Hyponatremia is present when the serum sodium concentration falls below 135 mEq/L. In healthy subjects, the sodium concentration is closely regulated to remain between 138 and 142 mEq/L despite wide variations in water intake (Figure 3–1). When excess water is ingested, the normal kidney dilutes the urine, excretes excess water, and prevents the development of hyponatremia. Hyponatremia develops when the intake of water exceeds the ability to excrete it leading to dilution of total body sodium.
Normal control of plasma osmolality.
Sodium concentration is the major determinant of plasma osmolality, therefore hyponatremia usually indicates a low plasma osmolality. Plasma osmolality can be estimated by the following equation:
Low plasma osmolality rather than hyponatremia, per se, is the primary cause of the symptoms of hyponatremia. Hyponatremia not accompanied by hypoosmolality does not cause signs or symptoms and does not require specific treatment.
The limitation in the kidney's ability to excrete water in hyponatremic states is, in most cases, due to the persistent action of antidiuretic hormone (ADH, vasopressin). ADH acts at the distal nephron to decrease the renal excretion of water. The action of ADH is, therefore, to concentrate the urine and, as a result, dilute the serum. Under normal circumstances, ADH release is stimulated primarily by hyperosmolality. However, under conditions of severe intravascular volume depletion or hypotension, ADH may be released even in the presence of serum hypoosmolality. Disease states characterized by a low cardiac output or systemic vasodilation result in “effective” intravascular volume depletion and may also stimulate ADH release.
Importantly, ADH alone is not sufficient to cause hyponatremia. Only when the intake of water exceeds its excretory capacity can hyponatremia result. In some cases, massive water ingestion or a defective urinary concentrating mechanism can cause hyponatremia despite the complete absence of circulating ADH.
The symptoms and signs of hyponatremia most likely result from cellular and cerebral edema. Headache, lethargy, confusion, weakness, psychosis, ataxia, seizures, and coma can all occur. Although no consistent correlation between the degree of hyponatremia and neurologic manifestations exists, patients with seizures and altered sensorium generally have serum sodium concentrations less than 120 mEq/L.
Understanding the physiology of water movement is essential to understand the symptomatology and proper treatment of the disorders of water balance. In hyponatremia, the fall in plasma osmolality causes osmotic movement of water from the hypotonic extracellular compartment into relatively hypertonic cells. When the movement of water into cells occurs rapidly and exceeds the ability of the cells to compensate, cellular edema occurs and the symptoms of hyponatremia can result. Over a period of days the cells of the brain are able to adapt to a decreased extracellular tonicity by losing osmolytes, thereby decreasing intracellular tonicity. Once cells have adapted, rapid correction of hyponatremia can leave the extracellular space relatively hypertonic. This causes water to move out of cells into the hypertonic extracellular space causing cellular dehydration. In the brain, this can lead to central pontine myelinolysis (CPM).
Consequently, acute hyponatremia developing over less than 48 hours is more likely present with typical symptoms due to the lack of complete cerebral adaptation. In contrast, hyponatremia developing over more than 48 hours, even when severe, may be entirely asymptomatic due to the adaptive capacity of the brain.
Typical clinical findings of hypovolemia include diminished skin turgor, flattened neck veins, dry mucous membranes and axillae, orthostatic hypotension, and tachycardia. In mild cases, hypovolemia may not be clinically apparent but usually results in renal sodium avidity and a urinary sodium concentration of less than 10 mEq/L. Vomiting is sometimes accompanied by metabolic alkalosis that obligates urinary bicarbonate and sodium losses, increasing the urinary sodium concentration to greater than 20 mEq/L. In this situation, hypovolemia can be confirmed by measuring the urinary chloride concentration, which is typically less than 10 mEq/L in this setting. Renal volume losses generally occur due to the administration of diuretics and result in a urinary sodium concentration greater than 10 mEq/L.
An increased extracellular volume may be evidenced by distended neck veins, pulmonary edema, ascites, or lower extremity edema. Hypervolemic hyponatremia is generally due to volume-retaining states such as congestive heart failure, cirrhosis, nephrotic syndrome, or advanced renal failure. In the absence of diuretic administration, hypervolemic hyponatremia is usually accompanied by “effective” hypovolemia and, consequently, a urinary sodium concentration less than 10 mEq/L.
Clinical determination of euvolemia is confirmed by the absence of signs of hypovolemia or hypervolemia. The urinary sodium concentration is greater than 20 mEq/L.
Hyponatremia should be approached systematically using an algorithm. The first step involves determining whether the observed hyponatremia is associated with a decreased, normal, or even elevated plasma osmolality (Figure 3–2).
Initial approach to hyponatremia.
Hyponatremia with a Normal or High Plasma Osmolality
Hyponatremia can be present in the absence of hypoosmolality when one of two situations is present. In the most common situation, osmotically active substances unable to enter the cell, such as glucose (in the absence of insulin), mannitol, or glycine (employed in hysteroscopy, laparoscopy, and transurethral resection of the prostate), cause water to move from the intracellular to the extracellular space. This water movement dilutes the extracellular sodium resulting in hyponatremia but, importantly, not hypoosmolality. Since serum tonicity does not change, symptoms of hyponatremia do not develop. When hyperglycemia is present, the underlying sodium concentration can be estimated by adding 1.6–2.4 mEq/L to the reported sodium concentration for every 100 mg/dL increase in the plasma glucose.
When present, severe hyperlipidemia or hyperproteinemia alter the usual ratio of serum water to solute. Since most clinical laboratories assume a constant ratio and perform a dilution of the serum prior to measuring sodium concentration, the serum water content is overestimated resulting in the reporting of incorrect or “pseudohyponatremia.” This error can be avoided by measuring the sodium concentration in undiluted serum using a sodium-selective electrode.
Hyponatremia with Low Plasma Osmolality and Low Urine Osmolality
Most often, hyponatremia is associated with a low plasma osmolality. In these cases, determination of the urinary osmolality allows differentiation between hyponatremia resulting from a functioning urinary diluting system that is overwhelmed by hypotonic fluid administration (urine osmolarity <100 mOsm/kg) and hyponatremia resulting from an inability to appropriately dilute the urine (urine osmolarity >100 mOsm/kg)(Figure 3–2).
Hyponatremia that develops despite normal urinary dilution is caused by excessive fluid ingestion or inadequate solute intake, or develops during the correction phase of hyponatremia.
Primary polydipsia is a common problem in psychiatric patients, particularly in those with schizophrenia. In contrast to the syndrome of inappropriate antidiuretic hormone (SIADH), primary polydipsia develops despite maximally suppressed ADH secretion and a maximally dilute urine. Though psychogenic stress may cause defects in urinary dilution, the primary cause of the hyponatremia is the ingestion of massive quantities of water that overwhelm the renal excretory capacity. Urine output in these patients is typically very high.
Subjects that ingest very little dietary solute may develop an ADH independent impairment in renal water excretion. Modest increases in water intake may lead to hyponatremia despite maximal urinary dilution. Poorly nourished, chronic beer drinkers classically develop this condition but other malnourished patients may be similarly affected.
Hyponatremia with a Low Plasma Osmolality and Elevated Urine Osmolality
When hyponatremia is associated with low plasma and elevated urinary osmolality it is useful to classify patients based on extracellular volume status (Figure 3–3). Since total body sodium content is the primary determinant of extracellular volume, patients with low, normal, or high extracellular volumes have low, normal, or high total body sodium contents, respectively. Hyponatremia occurs due to an increase in total body water relative to total body sodium.
Approach to hyponatremia with elevated urinary osmolality. (Adapted with permission from Johnson RJ, Freehaly J (editors): Comprehensive Clinical Nephrology, 2nd ed. Mosby, 2003.)
Hyponatremia with Extracellular Volume Depletion
In hypovolemic hyponatremia nonosmotic release of ADH occurs in response to hypovolemia. Despite serum hypoosmolality, circulating ADH causes urinary concentration, water retention, and hyponatremia.
A patient with hypovolemia has a deficit of total body sodium resulting from either extrarenal or renal sodium losses. Extrarenal sodium loss can occur from the gastrointestinal tract in the form of vomiting or diarrhea, skin, or through third-space fluid sequestration. Common causes of renal sodium loss occur following diuretic administration or osmotic diuresis. Rarer causes of renal sodium loss occur due to cerebral salt wasting, salt-losing nephropathy, or mineralocorticoid deficiency.
Hyponatremia with Normal Extracellular Volume
Euvolemic hyponatremia is the most common form of hyponatremia in hospitalized patients. Normally, euvolemic hyponatremia develops due to inadequate urinary dilution evidenced by an inappropriately elevated urine osmolality (urine osmolality > 100 mOsm/kg H2O).
Syndrome of Inappropriate Antidiuretic Hormone Release
SIADH is the commonest cause of euvolemic hyponatremia but remains a diagnosis of exclusion (Table 3–1).
Table 3–1. Essential Diagnostic Criteria for the Syndrome of Inappropriate Vasopressin Release (SIADH). ||Download (.pdf)
Table 3–1. Essential Diagnostic Criteria for the Syndrome of Inappropriate Vasopressin Release (SIADH).
Decreased extracellular fluid effective osmolality (<270 mOsm/kg H2O)
Inappropriate urinary concentration (>100 mOsm/kg H2O) Clinical euvolemia
Elevated urinary Na+ concentration (>20 mEq/L) under conditions of a normal salt and water intake
Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use
Under normal circumstances, in the setting of hypoosmolality and euvolemia, ADH is maximally suppressed and urine is maximally dilute. In SIADH, however, ADH is inappropriately released and the urine, consequently, is concentrated. Despite abnormal water handling, sodium regulatory mechanisms remain intact and patients do not become hypervolemic. Hypouricemia is commonly seen in SIADH due to both dilution and increased uric acid elimination.
SIADH is most commonly associated with medication administration (Table 3–2). With widespread use, selective serotonin reuptake inhibitor (SSRI) antidepressants deserve mention as frequent causative agents, particularly among the elderly. Malignancy, pulmonary or central nervous system (CNS) disease, infection, and trauma are responsible for the remainder of cases. SIADH is also been frequently described in association with human immunodeficiency virus (HIV) infection.
Table 3–2. Drugs Associated with Hyponatremia. ||Download (.pdf)
In SIADH, inappropriate urinary concentration may be due to either exogenous ADH secretion or potentiation of the effect of ADH on the nephron. Rarely, ADH is appropriately suppressed by hypoosmolality, but at an unusually low level. This “reset osmostat” has been described in the elderly, in pregnant women, and in paraplegics.
In both primary and secondary adrenal insufficiency, a deficiency of glucocorticoid is associated with elevated ADH levels and impaired water excretion. A standard cortisol stimulation test can be used to exclude glucocorticoid deficiency. If present, administration of replacement doses of glucocorticoid correct the hyponatremia.
Hyponatremia occurs in some patients with severe hypothyroidism. Though not clearly defined, ADH-dependent and ADH-independent mechanisms have been implicated. The hyponatremia associated with hypothyroidism is readily reversed by administration of levothyroxine.
Postoperative hyponatremia occurs mainly in the setting of excess infusion of hypotonic fluids following invasive procedures. Hyponatremia in the postoperative setting may also occur following the administration of isotonic fluids if serum ADH is elevated. Since sodium handling mechanisms are typically intact, excess infused sodium is excreted, water is retained, and hyponatremia results. Hyponatremia in the postoperative setting has been associated with the development of cerebral edema and catastrophic neurologic events. Premenopausal women appear to be at particular risk of developing complications.
Hyponatremia with Excess Extracellular Volume
In hypervolemic hyponatremia, both total body sodium and total body water are increased, but total body water is increased to a greater amount. Edematous disorders such as congestive heart failure, cirrhosis, and nephrotic syndrome trigger renal sodium retention and consequent hypervolemia. These disease states all have a low effective circulating arterial volume that results in excessive thirst and ADH release. The degree of hyponatremia often correlates with the severity of the disorder and is an important prognostic factor. In the absence of diuretic administration, the urinary sodium concentration is less than 10 mEq/L. Advanced acute or chronic renal failure may also be associated with hyponatremia if the intake of water exceeds the ability to excrete it.
Most commonly, euvolemic hyponatremia develops slowly and is often relatively asymptomatic. The principal risk in adapted patients is not hyponatremia, per se. Rather it is overzealous correction that either decreases the serum sodium further or increases it too quickly. Accordingly, therapy for asymptomatic patients is conservative, consisting initially of water restriction and, if possible, removal of the inciting etiology.
In most cases, restricting fluid intake to less than 1 L/24 hours will be sufficient to allow the sodium to rise slowly. Unless hypovolemia is suspected clinically, 0.9% saline should not be given empirically as it will in most cases of euvolemic hyponatremia cause the serum sodium to fall further and may precipitate neurologic symptoms.
In some patients with severely impaired urinary dilutional capacity, clinically achievable water restriction is not sufficient to correct the hyponatremia. In these patients, treatment with demeclocycline may decrease urinary concentration and allow greater ingestion of water. Vasopressin (V2-receptor) antagonists (Tolvaptan) have recently been described to promote excretion of electrolyte-free water or ‘aquaresis' thereby making them attractive treatment options for treatment of euvolemic hyponatremia. Such was described in the SALT-1 and 2 (Study of Ascending Levels of Tolvaptan in Hyponatremia) trials, performed in an outpatient setting. A combined V1/V2-receptor antagonist (Vaprisol) is currently approved for parenteral use in the US.
Rapid correction is indicated in patients with acute (<48 hours), symptomatic hyponatremia. Though safe, full correction is not necessary. Rapid correction can be achieved by the administration of hypertonic saline and concomitant furosemide.
When symptomatic, the treatment of chronic euvolemic hyponatremia is made dually challenging by the urgent need for correction and attendant risk of overrapid correction and CPM. Therapy must therefore be undertaken with caution in the intensive care unit.
Patients presenting with euvolemic hyponatremia accompanied by seizures require emergent treatment with hypertonic 3% saline at an initial rate of 1–2 mL/kg/hour. Once the serum sodium rises 10% or neurologic symptoms resolve, conservative therapy should be adopted.
Patients who are obtunded but not seizing do not require treatment with hypertonic saline. The goal in the treatment of moderately symptomatic, euvolemic hyponatremia is to force the excretion of excess total body water at a rate that will result in a safe rate of rise of the serum sodium concentration. The goal rate of rise of sodium should not exceed 1 mEq/L/hour or 12 mEq/day to minimize the risk of developing CPM. Excess total body water is estimated by the following equation:
The estimated time of correction can be calculated by dividing the desired change in sodium concentration by the goal rate of rise. Since there is no need to acutely correct the sodium concentration to a normal value, an increase in sodium concentration of 10% should be the initial goal. Division of the total body water excess by the estimated time of correction will result in the goal rate of water excretion.
Low doses of loop diuretic are used to initiate diuresis. Initially, the urinary volume, sodium, and potassium concentration should be measured hourly. Urinary, sodium, potassium, and water losses exceeding the goal rate should be corrected intravenously. The serum sodium must be monitored closely to ensure an appropriate rate of rise. If the sodium concentration increases rapidly, intravenous 5% dextrose should be given to decrease it to the desired level.
During treatment of euvolemic hyponatremia, as the underlying cause is corrected, a brisk water diuresis may result. Untreated, this rapid loss of hypotonic urine will correct the serum sodium too quickly and put the patient at increased risk of developing CPM. Water diuresis should be treated by replacing approximately 75% of the urine output with 5% dextrose (D5W) with close monitoring of the serum sodium. If the urine output is very high, water repletion alone may be impractical. In this case, the urine output can be slowed by the administration of exogenous desmopressin.
The treatment of hypovolemic hyponatremia involves removing the stimulus for ADH release by correction of the volume deficit and allowing renal excretion of excess water. In acute hyponatremia (<48 hours), developing over less than 48 hours, the brain has not had sufficient time to compensate for the extracellular hypoosmolality. Thus, acutely, cellular swelling and cerebral edema constitute the major risk. Asymptomatic patients should be treated with volume restoration with isotonic 0.9% saline. Once extracellular volume is restored, the stimulus for ADH release will be removed allowing renal excretion of water and a return to a normal sodium concentration.
The treatment of chronic hypovolemic hyponatremia is complicated by presumed cerebral adaptation to hypoosmolality and, therefore, the risk of overrapid correction of the serum sodium. When hypovolemic hyponatremia has been present for more than 48 hours or is unknown, the volume deficit should, in the absence of hemodynamic instability, be corrected slowly with 0.9% or 0.45% saline. As in euvolemic hyponatremia, the serum sodium concentration should be monitored closely and should not be allowed to rise at a rate greater than 1 mEq/L/hour or 12 mEq/L in 24 hours.
As extracellular volume is restored ADH release will be suppressed and a brisk water diuresis may result. This diuresis may result in an unsafe rise in the plasma sodium concentration and should be treated in a manner similar to the water diuresis occurring during correction of euvolemic hyponatremia.
Hypervolemic hyponatremia is generally chronic and relatively mild. Treatment involves sodium and water restriction, the use of loop diuretics, and management of the underlying disorder. V2-receptor antagonists (Tolvaptan) have been shown to promote excretion of electrolyte-free water thereby making them another option for treatment of hypervolemic hyponatremia. Furthermore, the EVEREST (Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan) and ACTIV (Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure) trial, demonstrated a significant improvement in hospitalized patients treated for acutely decompensated heart failure, in terms of clinical signs and symptoms. As expected, the most common side effects are dry mouth and increased thirst. It must be noted however, that the EVEREST trial did not show long term benefit in terms of cardiovascular events or mortality in the CHF population.
Decaux G: Treatment of symptomatic hyponatremia. Am J Med Sci 2003;326:25.