Chapter 3. Disorders of Water Balance: Hyponatremia & Hypernatremia

Essentials of Diagnosis

• Hyponatremia develops due to an excess of total body water in relation to total body sodium.
• Determination of extracellular volume status and urinary indices aids in the classification of hyponatremia.

General Considerations

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.

Pathogenesis

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.

Clinical Findings

Symptoms and Signs

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.

Laboratory Findings

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.

Differential Diagnosis

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).

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.

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).

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.

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.

Glucocorticoid Deficiency

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.

Hypothyroidism

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

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.

Treatment

Euvolemic Hyponatremia

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.

Hypovolemic Hyponatremia

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

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.

Essentials of Diagnosis

• Hypernatremia develops as a result of a relative deficiency of total body water to total body sodium.
• Urinary osmolality is useful in distinguishing renal and extrarenal water loss.

General Considerations

Hypernatremia is present when the serum sodium concentration exceeds 145 mEq/L. The renal concentrating mechanism represents the first defense against hypernatremia, but thirst becomes the operant mechanism preventing hypernatremia when the renal concentrating mechanism is impaired or overwhelmed (Figure 3–1). Thirst is such an effective defense that hypernatremia typically does not develop, even in the setting of severe diabetes insipidus, unless the thirst mechanism is impaired or access to water is restricted.

As in hyponatremia, the approach to hypernatremia involves categorizing patients into low, normal, or elevated total body volumes.

Clinical Findings

Symptoms and Signs

Hypernatremia is always reflective of a hyperosmolar state. In response to hyperosmolality, water shifts from the relatively hypotonic intracellular space to the extracellular compartment resulting in decreased cellular volume. In the CNS, depending on the acuity and severity, changes in cellular volume are associated with a spectrum of neurologic symptoms. Irritability, lethargy, muscle spasticity, seizures, coma, and death may all occur. If hypernatremia develops over more than 24 hours, the brain adapts by accumulating intracellular osmolytes that act to restore cellular tonicity and volume. Chronic hypernatremia may, therefore, be less symptomatic at the same degree of hypernatremia than if it had occurred acutely. Due to the accumulation of osmolytes, chronic hypernatremia carries the attendant risk of cerebral edema if rapidly corrected.

Differential Diagnosis

Hypernatremia is also best approached systematically using an algorithm (Figure 3–4).

Hypernatremia with Low Extracellular Volume

Hypernatremia with low total body volume occurs when patients sustain losses of both sodium and water. Relatively greater losses of water than sodium result in hypernatremia. Due to decreased total body sodium, patients typically exhibit clinical signs of hypovolemia. The underlying causes of hypovolemia are similar to those seen in patients with hypovolemic hyponatremia and may occur due to either renal or extrarenal losses. The fundamental divergence that leads to hypernatremia, as opposed to hyponatremia, in this situation is the lack of sufficient water replacement.

Extrarenal loss of hypotonic fluid may occur via the skin or the gastrointestinal tract. Burned patients are particularly susceptible to loss through the skin. Gastrointestinal losses by way of protracted vomiting or diarrhea commonly lead to hypovolemic hypernatremia. Renal loss of hypotonic fluid frequently occurs due to the effect of loop diuretics but may be associated with osmotic diuresis due to glucose with severe hyperglycemia or urea associated with high protein tube feedings. Massive urinary losses are seen in some patients following the relief of a prolonged urinary tract obstruction or during the polyuric recovery phase of acute tubular necrosis.

As in hypovolemic hyponatremia, urinary electrolytes are helpful in clarifying the source of fluid loss if it is not clinically apparent.

Hypernatremia with a Normal Extracellular Volume

Hypernatremia with normal body volume occurs as the result of loss of water without loss of sodium. Without sodium loss, the signs of systemic hypovolemia are characteristically absent. Extrarenal loss of water can occur through the skin through sweating or through the respiratory tract. High environmental temperature, fever, and mechanical ventilation are common causes of euvolemic hypernatremia. Rarely, water deficits may occur due to a primary defect in thirst.

As in hypovolemic hypernatremia, euvolemic hypernatremia can occur only if water losses exceed water replacement. Extrarenal water losses are evidenced by a normally functioning renal concentrating mechanism and are, therefore, manifested by oliguria and a maximally concentrated urine (urine osmolality >700 mOsm/kg H2O).

Primary renal loss of water occurs due to diabetes insipidus, which results from either the failure to synthesize or secrete ADH (neurogenic diabetes insipidus) or the failure of urinary concentration despite adequate circulating levels of ADH (nephrogenic diabetes insipidus). Both disorders are manifested by the inability to concentrate the urine, polyuria, and secondary polydipsia.

Diabetes insipidus may occur as either a complete or partial syndrome. In complete diabetes insipidus, either circulating ADH, or the renal response to it, is absent, resulting in production of large volumes of dilute urine (urine osmolality <100 mOsm/kg H2O). Partial diabetes insipidus manifests as a less severe defect in urinary concentration. Despite massive urinary losses, in patients with an intact thirst mechanism and access to water, fluid intake is typically adequate to replace urinary losses and hypernatremia is often absent.

Diagnosis of Diabetes Insipidus

Diabetes insipidus must be considered in the differential diagnosis of any patient with polyuria and polydipsia. Polyuria due to osmotic diuresis from glucose, mannitol, urea, or diuretics can be excluded by demonstrating a urinary concentration greater than 150 mOsm/kg H2O.

Neurogenic diabetes insipidus, nephrogenic diabetes insipidus, and compulsive water drinking all present similarly with polyuria and a maximally dilute urine (urine osmolality <100 mOsm/kg H2O). A measured plasma osmolality below 270 mOsm/kg H2O strongly suggests a positive water balance and supports the diagnosis of compulsive water drinking. Conversely, a serum sodium concentration greater than 143 mEq/L or plasma osmolality >295 mOsm/kg H2O suggests diabetes insipidus and effectively excludes compulsive water drinking. Water deprivation testing is useful in differentiating difficult cases.

During the water deprivation test, patients fast to ensure that no fluid is consumed during the testing period. Urine osmolality is measured hourly, and serum osmolality is measured every 6 hours. Vital signs and body weight must be monitored closely as patients with diabetes insipidus may rapidly become volume depleted. Fluid deprivation is continued until the body weight has declined 3%, the plasma osmolality is >295 mOsm/kg H2O, or the urine osmolality is unchanged over three consecutive measurements. At this point the plasma vasopressin level is measured and, subsequently, 5 units of aqueous vasopressin is administered subcutaneously. Urinary osmolality is again measured after 60 minutes.

In patients with complete diabetes insipidus, the urine remains dilute despite water deprivation. Vasopressin levels and response to exogenous vasopressin differentiate neurogenic from nephrogenic diabetes insipidus (Table 3–3).

Neurogenic Diabetes Insipidus

Since vasopressin is produced in the hypothalamus and released from the posterior pituitary gland, any disease process involving the hypothalamic–pituitary axis may lead to vasopressin deficiency and neurogenic diabetes insipidus. Common causes include head trauma, pituitary surgery, infection, primary or metastatic malignancy, thrombosis, and granulomatous disease (Table 3–4). Congenital forms have been described but are rare. Computed tomography or magnetic resonance imaging of the hypothalamic–pituitary region may reveal the etiology of neurogenic diabetes insipidus. Normally the posterior pituitary produces a bright spot on T1-weighted images that may be characteristically absent in neurogenic diabetes insipidus.

Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus also may be acquired or congenital. Though hundreds of mutations involving the vasopressin (V2) receptor or aquaporin-2 water channel have been discovered, the acquired form is much more common. Any advanced form of chronic renal failure may result in an impairment of urinary concentrating ability, though frank polyuria is uncommon. Some forms of renal disease, listed in Table 3–5, can result in clinically significant defects in urinary concentration despite relatively preserved renal function. Various pharmacologic agents, particularly lithium and demeclocycline, are also associated with the development of nephrogenic diabetes insipidus. Electrolyte disorders and obstructive uropathy comprise most of the remaining cases.

Gestational Diabetes Insipidus

An unusual form of diabetes insipidus resistant to vasopressin has been described in pregnancy. Rather than renal insensitivity to the hormone, placentally derived circulating vasopressinase neutralizes circulating vasopressin. Desmopressin (DDAVP) is not affected by vasopressinase and is effective in treating the disease.

Hypernatremia with an Increased Extracellular Volume

Hypernatremia with an increased total body volume is the least common form of hypernatremia and is most often associated with administration of hypertonic sodium chloride or hypertonic sodium bicarbonate during resuscitative efforts. Salt water drowning, hypertonic hyperalimentation solutions, and dialysis against a high sodium content dialysate may also result in hypervolemic hypernatremia. Excess mineralocorticoid states such as occur in Cushing's syndrome and primary hyperaldosteronism can manifest with a slightly elevated total body volume and clinically insignificant hypernatremia.

Treatment

In the clinical setting, hypernatremia is preventable. Clinicians must be aware of the obligate water losses of their patients and either provide access to water or intravenous repletion. Very young, very old, restrained, and water-restricted patients are at particular risk. The importance of prevention of hypernatremia is underscored by the associated increase in mortality in patients who develop hypernatremia in the hospital setting.

Once present, appropriate therapy for hypernatremia depends on the volume status, the time course over which the hypernatremia developed, and the degree of symptomatology demonstrated by the patient. Therapy should always be guided to reverse the underlying etiology once patients are clinically stable. Acute hypernatremia occurring over less than 24 hours may be rapidly corrected as little cerebral adaptation is likely to have occurred. Chronic hypernatremia must be attended to quickly, but the serum sodium concentration should be decreased by no more that 1–2 mEq/L/hour to minimize the risk of cerebral edema.

Hypovolemic Hypernatremia

Initial therapy of severe hypernatremia and hypovolemia involves the restoration of the volume deficit with isotonic (0.9%) saline. Since the osmolality of isotonic saline is typically lower than the serum osmolality of the patient, with administration the serum sodium concentration will fall. Once signs of circulatory compromise are resolved, the remainder of the sodium and water deficit should be carefully replaced with 0.45% saline.

Euvolemic Hypernatremia

Correction of euvolemic hypernatremia requires the estimation and replacement of the water deficit. Ongoing insensible, gastrointestinal, and renal losses must also be accounted for and corrected. The water deficit is estimated from the following equation:

Symptomatic acute hypernatremia should be treated by rapid replacement of the water deficit. Once neurologic symptoms have resolved, the remainder of the deficit may be replaced over 24–48 hours.

Symptomatic chronic hypernatremia requires urgent therapy, however, the serum sodium concentration should not be allowed to decrease at a rate faster than 1 mEq/L/hour. To estimate the hourly water replacement rate the following equation may be utilized:

The water deficit may be replaced either enterally as water or intravenously as 5% dextrose in water. During treatment the serum sodium concentration and neurologic status should be monitored closely. A rapid decline in the sodium concentration or deterioration (after improvement) in neurologic status suggests the development of cerebral edema and requires temporary discontinuation of water replacement.

Patients with neurogenic diabetes insipidus and an intact thirst mechanism do not develop hypernatremia if water is available. Treatment is aimed at relieving the inconvenience of persistent polyuria and polydipsia. In the acute setting after trauma or hypophysectomy, aqueous vasopressin is preferred because of its short duration of action. Chronically, desmopressin acetate (DDAVP) is more commonly utilized due to its longer duration of action and minimal vasopressor activity. DDAVP is generally administered intranasally every 8–24 hours. but may also be administered intravenously or subcutaneously if required.

Patients with nephrogenic diabetes insipidus do not respond to exogenous vasopressin. They are consequently reliant on an intact thirst mechanism. If identifiable, correction of the underlying etiology of acquired nephrogenic diabetes insipidus may ameliorate the symptoms over time. In resistant cases, the combination of a low-salt diet and therapy with thiazide diuretics has met with some success in producing mild volume contraction and decreased urinary flow. Nonsteroidal anti-inflammatory drugs are helpful as adjunctive therapy for some patients. Amiloride may be useful in lithium-induced nephrogenic diabetes insipidus to block lithium ion uptake by the collecting duct.

Hypervolemic Hypernatremia

Hypervolemic hypernatremia requires the removal of excess sodium, which can be achieved by the administration of diuretics. Water replacement is also necessary in some cases. For those with significantly impaired renal function, dialysis can be employed.