Hypernatremia

Hypernatremia is a common clinical problem, observed in up to 2% of the general hospital population and 15% of patients admitted to the intensive care unit.^1–4 In the outpatient setting, hypernatremia is most prevalent in the geriatric patient population; in hospitalized patients, it is observed in all age groups.^1,5 Mortality rates in patients with hypernatremia can range as high as 70%.^1–6 Although the high mortality rate no doubt reflects the severity of underlying disease in these patients, there is significant morbidity related to hypernatremia itself. Neurologic sequelae from hypernatremia are common, particularly in the pediatric population.⁶

Maintaining a normal serum sodium concentration (135–145 mEq/L) is dependent on the balance between water intake and water excretion. Hypernatremia results from a deficit of free water that leads to an increase in serum tonicity. The usual mechanism underlying the development of hypernatremia is inadequate water intake and increased free water loss, but it can also result from the intake of hypertonic sodium solutions. Hypernatremia may be associated with volume depletion, euvolemia, or hypervolemia, depending on the balance of salt and water loss and intake. Sodium content is low, normal, or high, respectively, in each of these circumstances. Relative sodium and volume status has important implications for the treatment of hypernatremic patients.

The brain is particularly susceptible to the effects of hypernatremia. When the sodium concentration in plasma is higher than normal, water moves across cytosolic membranes (from the inside of cells to the outside of cells) to preserve osmotic equilibrium. As a consequence of intracellular dehydration, there is a net loss of brain volume, which in turn places mechanical stress on cerebral vessels, possibly resulting in bleeding.⁶ With chronic hypernatremia, however, cellular adaptation occurs. Under these circumstances, so-called idiogenic osmoles accumulate in brain cells, minimizing cellular dehydration. Importantly, the presence of these idiogenic osmoles presents a risk for the development of cerebral edema during the treatment of hypernatremia.

The symptoms of hypernatremia are nonspecific and often difficult to separate from those of underlying illnesses in hospitalized patients. Central nervous system (CNS) abnormalities are most common and can include confusion, weakness, and lethargy in the early stages, progressing to seizures, coma, and death in later stages. The CNS symptoms result from the movement of water out of the brain cells rather than the hypernatremia per se. Neurologic deterioration can be seen during treatment as a result of the development of cerebral edema. Signs of volume depletion or volume overload may be present, depending on the cause of the hypernatremia.

The treatment of hypernatremia is water repletion (Box 13-1). Assuming total body water is 60%, the water deficit may be estimated as follows:

The percentage of water relative to total body weight is actually closer to 50% in women and about 50% in the elderly of both genders. Treatment should be instituted at a rate that balances the risk of hypernatremia with the risk of too rapid correction, particularly in cases of chronic hypernatremia. Half the calculated deficit should be replaced within the first 12 to 24 hours at a rate of sodium concentration correction not over 2 mEq/L per hour. The remainder of the water deficit can be replaced over the next 48 hours. The rapidity of replacement should be determined by the acuteness of onset and severity of symptoms.

Neurologic status has to be closely monitored during replacement for evidence of the development of cerebral edema. Ongoing replacement of fluid and electrolyte losses is also necessary during treatment. In patients with volume depletion and hemodynamic instability associated with hypernatremia, volume replacement with isotonic saline is initially indicated. Once hemodynamic stability is achieved, water replacement can be initiated. Hypotonic saline (e.g., 0.45% saline) may be preferable to water as the replacement fluid for these patients. If hypernatremia is associated with hypervolemia (e.g., as a consequence of treatment with hypertonic saline or hypertonic sodium bicarbonate solution), treatment should be directed toward reducing sodium intake while inducing sodium loss. In these patients, diuretics can be used along with free water (5% dextrose) infusion. Dialysis may be necessary if renal failure is present.

Hyponatremia

Hyponatremia is one of the most common electrolyte abnormalities seen in hospitalized patients. It occurs in 2% to 4% of hospitalized patients and up to 30% of patients in intensive care units.^7–10 Mortality for patients with acute hyponatremia is reportedly as high as 50%, whereas mortality for those with chronic hyponatremia is 10% to 20%.^7–11

Hyponatremia is a water problem, not a sodium problem; there is always an excess of water relative to sodium when hyponatremia is present. In hyponatremia, water excretion by the kidney is impaired. Patients who are hyponatremic may be hypovolemic (water deficit and sodium deficit), euvolemic (water excess and normal sodium content), or hypervolemic (water excess and sodium excess). As is the case with hypernatremia, the patient’s volume status has implications for the treatment of hyponatremia.

In the presence of hyponatremia, there is a decrease in extracellular tonicity relative to the intracellular space. The osmotic gap causes movement of water from the extracellular space into the intracellular space and results in cell swelling. In the CNS, cellular swelling manifests as cerebral edema and results in the symptoms associated with hyponatremia. The degree of cerebral cell swelling correlates with the severity of symptoms observed. The CNS adapts to hyponatremia in two ways. First, cerebral edema causes an increase in interstitial hydrostatic pressure and results in the movement of fluid from the interstitial space into the cerebrospinal fluid (CSF), leading to some amelioration of cerebral edema, assuming normal CSF production and resorption physiology. Second, solutes are lost from cells, resulting in a decrease in intracellular osmolarity and thus movement of water out of cells. The solutes lost initially are sodium and potassium, followed by organic solutes over the next several days. Because of cerebral adaptation, the severity of neurologic symptoms is related to the acuity and magnitude of the hyponatremia. If hyponatremia develops gradually, brain cells can compensate by decreasing intracellular osmolarity through the loss of osmolytes, thereby limiting the degree of cerebral edema and resultant neurologic dysfunction. Importantly, during the correction of chronic hyponatremia, the regeneration of these osmolytes lags, and cerebral dehydration can occur with rapid correction.

In acute hyponatremia, nausea, vomiting, lethargy, and confusion can progress to coma, seizures, eventual cerebral herniation, and death.^11,12 The elderly and the young are more likely to be symptomatic from hyponatremia.⁹ Menstruating women also tend to be more symptomatic and are at greater risk for neurologic complications from acute hyponatremia.¹¹ Early in the development of hyponatremia, the symptoms are difficult to separate from those related to the underlying disease process. Hyponatremic patients who have clinically significant space-occupying lesions in the CNS should be aggressively treated. Meanwhile, efforts should be made to determine the cause of hyponatremia by assessing intravascular volume status, measuring urine output, seeking the presence of exogenous sugars or sugar alcohols (e.g., mannitol), and determining urine sodium concentration and osmolarity.

Treatment of hyponatremia is dependent on the acuteness of the hyponatremia and the presence and severity of symptoms (Box 13-2). Acute (<48 hours) or chronic (>48 hours) symptomatic hyponatremia (e.g., seizures) requires immediate therapy. However, the optimal approach for the treatment of these patients is controversial.^12–14 The controversy results from reports of the occurrence of a central demyelination syndrome associated with the correction of hyponatremia in some patients.^15–22 This syndrome appears to be more common with chronic hyponatremia (>48 hours), overcorrection of hyponatremia, large corrections (>12 to 25 mEq/L per 24 hours), and rapid correction (>1 to 2 mEq/L per hour).^19–22

The approach to the treatment of acute symptomatic hyponatremia is infusion of hypertonic saline (3%). Therapy is targeted toward resolution of symptoms or a 10% to 15% increase in serum sodium concentration. In patients with a high urine osmolarity, the addition of a loop diuretic facilitates correction of the hyponatremia by decreasing urine osmolarity. The rate of correction should be less than 2 mEq/L per hour and less than 15 mEq/L total over 24 hours. The amount of hypertonic saline necessary to correct the serum sodium concentration to a safe level (e.g., 120 mEq/L) can be estimated by calculating the sodium deficit:

The amount of hypertonic saline required to replace the deficit is then infused at a rate that permits correction within the parameters noted earlier. Frequent checking of electrolytes is necessary to ensure that correction is not too rapid.

In treating patients with chronic (>48 hours or of unknown duration) symptomatic hyponatremia (seizures, coma, impending brain herniation), the higher risk of neurologic complications related to therapy mandates a more cautious approach. As with acute hyponatremia, neurologic symptoms predominate in the clinical presentation of these patients. Initial treatment with 3% sodium chloride should be directed toward the resolution of symptoms or a 10% increase in serum sodium concentration. The increase in serum sodium concentration should be at a rate less than 1.5 mEq/L per hour initially, and the total correction should not exceed 12 mEq/L per 24 hours. Close monitoring of serum electrolytes and neurologic status is mandatory. The resolution of symptoms allows for a decrease in the rate of correction. As noted earlier, calculation of sodium deficit can be used to estimate the volume of hypertonic saline necessary for correction.

Most patients with hyponatremia are asymptomatic. Aggressive correction of serum sodium in these patients is not indicated. Treatment in asymptomatic patients is based on the underlying cause of the hyponatremia and the patient’s volume status: euvolemic, hypovolemic, or hypervolemic (edema).

The majority of chronic hyponatremic patients are euvolemic. In this group, the syndrome of inappropriate antidiuretic hormone (SIADH) is the most common diagnosis. The inappropriate (nonosmotic) presence of antidiuretic hormone impairs free water excretion by the kidney; impaired water excretion coupled with water intake results in hyponatremia. Water restriction is the mainstay of therapy for these patients. The amount of water restriction must be sufficient to achieve negative water balance (i.e., the difference between the total intake and excretion of water), or correction of hyponatremia will not occur. Therefore, all water losses (insensible losses, urinary losses, and gastrointestinal losses) must be considered when deciding on the degree of water restriction. If urine osmolarity is high, it may be necessary to decrease it to achieve a negative water balance. This can be achieved by adding a loop diuretic, but salt intake must be increased to correct for losses resulting from the increased natriuresis with diuresis. Less commonly, demeclocycline (300–600 mg twice a day), which interferes with the action of antidiuretic hormone, is used to decrease urine osmolarity. In patients with more pronounced hyponatremia, the combination of normal saline and a loop diuretic can be used to correct hyponatremia. In asymptomatic patients, the use of hypertonic saline is rarely if ever indicated.

Two new Food and Drug Administration (FDA)-approved vasopressin receptor antagonists are now available in the United States. One of these agents, tolvaptan, is selective for the vasopressin 2 (V₂) receptor. The other agent, conivaptan, is less selective and binds to both V_1A and V₂ receptors. Both are indicated for treating euvolemic hyponatremia. Tolvaptan also is indicated for the treatment of hypervolemic hyponatremia. Neither drug has been extensively studied, and the effect of treatment with these agents on hard endpoints such as mortality have not been assessed. Both drugs, however, have been investigated for the adjunctive treatment of congestive heart failure, and neither has been shown to improve mortality or morbidity.^23,24 Given the paucity of clinically meaningful outcomes, we do not recommend the use of either of these antagonists for routine therapy of hyponatremia.

Hyponatremia associated with volume depletion is a result of the loss of both sodium and water, combined with the simultaneous intake of water or hypotonic fluids. The release of antidiuretic hormone stimulated by hypovolemia inhibits the kidney’s ability to excrete water. The net result is positive water balance and hyponatremia. The treatment of hyponatremia in this setting is infusion of normal saline to correct the volume depletion. As volume status is corrected, antidiuretic hormone excretion is switched off, and the kidney excretes the excess water, correcting the serum sodium concentration. The cause of the initial sodium and water loss should also be identified and treated.

Hyponatremia associated with hypervolemia is very common and generally associated with low “effective” volume states such as (but not limited to) heart failure, cirrhosis, adrenal insufficiency, profound hypothyroidism, and nephrotic syndrome. The hallmark of these conditions is the presence of edema. The mechanism for the development of hyponatremia in these settings is diminished effective circulating volume, leading to sodium and water retention. The water retention is a result of nonosmotic antidiuretic hormone release impairing the kidney’s ability to excrete water. In this respect, the mechanism is similar to that responsible for hyponatremia associated with volume depletion. Therapy is directed toward correcting the primary disease process responsible for the decrease in effective circulating volume. Specific treatment of the hyponatremia consists of sodium and water restriction. The use of loop diuretics may facilitate free water excretion and correction of the hyponatremia; notably, thiazide diuretics may exacerbate hyponatremia and should be avoided.