Hyponatremia

The low osmolality of the intravascular space and the relatively high osmolality of the intracellular space results in an osmotic gradient and diffusion of water into the cell. The resulting cellular edema is generally well tolerated by most tissues, except when it occurs in a confined space such as the central nervous system (CNS). The initial, rapid response to the increase in CNS cellular volume is diffusion of electrolytes and water out of the cell, which leads to a partial reduction in glial cell volume. Continuing hyponatremia over the next 48 to 72 hours generates slow diffusion of organic osmolytes, primarily large amino acids, out of the cell, thereby further reducing cell volume.⁴ Treatment of hyponatremia with intravenous fluid (IVF) may then lead to a state of relative hyperosmolality in the extracellular space with resultant diffusion of water out of the cell and continued reduction in cellular volume. This cycle creates the most serious treatment complication of hyponatremia: osmotic demyelination syndrome (otherwise known as central pontine myelinolysis).⁵

Hypernatremia

In hypernatremia, water diffuses out of the cell along the osmotic gradient, which results in loss of cellular volume. In the acute phase, electrolytes and water rapidly diffuse into the cell to partially restore cellular volume. With ongoing hypernatremia, slow redistribution of osmolytes occurs and water diffuses into the cell. With treatment, the relatively hyposmolar IVF leads to an osmotic gradient that promotes further diffusion of water into the cell. The size of the larger organic osmolytes prevents rapid diffusion out of the cell and results in the most serious treatment complication of hypernatremia: cerebral edema.^6,7

Hyponatremia

Most signs and symptoms of significant hyponatremia are related to an increase in CNS cellular volume and subsequent cerebral edema. The rapid compensatory mechanisms of the acute phase produce more obvious signs and symptoms, whereas the slow, adaptive phase of the chronic state results in minimal symptomatology.

The signs and symptoms of hyponatremia depend on both the rate of change and the absolute plasma sodium concentration. An acute fall in the serum sodium level below 120 almost always results in symptoms, whereas a more gradual decline to this level may go undetected.

Symptoms of hyponatremia include nausea, headache, and general malaise with sodium levels of 125 to 130 and lethargy, confusion, agitation, psychosis, and seizures as the sodium level falls to the range of 115 to 120; severe symptoms develop at 110 regardless of the rate of change. Severe CNS signs observed with hyponatremia include a decreased level of alertness, focal or generalized seizure activity, and signs of brainstem herniation such as unilateral dilated pupil, posturing, and respiratory arrest.⁸

Hypernatremia

The signs and symptoms of hypernatremia depend on age. Infants exhibit restlessness, tachypnea, characteristic high-pitched crying, alternating irritability and lethargy, and hypotonia. Elderly patients have nausea, weakness, altered mental status, agitation, irritability, lethargy, stupor, coma, and seizures. The severity of the CNS symptoms correlates with serum sodium levels.⁹

Hyponatremia

The differential diagnosis of hyponatremia begins with determination of serum osmolality (Fig. 164.1).⁴ Osmolality is measured by osmometry in the laboratory or is calculated according to the following formula:

Fig. 164.1 Diagnostic algorithm for hyponatremia.

CHF, Congestive heart failure; GI, gastrointestinal; Osm, osmolality; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

(Adapted from Kumar S, Berl T. Sodium. Lancet 1998;352:220-8.)

(BUN = blood urea nitrogen).

Depending on serum osmolality, the patient is classified as being either hyposmolar (plasma Osm < 275), isosmolar (275 to 290), or hyperosmolar (>290). In hyposmolar patients, clinical assessment of the patient’s volume status further differentiates hyponatremic patients as hypovolemic, euvolemic, or hypervolemic.

Hyposmolar hypovolemic hyponatremia, the most common type of hyponatremia encountered in the ED, is seen in patients with severe depletion of total body water (TBW) in excess of sodium loss.¹⁰ Urine osmolality and sodium determinations allow further narrowing of the differential diagnosis. Dilute urine (urine osmolality > 100 mOsm/kg) suggests polydipsia or beer potomania. In patients with urine osmolality greater than 100 mOsm/kg, urinary sodium levels lower than 20 mEq/L indicate an extrarenal source of the sodium and water loss. Extrarenal causes of hyponatremia include gastrointestinal problems such as vomiting or diarrhea and skin loss from severe burns. Urinary sodium levels higher than 20 mEq/L suggest a renal source of the sodium and water loss, such as sodium-losing nephropathy, hypoaldosteronism, diuretic excess, or osmotic diuresis.

Hyposmolar euvolemic hyponatremia is most commonly associated with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (Box 164.1). ADH, or vasopressin, decreases free water excretion and results in inappropriately concentrated urine (urine osmolality >100 mOsm/kg) and a urine sodium concentration higher than 20 mEq/L. SIADH may result from various malignancies, pulmonary disorders, CNS diseases, and several drugs.^11–13 Diagnostic criteria for SIADH include hyposmolar hyponatremia, inappropriately concentrated urine, and exclusion other causes of hyposmolar euvolemic hyponatremia such as hypothyroidism and adrenal insufficiency.

Hyposmolar hypervolemic hyponatremia occurs in patients retaining water in excess of sodium, which leads to an edematous state. Such patients with congestive heart failure, cirrhosis, or nephrotic syndrome retain sodium in response to a decreased effective intravascular volume, which results in a urine sodium level lower than 20 mEq/L, whereas patients with renal failure produce a urine sodium level higher than 20 mEq/L.

Isosmolar hyponatremia, or “pseudohyponatremia,” is observed when laboratory determination of the sodium concentration is affected by large molecules that increase the nonaqueous, sodium-free plasma fraction, which leads to a corresponding decrease in the concentration of sodium per unit volume of serum. The large molecules responsible for pseudohyponatremia are usually derived from a paraproteinemia (as with multiple myeloma) or from hyperlipidemia. Many newer laboratory methods for determination of sodium measure only the aqueous serum component, thereby eliminating the possibility of pseudohyponatremia.

Hyperosmolar hyponatremia commonly results from hyperglycemia. The high osmolality of the extracellular compartment secondary to high serum glucose drives water out of cells and dilutes the concentration of sodium. In the evaluation of a patient with hyperosmolar hyponatremia, a decrease in plasma sodium of 1.6 mEq/L for every 100-mg/dL increase in serum glucose provides an estimate of the degree of hyponatremia. A similar situation may also occur in patients receiving mannitol, sorbitol, or radiocontrast media.

Hypernatremia

Figure 164.2 is an algorithm for the diagnosis of hypernatremia.⁴ Hypernatremia may also be classified as hypovolemic, euvolemic, or hypervolemic.

Fig. 164.2 Diagnostic algorithm for hypernatremia.

DI, Diabetes insipidus; GI, gastrointestinal; Osm, osmolality.

(Adapted from Kumar S, Berl T. Sodium. Lancet 1998;352:220-8.)

Hypovolemic hypernatremia, the most common cause seen in the ED, results from severe depletion of TBW. Urine sodium measurement allows determination of an extrarenal or renal source of the water loss. Levels lower than 10 mEq/L suggest an extrarenal source of the water loss, such as the skin (excessive sweating or severe burns) or the gastrointestinal system (vomiting or diarrhea). Levels higher than 20 mEq/L suggest renal causes such as excessive diuretic use, osmotic diuresis, postobstructive diuresis, or intrinsic renal disease.⁶

Euvolemic hypernatremia results from water loss without solute loss, with the majority of water loss most notably being from the intracellular space. Water loss occurs from both extrarenal and renal sources. Extrarenal sources include insensible skin and respiratory loss, coupled with lack of water intake because of impaired thirst mechanisms or inability to procure fluids. Urine osmolality is typically high (>700 mOsm/kg) as a result of secretion of ADH. Urine sodium levels vary. Renal water loss occurs secondary to diabetes insipidus (DI) of central or nephrogenic origin and results in dilute urine (urine osmolality < 700 mOsm/kg). Patients with central DI produce dilute urine because of a decrease in ADH secretion from the hypothalamus; those with nephrogenic DI exhibit a decreased response to ADH at the renal tubule.⁶

Hypervolemic hypernatremia is the least common cause seen in the ED patient population. Usually iatrogenic in hospitalized patients, it is observed in the ED as a result of sodium overload from improperly prepared infant formula or home remedies, excessive use of salt tablets, and hyperaldosteronism.

Hyponatremia

Osmotic demyelination syndrome (ODS), the most serious complication of the treatment of hyponatremia, occurs when the administration of relatively hyperosmolar IVF causes intracellular water to rapidly diffuse out of CNS cells. Patients typically improve transiently after IVF administration, only to deteriorate a week after treatment. Signs and symptoms include altered mental status, dysarthria, vertigo, parkinsonism, pseudobulbar palsy, diffuse spastic hypertonia, quadriparesis, and coma. To minimize the risk for ODS, the absolute change in serum sodium over a 48-hour period must not exceed 15 to 20 mEq/L. Additional risk factors for the development of ODS include alcoholism, malnutrition, and liver transplantation.⁵

In patients with severe neurologic symptoms (seizures, coma, or respiratory arrest) and laboratory-confirmed hyposmolar hypovolemic hyponatremia, the likelihood of cerebral edema outweighs the potential risk for treatment-related ODS secondary to rapid correction of the hyponatremic state. In this clinical situation, administration of hypertonic saline (HTS, 3%) is suggested for the first 2 to 4 hours or less if the patient’s condition improves with a maximum rate of sodium correction of 1.0 to 2.0 mEq/L/hr. Seizure risk usually declines with a serum sodium correction of approximately 5 mEq/L. Patients with acute hyponatremia for less than 48 hours may tolerate more rapid correction of the sodium concentration. Hyponatremic patients with less severe symptoms usually have a more chronic condition. The risk for ODS outweighs the benefits of rapid correction in this group, and the recommended rate of sodium correction is less than 0.5 mEq/L/hr.^8,14

The following formula calculates the required volume of IVF needed to correct serum sodium to the desired level:

TBW in liters equals the patient’s mass in kilograms multiplied by a constant that depends on the patient’s gender and age (young men, 0.6; young women and elderly men, 0.5; elderly women, 0.4).¹⁵ See the “Facts and Formulas” box to determine the sodium content of 1 L of commonly used IVF.

For an 80-kg elderly man with seizures and a serum sodium level of 110 mEq/L, the goal of the emergency physician is to increase serum sodium to 115 mEq/L, with the probable effect being cessation of seizure activity. Using 3% saline, the required volume of IVF to attain a serum sodium level of 115 mEq/L is (115 − 110)(80)(0.5)/(513 − 110), which equals 0.496 L (496 mL) of 3% saline to be infused over approximately a 2- or 3-hour period.

Some authors do not endorse the use of formulas to guide the treatment of hyposmolar hyponatremic patients with seizures. Instead, they recommend an empiric IV bolus of 100 mL of 3% HTS, followed by up to two repeated doses if the seizures have not resolved, with the goal of increasing serum sodium 5 to 6 mEq/L in the first 1 to 2 hours of treatment. Monitoring of serum sodium after the second IV bolus and every 2 hours during HTS therapy is required to guide further therapy. HTS is discontinued once serum sodium levels have increased by 10 mEq/L in the first 5 hours or if the symptoms resolve. Further recommendations include avoidance of both overcorrection and an absolute increase exceeding 15 to 20 mEq/L in the first 48 hours of treatment.¹⁶

Most patients with euvolemic and hypervolemic hyponatremia require restriction of free water intake to 800 to 1000 mL/day. Patients with severe hyponatremia may need IVF to replace the total body sodium deficit.

Hypernatremia

ED management of hypernatremia requires restoration of plasma volume. The choice of IVF depends on the clinical situation, but 0.9% normal saline (NS) is appropriate in the initial resuscitative treatment phase, with subsequent conversion to a hypotonic IVF such as 0.45% NS when euvolemia is attained.

Once the serum sodium level is known, the goal rate of correction of the sodium concentration is 0.5 to 1.0 mEq/hr, not to exceed 10 mEq/L over a 24-hour period. One approach to correcting the water imbalance resulting in hypernatremia is to calculate the free water deficit and then replace the deficit over a 48-hour period under the assumption that plasma sodium increases approximately 5 mEq/L for each liter of water replaced. The free water deficit is calculated as follows:

In this formula, TBW equals patient mass (kg) multiplied by a constant that depends on the patient’s gender and age (young men, 0.6; young women and elderly men, 0.5; elderly women, 0.4). It is important to distinguish acute hypernatremia (<48 hours’ duration) from chronic hypernatremia (>48 hours’ duration) during ED management because this information has implications for the safe rate of correction of the patient’s free water deficit. Five percent dextrose in water (D₅W) and 0.45% NS are the fluids most commonly used to replace a free water deficit. Refer to the “Facts and Formulas” box for the sodium content of 1 L of commonly used IVF. The free water deficit in patients with acute hypernatremia is usually replaced over a period of 2 days, whereas the free water deficit in patients with chronic hypernatremia is usually replaced over a period of 3 days to minimize risk for the development of cerebral edema.

For a 55-kg elderly woman with somnolence and dehydration of gradual onset, normal vital signs, a serum sodium level of 158 mEq/L, and a target sodium level of 140 mEq/L, her free water deficit in liters is (158 − 140)(55)(0.4)/158, or 2.506 L (2506 mL). Therefore, she will require approximately 2.5 L of D₅W infused over a 3-day period to slowly correct her serum sodium to normal to minimize her risk for the development of cerebral edema.

Another correction method is to calculate the effect of 1 L of a given IVF on the patient’s sodium level by using the following formula and values described by Androgué and Madias (Box 164.2)⁷:

Calculation of the decrease in serum sodium for each liter of IVF administered permits close monitoring of the response to therapy. This method may facilitate changes during the course of therapy based on measured sodium levels.

The most serious complication of therapy for hypernatremia is the development of cerebral edema secondary to excessively rapid rehydration (see Box 164.2). In the chronic hypernatremic state, large organic osmolytes that slowly accumulated in CNS cells during the adaptive phase are unable to rapidly diffuse into the extracellular space when a relatively hypotonic fluid is administered.