceeds 40 mEq/L unless dietary sodium intake is very low. Measurements of the BUN and serum uric acid complement these measurements. When a hemodynamic abnormality is responsible for hyponatremia, the kidney is underperfused, urea and uric acid clearances are diminished, and the BUN and serum uric acid levels are usually elevated. Conversely, SIADH is a volume-expanded state, and BUN and uric acid levels are usually low. Uric acid is a more reliable indicator of volume status than the BUN, because the latter value is affected by dietary protein intake as well as renal clearance.
Assessment of acid-base and potassium balance may provide helpful clues to the diagnosis. The serum potassium and bicarbonate levels are normal in SIADH. Hypokalemia and metabolic alkalosis suggest diuretic therapy or vomiting, which can be surreptitious. Hyperkalemia and metabolic acidosis suggest the possibility of adrenal insufficiency. Hypokalemia and acidosis can result from diarrhea, and their presence may raise the possibility of surreptitious laxative abuse.
Withdrawal of hyponatremic drugs When a patient is taking a drug that can cause hyponatremia, it is important to exclude another underlying cause of hyponatremia before attributing the electrolyte disturbance to the medication. For example, thiazide diuretics can exacerbate hyponatremia caused by SIADH. The best way to confirm a diagnosis of drug-induced hyponatremia is to eliminate the offending agent and be sure that water excretion returns to normal when the patient is off the drug. Full resolution of hyponatremia and full recovery of diluting function may be delayed for a week or two in patients with thiazide-induced hyponatremia. During repair of sodium and potassium deficits, transient resetting of the osmostat is common and should not necessarily prompt an extensive search for an underlying cause.
Response to therapy On occasion, evidence regarding the cause of hyponatremia can be equivocal. In such cases, the patient’s response to isotonic saline (or a generous oral salt intake and the passage of time) is the best clue to the diagnosis. Patients with subclinical edematous conditions will retain the administered sodium, developing clinically obvious edema. Volume-depleted patients initially retain the administered sodium, but as soon as hypovolemia is corrected, the urine becomes dilute, the rate of urinary sodium excretion increases to match intake, and hyponatremia improves as water is excreted in the urine. Urinary sodium excretion promptly increases in patients with SIADH, but the urine remains concentrated and hyponatremia persists. Isotonic saline should be given with extreme caution to patients with very low plasma sodium concentrations; in SIADH, saline can exacerbate hyponatremia, whereas in volume depletion, hyponatremia may correct too rapidly.
Identifying a specific cause for SIADH SIADH is a mechanism for developing hyponatremia, not a diagnosis. In all patients with SIADH, a specific etiology for inappropriate vaso-pressin secretion should be sought. When hyponatremia develops during hospitalization, the cause is sometimes obvious (e.g., pneumonia, meningitis, or acute respiratory failure) and no further testing is indicated. In a patient with clinical features of SIADH but no obvious cause for it, a more extensive evaluation is indicated. The workup should include a careful search for malignancy and central nervous system pathology and an endocrine evaluation to exclude hypothyroidism and hypocorti-solism. Sometimes, no cause for SIADH is found, especially in elderly patients and patients with psychiatric disorders, mental retardation, or alcoholism.45 Careful follow-up is important, because malignancies may become clinically apparent after several years in so-called idiopathic SIADH.
Treatment
Patients with very low plasma sodium concentrations usually have some neurologic symptoms, and they are at risk of sustaining injuries from falls. However, unlike acute water intoxication, chronic hyponatremia poses little risk of an explosive onset of seizures or a fatal outcome, provided that water is withheld and the plasma sodium concentration is not allowed to fall any further. On the other hand, patients with chronic hyponatremia are at considerable risk for neurologic injury caused by overaggres-sive correction. Thus, there are four major goals in managing chronic hyponatremia: (1) prevention of a progressive decrease in plasma sodium concentration; (2) amelioration of hypona-tremic symptoms by promptly but carefully increasing the plasma sodium concentration (an increase of at least 4 mEq/L/day is desirable in most cases); (3) avoidance of excessive correction; and (4) gradual restoration and maintenance of a normal plasma sodium concentration.
Free-water restriction should be instituted in all patients until the plasma sodium concentration has begun to increase. Intravenous fluids should be at least isotonic, and oral fluid intake should be limited to 500 to 1,000 ml/day, depending on the severity of the electrolyte disturbance. In patients with reversible defects in water excretion, limitations on free-water intake should be lifted once the plasma sodium concentration has begun to increase.
Attempts to calculate the dose of sodium chloride needed to correct hyponatremia are doomed to failure. The increase in plasma sodium concentration depends on the amounts of administered sodium and potassium that the body retains, as well as on the amount of electrolyte-free water that is eliminated in the urine. Indeed, in some cases, the plasma sodium concentration will return to normal solely because of a water diuresis, with no sodium given.
The measures required to increase the plasma sodium concentration, along with the likelihood of inadvertent rapid correction, vary depending on the cause of hyponatremia. For therapeutic purposes, the causes can be divided into reversible and persistent defects in water excretion.
Reversible defects in water excretion Hyponatremia corrects easily when the cause of defective water excretion can be eliminated by volume expansion, by withdrawal of a therapeutic agent, or by treatment of an underlying illness [see Table 4]. In patients with reversible defects in water excretion, avoiding excessive correction may become a major challenge.
Hypovolemic hyponatremia responds readily to 0.9% sodium chloride because the sodium concentration of isotonic saline is higher than the cation concentration of the excreted urine. Once the volume deficit is repaired and the hemodynamic stimulus to vasopressin secretion is removed, the urine becomes dilute and a water diuresis may rapidly return the plasma sodium concentration to normal. Similarly, patients with diuretic-induced hy-ponatremia are extremely susceptible to rapid correction; restoration of the renal diluting mechanism when the diuretic is discontinued and replacement of sodium and potassium deficits contribute to the increase in plasma sodium concentration.
Intravenous saline should be discontinued once clinically apparent hypovolemia has been corrected and the plasma sodium concentration has begun to increase. Saline should be given cautiously, if at all, to hypokalemic patients who require potassium replacement. During repair of a potassium deficit, potassium enters cells, displacing sodium, which then returns to the extracellular fluid; administered potassium is therefore as effective as sodium in raising the plasma sodium concentration. Diuretic-induced hyponatremia does not usually necessitate use of intravenous saline; for most patients, an adequate diet, replacement of potassium deficits, and discontinuance of thiazide diuretics are sufficient. In severely hyponatremic patients, the plasma sodium concentration should be monitored every 6 to 8 hours for the first 2 to 3 days of therapy. If it appears that a water diuresis is going to increase the plasma sodium by more than the desired amount, replacement of fluid losses with oral water or D5W may become necessary.
Persistent defects in water excretion: SIADH Patients with SIADH tend to be resistant to rapid changes in plasma sodium concentration (unless the cause of SIADH is short-lived). Water restriction is the cornerstone of therapy, but if used alone, water restriction often leads to an extremely slow resolution of hy-ponatremia. Isotonic saline is ineffective and may even be counterproductive. Furosemide and other loop diuretics are often useful therapeutic adjuncts because by blocking sodium reab-sorption in the ascending limb of the loop of Henle, they interfere with the renal-concentrating mechanism, partially blocking the effect of vasopressin. Loop diuretics can be combined with oral salt or a slow infusion (approximately 15 ml/hr) of 3% saline. Oral and intravenous urea have been used extensively to treat SIADH in some parts of Europe, but experience with this agent in the United States is very limited. Demeclocycline, a tetracycline that blocks the effect of vasopressin on the collecting duct, is another therapeutic option in chronic SIADH; however, its expense and long duration of action limit its effectiveness. Several orally active vasopressin receptor blockers have been developed and are currently in clinical trials.
Persistent defects in water excretion: edematous conditions and renal failure Saline should rarely, if ever, be given to correct hyponatremia in edematous patients or patients with renal failure (except for those with prerenal azotemia). Because it has no effect on water excretion, 1 L of 0.9% saline will increase the plasma sodium concentration by only 1 mEq/L.12 In addition, saline exacerbates edema and ascites in patients with cirrhosis and may cause pulmonary edema in patients with heart failure or renal failure.
Although thiazide diuretics are contraindicated, loop diuretics are the mainstay of treatment of hyponatremia for patients with edematous conditions because they increase free-water excretion and improve hyponatremia, particularly when dietary salt intake is increased. There is a natural inclination to discontinue loop diuretics when severely edematous patients develop hyponatremia. The usual problem, however, is oliguria and diuretic resistance rather than overdiuresis; the proper response is to increase the dose of loop diuretics and restrict water intake. The combination of a loop diuretic and an angiotensin-convert-ing enzyme (ACE) inhibitor is particularly effective in patients with heart failure. The beneficial effect of an ACE inhibitor can be explained by reduced thirst and vasopressin secretion attributable to angiotensin II and by a direct effect on the hydro-osmotic effect of vasopressin, mediated by prostaglandins.
Hyponatremia in edematous conditions is mediated by vaso-pressin. Clinical trials have shown that vasopressin receptor antagonists can be effective in managing patients with hyponatremia and edema.
Treatment of hyponatremic seizures A small percentage of chronically hyponatremic patients with very low plasma sodium concentrations present with seizures. Regardless of the suspected duration or cause of the electrolyte disturbance, active seizures may be resistant to anticonvulsants alone and should be treated with hypertonic saline. The therapeutic approach is similar to that used for patients with acute water intoxication, except that even more vigilance is required to prevent an excessive increase in plasma sodium concentration once emergency measures have been discontinued.
Table 6 Causes of Hypernatremia
|
Electrolyte-free water losses |
Extrarenal |
|
Insensible loss (skin and lungs) |
|
|
Renal |
|
|
Neurogenic (central) diabetes insipidus |
|
|
Nephrogenic diabetes insipidus |
|
|
Congenital |
|
|
X-linked (V2 vasopressin receptor defect) |
|
|
Recessive (aquaporin defects) |
|
|
Acquired |
|
|
Electrolyte abnormalities: hypokalemia, hypercalcemia |
|
|
Drugs: lithium, demeclocycline, methoxyflurane |
|
|
Pregnancy (vasopressinase) |
|
|
Excess urea excretion |
|
|
Hypotonic losses |
Extrarenal |
|
Sweat |
|
|
Upper GI tract |
|
|
Osmotic cathartics |
|
|
Renal |
|
|
Glycosuria, mannitol, glycerol, diuretics |
|
|
Salt poisoning |
Oral |
|
Parenteral |
|
|
NaHCO3, 3% or 5% I.V. saline, therapeutic abortion (inadvertent 29% I.V. saline) |
|
|
Hemodialysis with hypertonic dialysate |
Complications of Therapy: Myelinolysis and Osmotic
Demyelination Syndrome
Excessive correction of chronic hyponatremia may be complicated by neurologic injury.43,48 Typically, the patient’s hypona-tremic symptoms improve as the plasma sodium concentration increases, but after a delay of one to several days, new findings emerge. The patient may become confused and may exhibit psychotic or catatonic behavior, pathologic crying, or a movement disorder. Swallowing dysfunction, progressive unrespon-siveness, and a spastic quadriparesis may develop. In severe cases, locked-in syndrome occurs—that is, the patient is awake but unable to move or respond. The stereotypical pattern of delayed neurologic deterioration after rapid correction of hypona-tremia has been named the osmotic demyelination syndrome, because these clinical features are associated with brain lesions (myelinolysis) characterized by disruption of myelin and sparing of neurons and axons.48-50 Lesions, which are best identified by magnetic resonance imaging, are typically found in the center of the basal pons (central pontine myelinolysis), but histolog-ically similar lesions may also occur in a symmetrical distribution in extrapontine areas of the brain where there is a close admixture of gray and white matter. The osmotic demyelination syndrome has been reproduced in animal studies49; these experiments have shown that the disorder is a complication of rapid correction of hyponatremia rather than the electrolyte disturbance itself. Observational studies in severely hyponatremic patients suggest that this therapeutic complication can be avoided if correction rates are maintained below 10 to 12 mEq/L/day and 18 mEq/L/48 hr. It should be emphasized that these values are limits and not goals. Because large increases in the serum sodium concentration are seldom required to relieve hypona-tremic symptoms and because unintentional excessive correction is common, the goal of therapy should be to increase serum sodium concentration by 8 mEq/L/day or less.
