Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

34. Disorders of Sodium and Water Homeostasis

Katherine Hammond Chessman and Gary R. Matzke


KEY CONCEPTS

 Images Blood volume and plasma osmolality are tightly regulated in the human body because they are essential for normal cellular function. Water balance determines the serum sodium concentration, and sodium balance determines the water status.

 Images Hypovolemic hypotonic hyponatremia is relatively common in patients taking thiazide diuretics; however, thiazide-induced hyponatremia is usually mild and relatively asymptomatic.

 Images Euvolemic (isovolemic) hyponatremia is most often caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Common causes of SIADH include some cancers, central nervous system (CNS) and pulmonary disorders, and certain drugs.

 Images Symptoms of hypo- or hypernatremia are usually neurologic and range from weakness, lethargy, restlessness, irritability, and confusion to twitching, seizures, coma, and death. Symptom severity depends on both the magnitude of the change in the serum sodium concentration and the rate at which it changes.

 Images Treatment goals in patients with either hypo- or hypernatremia should include cautious correction of the serum sodium concentration and, when appropriate, restoration of a normal extracellular fluid (ECF) volume. Too rapid correction of the serum sodium can result in cerebral edema, seizures, neurologic damage, osmotic demyelination syndrome, and possibly death. To minimize the risk of these complications, the serum sodium concentration should be corrected at a rate not to exceed 6 to 12 mEq/L (6 to 12 mol/L) in 24 hours, depending on the rate of change in the serum sodium concentration.

 Images Asymptomatic or mildly symptomatic hyponatremia should be managed conservatively with treatment directed at the underlying cause. IV infusion of 0.9% NaCl solution is most often used to correct the serum sodium concentration in patients with moderate to severe symptoms from hypovolemic hypotonic hyponatremia. A 3% NaCl infusion can be cautiously used in patients with moderate to severe symptoms and euvolemic or hypervolemic hypotonic hyponatremia (along with a loop diuretic).

 Images Hypernatremia is always hypertonic and most commonly occurs when increased water or hypotonic fluid losses are not offset by increased water intake or administration.

 Images Hypovolemic hypernatremia is relatively common in patients taking loop diuretics. After symptoms of hypovolemia are corrected with 0.9% NaCl solution, free water should be replaced.

 Images Patients with central diabetes insipidus (DI) can be treated with desmopressin acetate, with a goal to decrease urine volume to less than 2 L per day while maintaining the serum sodium concentration between 137 and 142 mEq/L (137 and 142 mmol/L). Patients with nephrogenic DI should be treated by correcting the underlying cause, when possible, and sodium restriction in conjunction with a thiazide diuretic to decrease the ECF volume by approximately 1 to 1.5 L.

 Images Edema develops as a primary defect in renal sodium handling or as a response to a decreased effective circulating volume. It is usually first detected in the feet or pretibial areas of ambulatory patients. Pulmonary edema, evidenced by auscultatory crackles, can be life threatening.

 Images Diuretics are the primary pharmacologic means for minimizing edema and improving organ function. Diuretic resistance often can be overcome by using an increased dose or by using a combination of a loop diuretic and a thiazide or thiazide-like diuretic.


Images Both blood volume and plasma osmolality are tightly regulated in the human body because they are essential for normal cellular function. Blood volume is a determinant of effective tissue perfusion which is required to deliver oxygen and nutrients to and remove metabolic waste products from tissues. Plasma osmolality, the primary determinant of which is sodium concentration, is an important determinant of intracellular fluid (ICF) volume. Maintenance of normal ICF volume is particularly critical in the brain, which is 80% water, and where alterations, especially rapid changes, can result in significant dysfunction and potentially death.

Simply put, water balance determines the serum sodium concentration, and sodium balance determines the volume status. Thus, the homeostatic mechanisms for controlling blood volume are focused on controlling sodium balance, and, in contrast, the homeostatic mechanisms for controlling plasma osmolality are focused on controlling water balance. Disorders of sodium and water homeostasis are common, caused by a variety of diseases, conditions, and drugs, and potentially serious. This chapter reviews the etiology, classification, clinical presentation, and therapy for disorders of sodium and water homeostasis.

SODIUM AND WATER HOMEOSTASIS

Hypo- and hypernatremia are syndromes of altered plasma tonicity and cell volume that reflect a change in the ratio of total exchangeable body sodium to total body water (TBW). TBW is distributed primarily into two compartments: the intracellular compartment (ICF; 60% of TBW) and the extracellular compartment or extracellular fluid (ECF; 40% of TBW). Sodium and its accompanying anions (chloride and bicarbonate) comprise more than 90% of the total osmolality of the ECF; whereas ICF osmolality is primarily determined by the concentration of potassium and its accompanying anions (mostly organic and inorganic phosphates). The intra- and extracellular sodium and potassium concentrations are maintained by the sodium–potassium–adenosine triphosphatase (Na+-K+-ATPase) pump. Most cell membranes are freely permeable to water, and thus the osmolalities of the ICF and the ECF are equal.

Effective osmoles are solutes that cannot freely cross cell membranes, such as sodium and potassium. The ECF concentration of effective osmoles determines its tonicity, which directly affects the distribution of water between the extra- and intracellular compartments. Addition of an isotonic solution (e.g., 0.9% sodium chloride [NaCl] solution) to the ECF will result in no change in intracellular volume because there will be no change in the effective ECF osmolality. However, addition of a hypertonic solution (e.g., 3% NaCl) to the ECF will result in a decrease in ICF (cell) volume, and addition of a hypotonic solution (e.g., 0.45% NaCl) to the ECF will result in an increase in cell volume. Table 34-1 summarizes the composition of commonly used IV solutions and their respective distribution into the ICF and ECF compartments following IV administration.

TABLE 34-1 Composition of Common IV Solutions

Images

Edelman’s equation defines serum sodium as a function of the total exchangeable sodium and potassium in the body and the TBW: NaS = Natotal body + Ktotal body/TBW, where NaS is the serum sodium concentration; Natotal body is the total body sodium content; Ktotal body is the total body potassium content; and TBW is the total body water in liters.1 The serum sodium concentration is tightly regulated and thus usually varies by no more than 2% to 3%. Regulation of the serum sodium concentration occurs indirectly via mechanisms that control its determinants: plasma osmolality and blood volume. The kidney regulates water excretion through a hypothalamic feedback mechanism, such that the serum osmolality remains relatively constant (275 to 290 mOsm/kg [275 to 290 mmol/kg]) despite day-to-day variations in water intake. Plasma osmolality is primarily determined by the sodium concentration, but serum glucose and blood urea nitrogen (BUN) may contribute significantly at times. Serum osmolality can be estimated as:

Images

where OsmS is the serum osmolality in mOsm/kg; NaS is the serum sodium concentration in mEq/L; GlucoseS is the serum glucose concentration in mg/dL; and BUN is the blood urea nitrogen concentration in mg/dL. Alternatively, when using SI units the equation becomes:

Images

where OsmS is the serum osmolality in mmol/kg; NaS is the serum sodium concentration in mmol/L; GlucoseS is the glucose concentration in mmol/L; and BUN is the blood urea nitrogen concentration in mmol/L.

Arginine vasopressin (AVP), commonly known as antidiuretic hormone (ADH), is synthesized in the hypothalamus and released from the posterior pituitary as a result of both osmotic and nonosmotic regulators. When the plasma osmolality increases by 1% to 2% or more AVP is released and binds to the vasopressin 2 (V2) receptors on the basolateral surface of renal tubular epithelial cells, resulting in the insertion of water channels (aquaporin 2) into the apical tubular lumen surface of the cell.2 Water can then pass through the cell into the peritubular capillary space where it is reabsorbed into the systemic circulation. As serum osmolality increases, even as little as 1%, AVP is released and thirst is stimulated. The combined effects of increased water intake and decreased water excretion (kidney’s response to AVP) result in a decrease in the serum osmolality and inhibition of further AVP secretion, once the normal plasma osmolality is restored.

Nonosmotic AVP release occurs when osmoreceptors in the brain detect a 6% to 10% reduction in the effective circulating blood volume or arterial blood pressure. The effective circulating volume is that part of the ECF responsible for organ perfusion. A decrease in the effective circulating volume (more accurately, the pressure associated with that volume) activates arterial baroreceptors in the carotid sinus and glomerular afferent arterioles, resulting in stimulation of the renin–angiotensin system and increased angiotensin II synthesis. Angiotensin II stimulates both nonosmotic AVP release and thirst. This volume stimulus can override osmotic inhibition of AVP release. Conservation of water then restores the effective circulating volume and blood pressure at the expense of producing a decreased serum osmolality and hyponatremia.2 Although hyponatremia and hypernatremia can be associated with conditions of high, low, or normal ECF sodium and volume, both conditions most commonly result from abnormalities of water homeostasis.

HYPONATREMIA

Epidemiology and Etiology

Hyponatremia, usually defined as a serum sodium concentration less than 135 mEq/L (135 mmol/L), is the most common electrolyte abnormality encountered in clinical practice in both adults and children.1,36 Although the prevalence is not well established and varies with the patient population studied, it has been estimated to be as high as 28% in patients admitted to an acute care hospital.7 Mild hyponatremia (serum sodium concentration less than 136 mEq/L [136 mmol/L]) was observed in 42.6%, while 6.2% of patients had values less than 126 mEq/L (126 mmol/L), and 1.2% had values less than 116 mEq/L (116 mmol/L). The incidence has been reported to be as high as 21% in patients seen in ambulatory hospital clinics, and 7% in community clinics.7 Drug-induced hyponatremia especially that associated with thiazide diuretics,8,9 and psychotropic medications,10,11 is common. Advancing age (older than 30 years) is also a risk factor for hyponatremia, independent of sex.7

Residents in nursing homes have a twofold higher incidence of hyponatremia than that observed in age-matched, community-dwelling individuals.3 More than 75% of these hyponatremic episodes were precipitated by increased intake of hypotonic oral or IV fluids. Similarly, ingestion of excessive fluid volumes has been identified as a key risk factor in the development of hyponatremia in marathon runners. Although women had a threefold higher rate of hyponatremia, smaller body size and longer racing time, not sex, appear to be the principal factors accounting for the increased incidence.11

Recognition of the high prevalence of hyponatremia is essential because this condition is associated with significant morbidity and mortality.2,1215 Transient or permanent brain dysfunction can result from either the acute effects of hypoosmolality or too rapid correction of hypoosmolality in patients with hyponatremia. Hyponatremia is predominantly the result of an excess of extracellular water relative to sodium because of impaired water excretion. The kidney normally has the capacity to excrete large volumes of dilute urine after ingestion of a water load. Nonosmotic AVP release, however, can lead to water retention and a drop in the serum sodium concentration, despite a decrease in both serum and intracellular osmolality. The causes of nonosmotic AVP release include hypovolemia, decreased effective circulating volume as seen in patients with chronic heart failure (HF), nephrosis, and cirrhosis. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH), a common cause of hyponatremia, is associated with some oncologic diseases, especially small cell lung cancer, and CNS damage (e.g., head trauma, meningitis). The pathophysiology, clinical features, and management of hyponatremia are detailed below.

Pathophysiology

Hyponatremia can be associated with normal, increased, or decreased plasma osmolality, depending on its cause. Figure 34-1 provides an algorithm for diagnosing patients with hyponatremia. Hyponatremia in patients with normal serum osmolality can be caused by hyperlipidemia or hyperproteinemia. This form of hyponatremia, termed pseudohyponatremia, is an artifact of a specific laboratory method (flame photometry) used to measure serum sodium concentration. This laboratory method is used rarely today, replaced by the use of ion-specific electrodes to measure the serum sodium concentration. If flame photometry is used, the serum volume will be overestimated because the elevated lipids or proteins account for a greater proportion of the total sample volume (Fig. 34-2). Because sodium is distributed in the water component of serum only, the measured serum sodium concentration will be falsely decreased. The measurement of serum osmolality, however, is not significantly affected, leading to a discrepancy between the calculated and measured serum osmolality.

Images

FIGURE 34-1 Diagnostic algorithm for the evaluation of hyponatremia. (CHF, congestive heart failure; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; UNa, urine sodium concentration [values in mEq/L are numerically equivalent to mmol/L]; Uosm, urine osmolality [values in mOsm/kg are numerically equivalent to mmol/kg].)

Images

FIGURE 34-2 Elevated lipids or proteins result in a larger discrepancy between the volume of the sample and plasma water, leading to a falsely low measurement of the serum sodium concentration when using the method of flame photometry. (SNa, serum sodium concentration [values in mEq/L are numerically equivalent to mmol/L].)

Hyponatremia associated with an increased serum osmolality, hypertonic hyponatremia, suggests the presence of excess, effective osmoles (other than sodium) in the ECF. This type of hyponatremia is most frequently encountered in patients with hyperglycemia. The elevated glucose concentration provides effective plasma osmoles, resulting in diffusion of water from the cells (ICF) into the ECF, thereby decreasing the ICF, expanding the ECF, and decreasing the serum sodium concentration. In fact, this relationship can be quantified: for every 100 mg/dL (5.6 mmol/L) increase in the serum glucose concentration, the serum sodium concentration decreases by 1.7 mEq/L (1.7 mmol/L) or 0.29 mmol/L for every 1 mmol/L decrease, and the serum osmolality increases by 2 mOsm/kg (2 mmol/kg). This correction is only a rough estimate because the decrease in the serum sodium concentration may vary significantly with any degree of hyperglycemia.15 Other substances such as mannitol, glycine, and sorbitol that do not cross cell membranes provide effective osmoles and can also cause hypertonic hyponatremia. The presence of any one of these unmeasured osmoles should be suspected in patients with hypertonic hyponatremia if there is a significant osmolal gap, defined as the difference between the measured and calculated plasma osmolality.

Hyponatremia associated with decreased plasma osmolality, hypotonic hyponatremia, is the most common form of hyponatremia and has many potential causes (see Table 34-2). Clinical assessment of ECF volume is an important step in the diagnostic evaluation of a patient with hypotonic hyponatremia. Categorization of these patients into one of three groups (decreased, increased, or clinically normal ECF volume) is essential in identifying the pathophysiologic mechanisms responsible for the hyponatremia and developing an appropriate treatment plan.

TABLE 34-2 Characteristics of Hypotonic Hyponatremic States

Images

Hypovolemic Hypotonic Hyponatremia

Most patients with ECF volume contraction lose fluids that are hypotonic relative to plasma and thus can become transiently hypernatremic. This includes patients with fluid losses caused by diarrhea, excessive sweating, and diuretics. This transient hypernatremic hyperosmolality results in osmotic AVP release and stimulation of thirst. If sodium and water losses continue, the resultant hypovolemia results in more AVP release. Patients who then drink water (a hypotonic fluid) or who are given hypotonic IV fluids retain water, and hyponatremia develops. These patients typically have a urine osmolality greater than 450 mOsm/kg (450 mmol/kg), reflecting AVP action and formation of a concentrated urine. The urine sodium concentration is less than 20 mEq/L (20 mmol/L) when sodium losses are extrarenal, as in patients with diarrhea, and greater than 20 mEq/L (20 mmol/L) in patients with renal sodium losses, as occurs with thiazide diuretic use or in adrenal insufficiency.17

Images Hypotonic hyponatremia is relatively common in patients taking thiazide diuretics.9,18 Thiazide-induced hyponatremia is usually mild and relatively asymptomatic; only occasionally is it severe and symptomatic.18Hyponatremia typically develops within 2 weeks of therapy initiation, but can occur later in therapy, particularly after dosage increases or if other causes of hyponatremia develop.18 The elderly, especially women, are at the greatest risk for thiazide diuretic-induced hyponatremia.

The mechanism of thiazide-induced hyponatremia is likely related to the balance of its direct and indirect effects. Thiazide diuretics exert their effects by blocking sodium reabsorption in the distal tubules of the renal cortex, thereby increasing sodium and water removal from the body. The resulting decrease in effective circulating volume stimulates AVP release, resulting in increased free water reabsorption in the collecting duct, as well as increased water intake because of stimulation of thirst. Hyponatremia develops when the net result of these effects is the loss of more sodium than water.

Conversely, hyponatremia occurs infrequently with loop diuretics due to their different sites of action. Loop diuretics exert their diuretic effect by blocking sodium reabsorption in the ascending limb of the loop of Henle. This action decreases medullary osmolality. Thus, when the loop diuretics decrease effective circulating volume and stimulate AVP release, less water reabsorption occurs in the collecting ducts than would occur if the osmolality of the renal medulla were normal. Thiazide diuretics do not alter medullary osmolality because their site of action is in the renal cortex not the medulla. In addition, most loop diuretics have a shorter half-life than the thiazides, and patients can usually replete the urinary sodium and water losses prior to taking the next dose, thereby minimizing AVP stimulation.

Euvolemic Hypotonic Hyponatremia

Images Euvolemic (isovolemic) hypotonic hyponatremia is associated with a normal or slightly decreased ECF sodium content and increased TBW and ECF volume. The increase in ECF volume is usually not sufficient to cause peripheral or pulmonary edema or other signs of volume overload, and thus patients appear clinically euvolemic. Euvolemic hyponatremia is most often caused by SIADH.

In SIADH, water intake exceeds the kidney’s capacity to excrete water, either because of increased AVP release via nonosmotic and/or nonphysiologic processes or enhanced sensitivity of the kidney to AVP. In patients with SIADH, the urine osmolality is generally greater than 100 mOsm/kg (100 mmol/kg), and the urine sodium concentration is usually greater than 20 mEq/L (20 mmol/L) due to the ECF volume expansion (Table 34-2).

The most common causes of SIADH include tumors such as small cell lung or pancreatic cancer, CNS disorders (e.g., head trauma, stroke, meningitis, pituitary surgery), and pulmonary disease (e.g., tuberculosis, pneumonia, acute respiratory distress syndrome). Patients with kidney and adrenal insufficiency or hypothyroidism can also present with euvolemic hyponatremia, and the evaluation of patients with suspected SIADH should always include consideration of these disorders as the etiology. A variety of drugs can cause SIADH by enhancing AVP release, the effect of AVP on the kidney, or by other unknown mechanisms10,14,15,20 (Table 34-3). The differential diagnosis of euvolemic hypotonic hyponatremia also includes primary or psychogenic polydipsia. Patients with this disorder drink more water (usually more than 20 L/day) than the kidneys can excrete as solute-free water. However, unlike in SIADH, AVP secretion is suppressed, resulting in a urine osmolality that is less than 100 mOsm/kg (100 mmol/kg). The urine sodium is typically low (less than 15 mEq/L [15 mmol/L]) as a result of dilution.11 Hyponatremia can develop even with more modest water intakes in patients who are ingesting very low-solute diets.

TABLE 34-3 Potential Causes of SIADH

Images

Hypervolemic Hypotonic Hyponatremia

Hyponatremia associated with ECF volume expansion occurs in conditions in which the kidney’s sodium and water excretion are impaired. Patients with cirrhosis, HF, or nephrotic syndrome have an expanded ECF volume and edema, but a decreased effective arterial blood volume (EABV). This decreased volume results in renal sodium retention, and eventually ECF volume expansion and edema. At the same time, there is nonosmotic stimulation of AVP release and water retention in excess of sodium retention, which perpetuates the hyponatremic state.


Clinical Controversy…

Some clinicians advocate using combinations of diuretics in cases of diuretic-resistant edema associated with nephrotic syndrome, while others prefer to use larger-than-average doses of single agents to overcome enhanced protein binding in the tubular lumen associated with proteinuria.

Clinical Presentation

Images The clinical presentation of patients with hyponatremia is summarized in Table 34-4. Patients with chronic (defined as lasting longer than 48 hours), mild hyponatremia (serum sodium concentration 125 to 134 mEq/L [125 to 134 mmol/L]) are usually asymptomatic, with hyponatremia being discovered incidentally when serum electrolytes are measured for other purposes.21 However, mild symptoms of hyponatremia are frequently unnoticed by both clinicians and patients.22 Chronic, mild hyponatremia is associated with impairment of attention, posture, and gait, all of which contribute to a substantially increased fall risk. Even “asymptomatic” patients, when formally tested, have impaired attention and gait to a degree that is comparable to symptoms seen with a blood alcohol level of 0.06% (13 mmol/L).23,24

TABLE 34-4 Clinical Presentation of Hyponatremia

Images

Patients with moderate (serum sodium concentration 115 to 124 mEq/L [115 to 124 mmol/L]), severe (serum sodium concentration 110 to 114 mEq/L [110 to 114 mmol/L]), or rapidly developing hypotonic hyponatremia often present with a range of neurologic symptoms resulting from hypoosmolality-induced brain cell swelling. Classic neurologic symptoms include nausea, malaise, headache, lethargy, restlessness, and disorientation. In severe cases, seizures, coma, respiratory arrest, brainstem herniation, and death can occur.

The presence of these symptoms and their severity depend on both the magnitude of the hyponatremia and the rate at which the hyponatremia develops. The magnitude of the hyponatremia is important because serum osmolality decreases in direct proportion to the serum sodium concentration, and water movement into brain cells increases as serum osmolality decreases. The rate of change of the serum osmolality is an important factor because brain cells are able to adjust their intracellular osmolality to minimize cellular volume changes in response to volume changes, but time is required for this adaptation to occur.25 When a decline in plasma osmolality causes water movement into brain cells, inorganic Cl and K+, and organic osmolytes, such as taurine, glutamate, and myoinositol, move out of the cells to decrease intracellular osmolality and minimize intracellular water shifts.26 Organic osmolytes, such as myoinositol, a osmotically active substances contribute substantially to controlling intracellular osmolality in the brain without directly altering cellular function.25,26 The various components of this adaptive mechanism occur over different time frames, with sodium and potassium efflux occurring within minutes to several hours and organic osmolyte efflux occurring within hours to several days.25,26 Maximal compensation for decreased plasma osmolality typically requires up to 48 hours. Thus, acute changes in plasma osmolality are more likely to be associated with symptoms. Concurrent respiratory failure and hypoxemia increase the risk of adverse neurologic outcomes because hypoxemia diminishes the brain’s capacity to actively transport solute out of cells, leading to a higher incidence of cerebral edema.25,26 Children and women have poorer clinical outcomes than adults and males, respectively. For example, post-menopausal women have a 25-fold higher risk of death or permanent neurological damage with acute hypervolemic hypotonic hyponatremia than men.27 Hyponatremia is a severe risk factor for morbidity and mortality in patients with HF and cirrhosis.2

In addition to neurologic symptoms, patients with hypovolemic hyponatremia can present with signs and symptoms of hypovolemia, including dry mucous membranes, decreased skin turgor, tachycardia, decreased jugular venous pressure, hypotension, and orthostatic hypotension. These findings often are helpful in identifying the type of hyponatremia present.

Images The brain’s adaptation to a chronic change in the plasma osmolality leads to development of neurologic symptoms if hyponatremia (hypoosmolality) is corrected too rapidly. The combination of the adaptive decrease in intracellular osmolality and rapid increase in serum osmolality results in excessive movement of water out of the brain cells and ICF volume depletion. Too rapid correction of the serum sodium concentration can lead to an acute decrease in brain cell volume, which contributes to the pathogenesis of osmotic demyelination syndrome (ODS),2,28 also known as central pontine myelinolysis, because the demyelinated lesions, which appear on magnetic resonance imaging, most often occur in the central pons; however, it can extend to extrapontine structures.1 Patients with this complication might develop hyperreflexia, para- or quadriparesis, parkinsonism, pseudobulbar palsy, locked-in syndrome (a condition in which a patient is aware and awake but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for the eyes), or death approximately 1 to 7 days after treatment.1,12,29 Patients with a significant degree of cerebral adaptation (e.g., chronic serum sodium concentration less than 110 mEq/L [110 mmol/L]) to hypotonic hyponatremia are at highest risk of developing this syndrome because these patients have lower intracellular osmolalities at the initiation of therapy, resulting in a greater decrease in intracellular volume in brain cells when the plasma osmolality is raised too rapidly.28 Other conditions that increase the risk of ODS include alcoholism, liver failure, orthotopic liver transplantation, potassium depletion, and malnutrition. Thus, if duration of hyponatremia is unknown; then it is generally safer to treat as if it is chronic when developing an initial treatment plan.1

TREATMENT

Images The following principles serve as general guidelines for the treatment of patients with hyponatremia:1,18,21,30 (a) It is important for both short- and long-term management to treat the underlying cause of hyponatremia. (b) Appropriate treatment of hypotonic hyponatremia requires balancing the risks of hyponatremia versus the risk of ODS. In general, patients who acutely developed moderate to severe hyponatremia and/or patients who have severe symptoms are at greatest risk and potentially benefit most from more rapid correction of hyponatremia. (c) Correction of hypovolemic hypotonic hyponatremia is usually best accomplished with 0.9% NaCl solution, as these patients have both sodium and water deficits. (d) Active correction of euvolemic and hypervolemic hypotonic hyponatremia in patients who do not require rapid correction is usually best accomplished by water restriction. Demeclocycline, AVP vasopression 2 receptor antagonists (vaptans), or 0.9% NaCl solution plus a loop diuretic (furosemide, bumetanide) can be used if the initial response to water restriction is not adequate. (e) In patients with severe symptoms, 3% NaCl solution (possibly combined with a loop diuretic) should initially be used to more rapidly correct the hyponatremia. A loop diuretic such as furosemide can be administered concurrently with 3% NaCl to enhance the serum sodium correction by increasing free water excretion. (f) Long-term management will be required for patients in whom the underlying cause of hyponatremia cannot be corrected. Depending on the cause, water restriction, increasing sodium intake, and/or the use of an AVP antagonist (vaptan) can be used. Application of these principles to the treatment of patients with various forms of hypotonic hyponatremia is discussed in the following sections.

Desired Outcome

Regardless of the type or cause of hyponatremia, the goals of treatment for all patients are to resolve the underlying cause of the sodium and ECF volume imbalance, if possible, and to safely correct the sodium and water derangements. The treatment plan for patients with hyponatremia depends on the underlying cause of the hyponatremia and the severity of the patient’s symptoms. Patients with an acute onset of hyponatremia or severe symptoms require more aggressive therapy to correct the hypotonicity. The initial goal for these patients is to increase plasma tonicity just enough to control severe symptoms; this typically requires only a small increase (5%) in serum sodium concentration. Once severe symptoms have abated, then continued correction of the serum sodium concentration should be achieved at a controlled rate. Patients who are asymptomatic or who have only mild to moderate symptoms do not require rapid correction of the serum sodium concentration. Treatment is dictated by the underlying etiology. In all cases the goal is to avoid an increase in the serum sodium concentration of more than 12 mEq/L (12 mmol/L) in 24 hours or 0.5 mEq/L (0.5 mmol/L) per hour.1,2,21,30 However, because of the usual uncertainty regarding duration of hyponatremia, correction of no more than 6 to 8 mEq/L (6 to 8 mmol/L) or 0.33 mEq/L/h (0.33 mmol/L/h) is prudent to avoid ODS.1

ACUTE OR SEVERELY SYMPTOMATIC HYPOTONIC HYPONATREMIA

A patient who has or is at high risk of experiencing severe symptoms caused by hyponatremia should receive either 3% NaCl (513 mEq/L [513 mmol/L]) or 0.9% NaCl (154 mEq/L [154 mmol/L]) solution until severe symptoms resolve.1,3,18,22,32 Resolution of severe symptoms frequently requires only a small (~5%) increase in serum sodium concentration; although, some clinicians suggest that the initial safe target should be a serum sodium concentration of approximately 120 mEq/L (120 mmol/L).3,33 The relative concentrations of urine sodium and potassium (osmotically effective urine cations) must be compared with those of the infusate in planning a treatment regimen for patients with hypotonic hyponatremia. For the serum sodium concentration to increase after infusion of a sodium chloride solution, the sodium concentration of the infusate must exceed the sum of the urinary sodium and potassium concentrations to produce an effective net free-water excretion.

Patients with SIADH often have urinary concentrations of osmotically effective cations that exceed the sodium concentration of 0.9% NaCl. In this case, use of isotonic sodium chloride can actually worsen hyponatremia.31 These patients should be preferentially treated with 3% NaCl solution. The relatively high urinary sodium concentration in patients with SIADH is due to ECF expansion, which minimizes sodium reabsorption along the nephron. When the urine osmolality exceeds 300 mOsm/kg (300 mmol/kg), it is generally advisable to administer an IV loop diuretic, not only to increase solute-free water excretion but also to prevent volume overload, which can result from infusion of hypertonic sodium chloride. IV furosemide, 20–40 mg every 6 hours, or bumetanide, 0.5 to 1 mg/dose every 2 to 3 hours for two doses, is generally sufficient to prevent volume overload and to decrease the urinary concentration of osmotically active cations to less than 150 mEq/L (150 mmol/L). If intermittent loop diuretic doses are not sufficient to manage edema, then continuous infusions have been used. Furosemide, 20 to 40 mg, given IV, followed by a 10 to 40 mg/h infusion, or bumetanide 1 mg given IV followed by a 0.5 to 2 mg/h infusion have been used.

Patients with hypovolemic hypotonic hyponatremia can be treated with 0.9% NaCl solution. In contrast to patients with SIADH, patients with this condition avidly reabsorb sodium throughout the nephron because the effective circulating blood volume is decreased. Thus, the urine sodium concentration is often less than 20 mEq/L (20 mmol/L), substantially less than the sodium content of 0.9% NaCl solution. While the use of 3% NaCl solution will correct hyponatremia in these patients, it will not correct the hypovolemia; thus, its use should be reserved for patients with severe symptoms requiring very rapid correction of the serum sodium concentration.

Acute hypervolemic hypotonic hyponatremia is particularly problematic to manage because the sodium and volume needed to minimize the risk of cerebral edema or seizures can worsen already compromised liver, heart, or kidney function. These patients generally should be treated with 3% NaCl and initiation of fluid (water) restriction. Loop diuretic therapy will also likely be required to facilitate urinary free water excretion.

Determination of a Sodium Chloride Infusion Regimen

Several methods for determining the correct sodium chloride solution infusion regimen for a patient with hyponatremia have been proposed.1,2,18,29,32,33 These empiric approaches provide only an initial estimate of the correct infusion regimen. More complex equations have been derived, but improved outcomes using these equations have not been demonstrated.18,29

One common approach to acute treatment of hyponatremia is to estimate the change in serum sodium concentration resulting from the infusion of 1 L of 3% or 0.9% NaCl solution. An example of this approach is shown in Box 34-1. Another method involves calculating the sodium deficit, then replacing one-third of the deficit in the first 6 hours with the remaining two thirds being replaced over the following 24 to 48 hours. Sodium deficit can be calculated using the following equation:

Images

where NaD is the goal serum sodium (usually 125 to 130 mEq/L [125 to 130 mmol/L] to avoid too rapid correction); NaS is the patient’s current serum sodium concentration; and, TBW is the patient’s current total body water calculated as shown in Box 34-1. The appropriate infusion volume for a given patient can then be estimated using the desired proportion of the estimated change that would result from a 1-L infusion or the amount of fluid needed to provide the calculated sodium deficit. The final step is to calculate an appropriate infusion rate for the calculated volume that will control the rate of increase of the serum sodium concentration to 6 to 12 mEq/L (6 to 12 mmol/L) in 24 hours (Box 34-1). Using desmopressin in combination with 3% NaCl solution to minimize the risk of treating hyponatremia has been suggested but is generally not recommended.1


BOX 34-1 Assessment and Treatment of Euvolemic Hyponatremia

Calculating the change in serum sodium concentration after an IV fluid bolus:

Images

where ΔNaS is the change in serum sodium concentration; NaIV is the sodium concentration of infusate (e.g., 154 mEq/L [154 mmol/L] for 0.9% NaCl; 513 mEq/L [513 mmol/L] for 3% NaCl); NaS is the initial serum sodium concentration; TBW is the total body water (in liters); and VolIV is the volume of infused fluid in liters

TBW can be estimated as follows:

Children and men younger than 70 years: 0.6 L/kg × wt (kg)

Men older than 70 years and women younger than 70 years: 0.5 L/kg × wt (kg)

Women older than 70 years: 0.45 L/kg × wt (kg)

Dehydrated, older patients: 0.4 L/kg × wt (kg)

where wt is the current body weight

Clinical Example

A 66-year-old woman (weight, 60 kg [132 lb]; height, 170 cm [5 ft 7 in]) presents with nausea, vertigo, and disorientation which developed over several days. Ten days ago, she began taking carbamazepine for trigeminal neuralgia. Her serum sodium concentration on admission to the emergency room was 108 mEq/L (108 mmol/L). She receives the diagnosis of SIADH.

Plan of Care

   1. Discontinue carbamazepine (the likely etiology of her SIADH)

   2. Admit to hospital for correction of hyponatremia

   3. Increase serum sodium concentration to no higher than 120 mEq/L (120 mmol/L) during the first 24 hours. Limit increase to 6 to 12 mEq/L (6 to 12 mmol/L) during first 24 hours

    4. Due to degree of hyponatremia and presence of symptoms, give 3% NaCl solution. Calculate change in serum sodium after 1 L bolus as follows:

ΔNaS = (513 mEq/L – 108 mEq/L)/[(0.5 L/kg × 60 kg) + 1 L] = 13.1 mEq/L or 1.31 mEq/100 mL

[Note: In SI units, the calculation is the same using mmol/L rather than mEq/L.]

Infusion of 1 L of 3% NaCl solution will result in a 13.1 mEq/L (13.1 mmol/L) rise in the serum sodium concentration. A 12 mEq/L (12 mmol/L) increase is desired; thus, the appropriate infusion volume is 916 mL [(12 mEq/L/13.1 mEq/L) × 1,000 mL] or [(12 mmol/L/13.1 mmol/L) × 1,000 mL]. (Note: The approach to this calculation would be similar if 0.9% NaCl was used, except that for each 1 L infusion, the expected increase in serum sodium concentration would be only 1.5 mEq/L (1.5 mmol/L), and an infusion volume of approximately 8 L would be required to achieve the targeted serum sodium concentration.)

    5. Moderate to severe symptoms: serum sodium concentration should be increased by ~1.5 mEq/L/h (1.5 mmol/L/h) over the first 2 to 4 hours of treatment for a total of 3 to 6 mEq/L [3 to 6 mmol/L] or until the symptoms have resolved. An initial infusion rate of 114 mL/h for the first 2 to 4 hours is needed.

    6. Check serum sodium concentration every 2 to 3 hours

    7. Once symptoms subside, continue infusion rate at ~23 to 31 mL/h for the next 20 to 22 hours, to slowly correct hyponatremia. Monitor serum sodium concentration every 4 hours or more often if serum sodium is rapidly changing


Clinical Controversy…

Clinicians often disagree whether or not to administer 3% NaCl to patients with symptomatic hypotonicity. Advantages of 3% NaCl include more rapid correction of serum sodium concentration with smaller infusion volumes. The disadvantage of 3% NaCl is a higher risk of too rapid correction of serum sodium concentration causing ODS. The clinician must carefully consider the cause and the rapidity of development of the patient’s hyponatremia as well as the relative risk of slower correction of the hyponatremia versus the development of ODS.

Evaluation of Therapeutic Outcomes

Patients with severely symptomatic hypotonic hyponatremia should be admitted to the intensive care unit (ICU) or other setting where frequent monitoring of neurologic and volume status is feasible. Examination of the heart, lungs, and neurologic status should be performed frequently during the initial 12 hours of therapy. The serum sodium concentration should be measured every 2 to 4 hours, and the urine osmolality, sodium, and potassium should be measured every 4 to 6 hours over the first day of therapy so that the infusion rate can be adjusted to avoid increasing the serum sodium too rapidly.1

NONEMERGENT HYPOVOLEMIC HYPOTONIC HYPONATREMIA

Most patients with hypovolemic hypotonic hyponatremia are either asymptomatic or have only mild-to-moderate symptoms so they do not require rapid correction of their hyponatremia. Many of these patients are at higher risk of developing ODS if serum sodium correction occurs too rapidly because they have chronic hyponatremia that has been maximally compensated for by the brain’s osmotic adaptation. Treatment of these patients should include correction of the underlying condition, if possible, and administration of 0.9% NaCl solution to correct hypovolemia. This solution effectively replaces the sodium and water deficits that exist in these patients, and its use carries a lower risk of an excessive rate of correction than using a 3% NaCl solution.

The ECF deficit can be estimated based on sex, change in body weight, and age. One method to estimate the ECF deficit and an example of its use is shown in Box 34-2. If the patient’s previous weight is not known, the ECF deficit can be roughly estimated based on clinical signs and symptoms. The presence of hyponatremia suggests an ECF deficit of 5% or more, whereas the presence of orthostatic hypotension suggests an ECF deficit of at least 10% to 15%. A 0.9% NaCl solution or Lactated Ringers soluton, isotonic fluids, would be optimal to correct the patient’s volume deficit because 100% of it will remain in the ECF space (Table 34-1). The overriding initial treatment goal is to restore effective circulating volume; thus, it might be necessary to infuse 0.9% NaCl at 200 to 400 mL/h until symptoms of hypovolemia improve. The infusion rate can then be decreased to 100 to 150 mL/h so that the serum sodium concentration increases by no more than 6 to 12 mEq/L (6 to 12 mmol/L) or 0.5 to 1 mEq/L/h over the initial 24 hours. Infusion of 0.9% NaCl at a rate greater than 250 mL/h should be used cautiously in patients with left ventricular dysfunction or kidney insufficiency.


BOX 34-2 Assessment and Treatment of Hypotonic Hypovolemic Hyponatremia

Images

Clinical Example

A 56-year-old woman (height, 173 cm [5 ft 8 in]; weight, 62 kg [137 lb]) was started on hydrochlorothiazide 25 mg once daily 10 days ago for hypertension. She presents with complaints of mild nausea and dizziness when she stands up. Her current weight is 55.5 kg (122 lb). Physical examination reveals dry mucous membranes and orthostatic hypotension. Her serum sodium concentration is 125 mEq/L (125 mmol/L).

Her ECF deficit can be estimated as follows:

Images

The expected increase in the serum sodium concentration following the infusion of 1 L of 0.9% NaCl can be estimated as (see Box 34-1):

ΔNaS with 1 L of infusate = [154 mEq/L – 125 mEq/L]/[(0.5 L/kg × 55.3 kg) + 1 L] = 1.0 mEq/L (mmol/L)

The patient’s serum sodium concentration will be 126 mEq/L (mmol/L) [(125 mEq/L (mmol/L) + 1 mEq/L (mmol/L)] following the infusion of 1 L 0.9% NaCl.

Treatment goals: restore effective circulating volume and correct serum sodium concentration

Treatment plan:

   1. Infuse 0.9% NaCl at 200 to 400 mL/h until symptoms of hypovolemia improve; then decrease infusion to 100 to 150 mL/h so that the serum sodium concentration increases by no more than 6 to 12 mEq/L (6 to 12 mmol/L) or 0.5 to 1 mEq/L/h (0.5 to 1 mmol/L/h) over the initial 24 hours.

   2. Hold thiazide diuretic until volume status is restored.

   3. Consider restarting diuretic at lower dose, e.g., 12.5 mg once daily.

It is important to recognize that the rate of increase in the serum sodium concentration can substantially increase once hypovolemia has been corrected if infusion rates are not adjusted appropriately.1 When the ECF volume is restored, AVP secretion will cease, and a rapid water diuresis can ensue, which can potentially result in an increase in the serum sodium concentration at a rate greater than desired. Estimation of the patient’s ECF deficit at the initiation of therapy can be helpful. If the serum sodium concentration is observed to be increasing at a rate greater than 0.5 mEq/L/h (0.5 mmol/L/h), the infusate can be changed to 0.45% NaCl, and the infusion rate set to one that slows the rate of increase in the serum sodium concentration. Caution should be exercised if 0.45% NaCl is infused alone as this solution is hypo-osmolar (osmolality is 154 mOsm/L) and may result in hemolysis. Most often, Dextrose 5%/0.45% NaCl is infused to provide an iso-osmolar solution. Potassium depletion or repletion can also affect hyponatremia and its correction. One mEq of retained potassium equals 1 mEq retained sodium; thus, if concomitant hypokalemia is corrected at the same time as the hyponatremia, too rapid correction of hyponatremia can occur.1

Evaluation of Therapeutic Outcomes

Patients presenting with evidence of volume depletion should be reexamined frequently during the initial few hours of therapy. The serum sodium concentration should be measured every 2 to 4 hours to allow timely adjustment of the rate and composition of IV fluids to avoid too rapid increase in the serum sodium concentration. IV 0.9% NaCl solution should be administered judiciously in patients with a history of HF or kidney insufficiency, with frequent cardiopulmonary assessments so that the infusion rate can be appropriately decreased at the earliest sign of pulmonary congestion.

NONEMERGENT EUVOLEMIC HYPOTONIC HYPONATREMIA

The fact that an individual’s neurological performance is restored to normal with correction of their hyponatremia provides a rationale for therapeutic management of all patients to maintain their serum sodium concentration at or above 130 mEq/L (130 mmol/L). Long-term management is thus required for patients in whom the underlying cause of hyponatremia is not readily correctable.

The treatment of SIADH always involves restricting water and correcting the underlying cause, if possible (Table 34-2). Drugs that could be contributing should be identified and discontinued. The goal of treatment is to induce negative water balance by restricting water intake to less than 1,000 to 1,200 mL/day, such that water losses from insensible sources (skin and lung) and from obligate urine and stool losses exceed intake. Daily insensible water losses via skin and lungs are approximately 900 mL/day; whereas approximately 200 mL and a minimum of 500 mL/day is lost in stool and in urine output, respectively. Because approximately 850 mL of water per day is ingested in food, and an additional 350 mL are generated from oxidative processes, this degree of water restriction should result in a negative water balance of several hundred milliliters per day. Other therapy goals include keeping the serum sodium concentration between 125 and 130 mEq/L (125 and 130 mmol/L) to prevent symptoms of hypotonicity and avoiding iatrogenic hypo- or hypervolemia.

Patients with chronic SIADH who are unable to restrict water sufficiently to maintain the serum sodium at least between 120 and 125 mEq/L (120 and 125 mmol/L) can be treated by increasing solute intake with sodium chloride and/or administration of a loop diuretic. Sodium chloride tablets increase the obligatory daily solute excretion, which augments the kidney’s capacity for water excretion. The goal is to increase the daily solute intake and excretion to approximately 900 mOsm (900 mmol) per day. Because an average diet contains approximately 600 mOsm (600 mmol), 9 g of sodium chloride would be required to increase the osmolar excretion to 900 mOsm/day (900 mmol/day) (each 1 g sodium chloride tablet contains 17 mmol of sodium and 17 mmol of chloride). Because extracellular volume expansion is an expected adverse effect, a loop diuretic should be administered concurrently to avoid pulmonary and peripheral edema. Loop diuretics also enhance water excretion by limiting the formation of the medullary concentration gradient.

Demeclocycline is another treatment option for SIADH in patients whose sodium is not adequately controlled by water restriction alone or to replace water restriction. Demeclocycline causes nephrogenic diabetes insipidus by inhibiting tubular AVP activity, resulting in increased water excretion. The usual demeclocycline dosage is 300 mg given orally two to four times daily. Because of its delayed onset of action (3 to 6 days), this agent has no role in the acute management of severe hyponatremia, and dosage adjustments should be made no more frequently than every 3 to 4 days.34 Demeclocycline should not be used in patients with liver disease or compromised fluid intake, who are at high risk for demeclocycline-induced renal tubular toxicity and acute kidney failure,34,35 in children younger than 8 years of age because it can interfere with tooth and bone development, and in pregnant women.

The usual therapeutic options of water restriction, loop diuretic therapy, and increased sodium intake have recently been augmented with the introduction of the vaptans. These agents can be used to treat SIADH, as well as other causes of euvolemic and hypervolemic hypotonic hyponatremia.34,3640 Vaptans should not be used for emergency treatment of hyponatremia or in patients with hypovolemia.

Blockade of AVP binding can occur at one or more of its three distinct AVP receptors: V1, predominantly found in the liver, CNS, and cardiomyocytes; V2, located in the distal nephron; and V3, localized in the anterior pituitary and pancreas. Selective V2 receptor antagonism prevents aquaporin-2 water channel transport to the apical surface, thereby decreasing AVP-dependent water reabsorption in the collecting duct. The inhibition of AVP activity leads to excretion of large volumes of water, decreased urine osmolality, and an increase in the serum sodium concentration.2 These positive outcomes are achieved without significantly increasing electrolyte excretion; thus, these agents also have been called “aquaretics.” While several new compounds are currently under investigation, only two vaptans are currently marketed in the United States.

Conivaptan (Vaprisol®, Astellas Pharma US, Inc., North Brook, IL), a mixed vasopressin V1- and V2-receptor antagonist, is FDA-labeled for use in the treatment of acute euvolemic hyponatremia in hospitalized patients. Its utility in the treatment of chronic hyponatremia is limited because it is available only for IV administration and is not labeled for use in patients with HF.

Tolvaptan (Samsca®, Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan) is an oral, nonpeptide selective AVP V2-receptor blocker with a greater affinity for the V2 receptor than endogenous AVP. It is FDA-labeled for use in the treatment of clinically significant (serum sodium concentration less than 125 mEq/L [125 mmol/L]) euvolemic or hypervolemic hyponatremia or less marked symptomatic hyponatremia that is unresponsive to other therapeutic interventions in patients with HF, cirrhosis, and SIADH. It appears to be safe and effective when given alone at promoting aquaresis and raising serum sodium concentration in both short- and intermediate-term studies (SALT-1 and SALT-2), respectively.40 In addition, when used alone, it is superior to furosemide or water restriction, and when given in combination with furosemide, synergistic effects have been noted.41 Tolvaptan is primarily metabolized to inactive metabolites by CYP3A4 enzymes and less than 1% is eliminated unchanged in the urine; thus clinicians should avoid its use in those receiving potent inhibitors of CYP3A4 (e.g., ketaconazole, clarithromycin, itraconazole, ritonivir). Concomitant therapy with P-glycoprotein inhibitors and grapefruit juice has also been noted to result in increased serum tolvaptan concentrations. For example, digoxin steady-state concentrations increased 20%, peak concentrations increased ~30%, and renal clearance decreased 59% when given concomitantly with tolvaptan (60 mg/day).42 Conversely, the optimal benefits of tolvaptan therapy may not be realized and its dosage may need to be increased in patients who are receiving potent CYP3A4 inducers (e.g., phenytoin, phenobarbital, St. John’s Wort). Dose linearity has been observed within the therapeutic range, and based on its terminal half-life (5 to 12 hours after 7 days or more of therapy), minimal accumulation occurs.43,44 The usual starting tolvaptan dosage is 15 mg given orally once daily. Tolvaptan has an oral bioavailabilty of about 56%. For patients who can not take tolvaptan tablets orally, the tablets can be crushed, suspended in water and administered via a nasogastric tube, but a 25% mean decrease in the tolvaptan area under the concentration-time curve has been demonstrated in healthy adults with this administration method.45 If, after 24 hours, a greater increase in serum sodium concentration is needed, the dosage may be increased to 30 mg once daily and after another 24 hours, to a maximum of 60 mg once daily. Tolvaptan therapy is contraindicated in those needing rapid correction of their serum sodium concentration, those unable to sense or respond appropriately to thirst, patients with hypovolemic hyponatremia, patients taking strong CYP3A4 inhibitors, and patients who are anuric. Among clinical trial participants who had a serum sodium concentration less than 125 mEq/L (125 mmol/L) at the start of tolvaptan therapy, the most common adverse events were thirst, dry mouth, weakness, constipation, hyperglycemia, and urinary frequency; although, these adverse events have rarely necessitated therapy discontinuation. Reversible elevations in hepatic transaminases have also been reported. However, irreversible liver damage with the potential to cause death or require a liver transplant was reported in three patients in a large clinical trial evaluating the use of tolvaptan in patients with autosomal dominant polycystic kidney disease.46 As a result of this finding, the FDA issued a warning that tolvaptan should not be used for more than 30 days, should not be used by anyone with cirrhosis, and if any sign of liver disease occurs, it should be stopped. The FDA-approved labeling includes a boxed warning stating that tolvaptan therapy should begin or resume only in a hospital where the patient’s serum sodium concentration can be closely monitored. To reduce the ODS risk, the initial FDA-approved labeling required that each patient should receive a medication guide with each prescription as part of a Risk Evaluation and Mitigation Strategy (REMS). This information is now included in the package insert given to all patients, and the medication guide is not required.

The vaptans have dramatic effects on water excretion, and the marketing of tolvaptan represented the first significant breakthrough in the therapy of hyponatremia and disorders of fluid homeostasis since the introduction of loop diuretics. However, the role of vaptans in the clinical management of patients with SIADH, HF, and cirrhosis is still unclear, especially given their cost. It is important to recognize that AVP receptor antagonists are contraindicated in patients with hypovolemia as their use would worsen the hypovolemia.

Evaluation of Therapeutic Outcomes

The serum sodium concentration should be measured every 24 to 48 hours after water restriction is initiated until it stabilizes at a concentration at or above 125 mEq/L (125 mmol/L). A continued decline in the serum sodium concentration would indicate either nonadherence to the prescribed water restriction or the need for a stricter restriction. Once the serum sodium concentration is stable at 125 mEq/L (125 mmol/L) or higher, the patient should be evaluated every 2 to 4 weeks to assess neurologic status and to obtain serum and urine sodium, potassium, and osmolality. Volume status (e.g., blood pressure, mucous membranes, skin turgor, and heart and lung examination) should also be assessed, particularly in patients who are being treated with sodium chloride tablets and/or loop diuretics.

NONEMERGENT HYPERVOLEMIC HYPOTONIC HYPONATREMIA

The initial treatment goals for patients with asymptomatic or minimally symptomatic hypotonic hyponatremia and an expanded ECF volume include achieving a negative water balance while minimizing rapid changes in cell volume until the serum sodium concentration is at or above 125 mEq/L (125 mmol/L). This involves correction of the underlying cause, when possible, as well as water restriction to an intake of less than 1,000 to 1,200 mL/day. Dietary sodium intake should be restricted to 1,000 to 2,000 mg/day, depending on the degree of ECF volume expansion and edema.

Patients with hypervolemic hypotonic hyponatremia caused by HF should be treated with measures that can potentially improve cardiac contractility and improve the effective circulating volume, thereby limiting nonosmotic AVP release. Therapeutic options include digitalis or afterload reduction with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Of these, only ACEIs have been shown in clinical trials to be of benefit in partially correcting hyponatremia in patients with HF;48 however, correction of sodium with ACEIs has not been shown to lead to better outcomes.49No specific ACEI offers any particular advantage for this indication, and the dosage should be titrated to keep the systolic blood pressure between 110 and 130 mm Hg. Dose-limiting adverse effects of ACEIs include hyperkalemia (serum potassium concentration greater than 5.5 mEq/L [5.5 mmol/L]), as well as a decline in kidney function. The benefits and risks of continuing ACEI use must be weighed carefully in each case, but a decrease in glomerular filtration rate (GFR) of less than 30% that stabilizes within 2 months of beginning ACEI therapy generally does not require ACEI dosage reduction or discontinuation.46

Other potentially treatable causes of asymptomatic hyponatremia associated with an expanded ECF volume include nephrotic syndrome and cirrhosis. ACEIs can be used to decrease proteinuria in patients with nephrotic syndrome, leading to partial correction of hypoalbuminemia and to a decrease in nonosmotic AVP release. Patients with advanced cirrhosis can benefit from placement of a transjugular intrahepatic portosystemic shunt, which can increase the effective circulating volume and thus reduce nonosmotic AVP release. This procedure can potentially exacerbate or precipitate hepatic encephalopathy and should be avoided in patients with a history of encephalopathy.

Vaptans have also been used for the treatment of hypervolemic hypotonic hyponatremia in patients with HF or cirrhosis.36,38,50,51 The effectiveness of tolvaptan use in the short-term management of patients with HF with hypervolemic hyponatremia has been evidenced by decreased body weight, increased urine output, decreased pulmonary capillary wedge pressure, and decreases in urine osmolality.5257 Long-standing beneficial effects, reduction in hospitalization or death, or progression of HF have not been observed in several pivotal trials.54,56,58 Prolonged tolvaptan use leads to an increased endogenous AVP concentration and this overstimulation of V1A receptors could lead to increased afterload and progression of HF.59 However, no worsening of left ventricular dilatation has been observed after 52 weeks of tolvaptan therapy (30 mg daily).58

Evaluation of Therapeutic Outcomes

Patients being treated for hypervolemic hypotonic hyponatremia should initially be evaluated on a daily basis for lung congestion, ascites, peripheral edema, and signs or symptoms of hyponatremia. The serum sodium concentration should be measured daily until it stabilizes at or above 125 mEq/L (125 mmol/L) following initiation of water restriction. Patients should then be assessed 1 week following discharge, and then every 2 to 4 weeks to assess compliance with the water restriction and other treatment measures, volume status, and hyponatremia-related symptoms.

HYPERNATREMIA

Epidemiology and Etiology

Images Hypernatremia, defined as a serum sodium concentration greater than 145 mEq/L [145 mmol/L], is always associated with hypertonicity and cellular dehydration, resulting from a deficit of water relative to ECF sodium content. A hypertonic state is a potent stimulus for AVP secretion and activation of the thirst mechanism. Therefore, hypernatremia is most commonly observed in patients with an impaired thirst response or in those without access to water. Young infants and children, comatose patients, the elderly, and disabled patients with an impaired sensorium or functional status are therefore at highest risk for this disorder.60 The incidence of hypernatremia in general medical–surgical hospitalized patients and patients in ICUs has been estimated to be at least 1% and 4% to 8%, respectively.6163 In 92% of 130 ICU cases, hypernatremia was iatrogenic: the result of too little free water and too much hypertonic solution along with increased renal water loss.64

Outcome in patients with hypernatremia generally depends on the severity of the decrease and the rapidity with which it developed. In children, mortality from acute hypernatremia developing in less than 72 hours ranges from 10% to 70%. In contrast, chronic hypernatremia, defined as that which develops over 3 or more days, has a mortality rate of only 10%.65 In adults, an acute increase in serum sodium concentration to greater than 160 mEq/L (160 mmol/L) is associated with a 75% mortality rate.33 In contrast to children, adults in whom hypernatremia developed at a slower rate still have a high mortality rate of approximately 60%. Hypernatremia in adults is often associated with a serious underlying illness, which likely contributes to the higher mortality rate.

Pathophysiology

Hypernatremia most often results from water loss by either renal or extrarenal mechanisms. Less commonly, hypernatremia can result from administration of hypertonic fluids or excess sodium ingestion. Patients develop hypovolemic, hypervolemic, or isovolemic hypernatremia depending on the relative magnitude of sodium and water loss or gain caused by the underlying condition (Table 34-5).

TABLE 34-5 Characteristics of Hypernatremic States

Images

Water loss commonly occurs as a result of insensible losses (evaporative water loss through the skin and lungs) in patients deprived of water. Hospitalized patients who are febrile or receiving mechanical ventilation are often treated with IV fluids containing insufficient free water to replace insensible losses. Hypernatremia can be observed in patients with hypotonic GI losses (diarrhea or vomiting) or in patients who have been exposed to high temperatures who suffer large water losses from both sweat and insensible losses.

A water diuresis can also be caused by diabetes insipidus (DI), which can be classified as either central DI (decreased AVP secretion) or nephrogenic DI (decreased kidney response to AVP). Patients with untreated DI excrete large volumes (3 to 20 L/day) of dilute urine, resulting in hypernatremia. Possible causes of DI are listed in Table 34-6.

TABLE 34-6 Causes of Diabetes Insipidus

Images

Administration of hypertonic sodium chloride can result in hypernatremia and an expanded ECF volume. This type of hypernatremia is typically iatrogenic and can follow excess sodium bicarbonate administration, use of hypertonic sodium chloride enemas, or intrauterine injection of hypertonic sodium chloride. Isotonic sodium chloride solutions can lead to sodium accumulation if dilute urine is excreted.66 Patients with hyperaldosteronism rarely spontaneously present with an expanded ECF and mild hypernatremia. A common cause of hypernatremia in the ICU is sodium intake from IV and enteral fluids and medications.67 Sodium balance should be carefully monitored in critically ill patients to avoid iatrogenic hypernatremia.

Clinical Presentation

Hypernatremia results in movement of water from the ICF to the ECF. Patients with central DI often present with sudden onset of polyuria, whereas patients with nephrogenic DI develop polyuria more gradually. Symptoms seen in patients with hypernatremia (Table 34-7) are primarily caused by a decrease in neuronal (brain) cell volume and can include weakness, lethargy, restlessness, irritability, and confusion. Symptoms of more severe or rapidly developing hypernatremia include twitching, seizures, coma, and death. As discussed in the hyponatremia section, neurons can adapt to ECF tonicity changes by adjusting ICF osmolality by decreasing or increasing the concentration of inorganic (potassium, chloride) and organic osmolytes (glutamate, taurine, and myoinositol).26 ECF hypertonicity results in generation of intracellular organic osmolytes within 24 hours of onset leading to an increase in ICF tonicity that then draws water into the neurons, limiting the decrease in cell volume. Patients with chronic hypernatremia are therefore less likely to present with symptoms compared to patients with acute onset hypernatremia.

TABLE 34-7 Clinical Presentation of Hypernatremia

Images

Hypernatremia is often associated with serious underlying illness, and signs and symptoms related to the illness are often present. Patients with a history of severe diarrhea or vomiting can present with ECF volume depletion. Elderly patients deprived of water after sustaining a stroke or hip fracture often present with mental status changes and other signs of ECF volume depletion. Clinically detectable ECF volume depletion, however, might not be evident until the serum sodium concentration exceeds 160 mEq/L (160 mmol/L) because these patients primarily have water loss, two thirds of which is derived from the ICF. The urine is concentrated, osmolality often exceeds 450 mOsm/kg (450 mmol/kg), as a result of both osmotic and nonosmotic AVP release. The first step in evaluating patients with hypernatremia is the clinical assessment of the ECF and urine volume and the serum and urine osmolality (Fig. 34-3).

Images

FIGURE 34-3 Diagnostic and treatment algorithm for hypernatremia. (D5W, 5% dextrose in water; ECF, extracellular fluid; H2O, water; Na, sodium; Uosm, urine osmolality [values in mOsm/kg are numerically equivalent to mmol/kg]; Uvol, daily urine volume.) See the text for guidelines regarding calculations of infusion rates for IV solutions.

Patients with a contracted ECF volume and a low urine output include those who have sustained insensible water losses that exceed intake, as well as those with extrarenal losses of hypotonic fluids. On physical examination, the patient will have postural hypotension, diminished skin turgor, and delayed capillary refill. The daily urine output is typically less than 1 L.

A multicenter, case–control study examined the clinical presentation of hypernatremia in 150 elderly patients in geriatric care facilities.68 Low blood pressure, tachycardia, dry oral mucosa, decreased skin turgor, and recent changes in consciousness were all more common in patients with hypernatremia than in controls. In this mixed patient population, the presence of signs of dehydration was variable, with orthostatic hypotension and decreased subclavicular and forearm skin turgor present in at least 60% of patients. Abnormal subclavicular and thigh skin turgor, dry oral mucosa, and recent change in consciousness were significantly and independently associated with hypernatremia.

Osmotic Diuresis

In the presence of an ongoing osmotic diuresis, patients will have a urine volume greater than 3 L/day. Excessive urinary excretion of glucose, sodium, urea, or an exogenously administered solute (e.g., mannitol) is identified either by history or by direct measurement of serum and urinary concentrations of the suspected solute. Patients with postobstructive diuresis, such as those with bladder outlet obstruction caused by prostatic hypertrophy, are usually volume expanded as a result of retained excess solute because of a decline in the GFR. The osmotic diuresis that follows alleviation of the obstruction is appropriate in that it promotes excretion of the excess retained solute.

Patients with severe hyperglycemia, conversely, present with signs of volume depletion, and the diuresis is inappropriate as it further exacerbates the degree of ECF volume contraction associated with hyperglycemia. The estimated serum sodium concentration can be calculated by adding 1.7 mEq/L (1.7 mmol/L) for every 100 mg/dL (5.6 mmol/L) increase in the serum glucose concentration before estimating the water deficit.3

Diabetes Insipidus

Patients with DI tend to maintain a normal ECF volume as long as they are conscious and have free access to water. Patients typically have only a slight elevation in the serum sodium concentration (usually141 to 145 mEq/L [141 to 145 mmol/L]), and a daily urine volume greater than 3 L.

A water deprivation test is sometimes recommended to aid in the differential diagnosis.33,66 This diagnostic test consists of depriving a patient of water for 8 to 12 hours. Urine osmolality, urine volume, and body weight are then measured before and after subcutaneous administration of 5 mcg of desmopressin acetate. Patients with central DI will show a prompt increase in urine osmolality to approximately 600 mOsm/kg (600 mmol/kg) and a decrease in urine volume after desmopressin administration. In those with nephrogenic DI, the urine osmolality will not increase above 300 mOsm/kg (300 mmol/kg).

The value of performing a water deprivation test in patients with polyuria and hypernatremia has recently been questioned.69 Because hypernatremia provides a maximal stimulus for AVP secretion, discriminating between nephrogenic and central DI can be based on the plasma AVP concentration and urinary response to desmopressin without the need for water deprivation. The water deprivation test is likely to be of diagnostic value only in patients with polyuria and a normal serum sodium concentration.

Sodium Overload

Patients who have ingested large amounts of sodium (more than four tablespoons table salt [1,400 mEq or 1,400 mmol sodium]) or who have received more than 5 L of hypertonic fluids are volume expanded; although this may not always be clinically evident as edema. This volume expansion results in an osmotic diuresis, polyuria, and a urine osmolality greater than 300 mOsm/kg (300 mmol/kg). The excess sodium will be excreted in the urine in patients with normal perfusion and kidney function. With organ dysfunction, volume expansion will occur.


Clinical Controversy…

The relative merits of the various drug treatment options, including NSAIDs and amiloride, for nephrogenic DI have not been well studied. Choice of agents is therefore subject to clinician preference. It is unclear if there is a significant difference among these agents in the risk of clinically important decreases in GFR when they are used to produce mild ECF volume decreases.

TREATMENT

Desired Outcome

Treatment goals for patients with hypernatremia include correcting the serum sodium concentration to 145 mEq/L (145 mmol/L) at a rate that restores and maintains brain cell volume as close to normal as possible and normalizing the ECF volume, if indicated. Adequate treatment should result in the resolution of symptoms associated with hypovolemia. Careful titration of fluids and medications should minimize the adverse effects from too rapid correction of the serum sodium concentration. Rapid correction can result in movement of excessive water into the brain cells, resulting in cerebral edema, seizures, neurologic damage, and potentially death. Restriction of dietary sodium intake and water replacement can be necessary to prevent recurrence of hypernatremia.

Physical examination with attention to volume status and measurement of serum and urine sodium concentrations and osmolalities should be completed every 2 to 3 months during chronic therapy. A 24-hour urine collection to measure urine volume and sodium excretion will help guide therapy with diuretics and determine adherence to sodium restriction.

Pharmacologic Therapy

Hypovolemic Hypernatremia

Images Patients with hypovolemic hypernatremia should be treated initially with 0.9% NaCl until hemodynamic stability is restored. An initial infusion rate of 200 to 300 mL/h will likely be appropriate for most adults; children generally receive 10 to 20 mL/kg/h. Once intravascular volume is restored, 0.45% NaCl or 5% dextrose in water (D5W) can then be infused to correct the water deficit. The ECF volume deficit can be estimated as:

Images

where TBWcurrent is the current total body water; NaS1 is the initial serum sodium concentration (in mEq/L [mmol/L]); and 140 is the normal or goal serum sodium concentration in mEq/L (mmol/L). Although this formula provides an adequate estimate of the water deficit caused by pure water loss, it underestimates the deficit in patients with hypotonic fluid loss. The formula is not useful when sodium and potassium must be prescribed in addition to water.1

The appropriate rate of correction depends on the rapidity with which the hypernatremia developed. Hypernatremia that has developed over a period of only a few hours can be initially corrected at a rate of approximately 1 mEq/L (1 mmol/L) per hour, whereas a rate of 0.5 mEq/L (0.5 mmol/L) per hour or less should be used when hypernatremia has developed more slowly.1,21 The rate of correction should generally be limited to no more than 10 to 12 mEq/L (10 to 12 mmol/L) per day.1,30

The serum sodium concentration and fluid status should be monitored every 2 to 3 hours during the first 24 hours of treatment in patients with symptomatic hypernatremia to permit appropriate adjustment of the rate of infusion of hypotonic fluids. After symptoms resolve and the serum sodium concentration is less than 148 mEq/L (148 mmol/L), serum sodium determinations every 6 to 12 hours and fluid status assessment every 8 to 24 hours are generally sufficient to monitor therapy.

Treatment of hyperglycemia-induced osmotic diuresis consists of correcting the hyperglycemia with insulin, as well as administering 0.9% NaCl until signs of ECF volume depletion resolve. Once hemodynamic stability is restored, the free water deficit should be corrected as described above.

Hypernatremia in patients undergoing a postobstructive diuresis should be treated with infusion of hypotonic fluids (e.g., 0.45% NaCl) at a maintenance rate of approximately 1.5 mL/kg per hour. Because this solution is hypotonic, care should be taken to avoid infusing it alone to prevent hemolysis. Administering fluids to replace urine output on a 1:1 volume basis tends to perpetuate the diuresis and should be avoided. Some clinicians use a 0.5:1 volume replacement to avoid this complication.

Central Diabetes Insipidus

Images Patients with central DI should generally receive AVP replacement therapy with desmopressin, an AVP analog.1,21 Because of variable absorption of orally administered desmopressin, central DI is best treated with the intranasal formulation, 1-desamino-8-D-arginine vasopressin (DDAVP); however, oral tablets are available and are useful in some patients. The initial intranasal dose should be 10 mcg once daily, titrating up to 10 mcg twice daily based on serum sodium concentration. Each insufflation of intranasal DDAVP (100 mcg/mL) delivers 10 mcg of desmopressin acetate. Additionally, several medications with antidiuretic properties have been used successfully in the management of central and nephrogenic DI (Table 34-8). They can be used as adjunctive therapy with DDAVP or as an alternative to DDAVP.

TABLE 34-8 Drugs Used to Manage Central and Nephrogenic Diabetes Insipidus

Images

The desmopressin dose should be adjusted to achieve adequate urinary concentration during sleep to prevent nocturia, a daily urine volume of approximately 1.5 to 2 L, and a serum sodium concentration between 137 and 142 mEq/L (137 and 142 mmol/L). The serum sodium concentration should be measured every 3 to 4 days during the initial dose titration period, and then every 2 to 4 months. Desmopressin administration results in nonsuppressible AVP activity and presents a risk of water intoxication with excess water retention. Patients using desmopressin should therefore be monitored for signs and symptoms of both hyponatremia and hypervolemia. It has been suggested that patients who experience water intoxication can minimize the risk of a second episode by delaying one desmopressin dose each week until polyuria and thirst develop, thus demonstrating the continued need for desmopressin therapy.21

Nephrogenic Diabetes Insipidus

In patients with nephrogenic DI, concomitant hypercalcemia and hypokalemia, if present, should be corrected, and any medications that potentially contribute to the pathogenesis should be discontinued, if possible.70,71 One key goal in treating nephrogenic DI is to induce a mild ECF deficit (1 to 1.5 L) with a thiazide diuretic and dietary sodium restriction (85 mEq [85 mmol] Na+ or 2,000 mg NaCl per day), which often can decrease urine volume by as much as 50% (Table 34-8). This ECF deficit will increase proximal tubule water reabsorption, decrease the volume of filtrate delivered to the distal nephron, and decrease urine volume. Indomethacin at a dosage of 50 mg given orally three times daily potentiates AVP activity and thus can be used as adjunctive therapy.

Sodium Overload

Treatment of sodium overload consists of administration of loop diuretics to facilitate excretion of the excess sodium and IV D5W. The volume of infusate needed to correct the water deficit and hypernatremia at an appropriate rate can be estimated as described previously. Furosemide, 20 to 40 mg given IV every 6 hours, should also be administered.

The serum sodium concentration should initially be measured at least every 2 to 4 hours, and the diuretic continued until signs of ECF volume overload (pulmonary congestion and edema) resolve. The serum sodium concentration can be determined every 6 to 12 hours once the concentration is less than 148 mEq/L (148 mmol/L) and symptoms of hypertonicity have resolved.

EDEMA

Images The development of edematous states is usually due to heart, kidney, or liver failure, or a combination of these conditions; although, it can develop secondary to a rapid decrease in serum albumin concentration along with excess fluid intake in the setting of burns or trauma.72,73 The body closely monitors blood volume to help ensure adequate tissue perfusion. A decline in the effective circulating volume (actually the blood pressure resulting from that volume) results in decreased kidney sodium and water excretion. Under these conditions, the kidneys retain all the water and sodium ingested until the effective circulating volume is restored to near normal. An increase in dietary sodium is accompanied by an increase in water intake caused by the initial increase in serum osmolality and stimulation of thirst. The resultant increase in ECF volume augments kidney perfusion, effecting a transient increase in GFR which leads to enhanced sodium filtration and excretion. These homeostatic mechanisms are crucial for maintaining sodium balance, as retention of just a few milliequivalents (mmoles) of sodium per day can eventually lead to an expanded ECF volume and edema formation.

Pathophysiology

Edema can be defined as a clinically detectable increase in interstitial fluid volume. In adults, edema formation generally requires an interstitial volume increase of at least 2.5 to 3 L. Edema develops when excess sodium is retained either as a primary defect in renal sodium excretion or as a response to a decrease in the effective circulating volume despite a normal or expanded ECF volume. An increase in the capillary hydrostatic pressure because of ECF volume expansion or an increase in central venous pressure can lead to edema formation. Edema may also occur when there is an alteration in Starling forces within the capillary.72 The Starling equation denotes the relationship between factors affecting the movement of fluid between the capillary and interstitium and is discussed in detail in Chapter 13.

Edema may develop rapidly in those with an acute decompensation in myocardial contractility which leads to an elevation in pulmonary venous pressure that is transmitted back to the pulmonary capillaries and ultimately results in acute pulmonary edema. Edema may also develop insidiously as in the case of renal sodium and water retention due to diminished effective circulating volume which leads to a rise in the ECF volume and edema formation in both peripheral and pulmonary interstitial tissues.

Edema is the classical presentation in patients with nephrotic syndrome. There are two theories posited to explain edema in nephrotic syndrome: the underfill and the overfill hypothesis.72 The underfill hypothesis states that decreased oncotic pressure from hypoalbuminemia (most pronounced with a serum albumin concentration less than 2 g/dL [20 g/L]) leads to excess filtration of fluid from the intravascular space to the interstitial space (third spacing) causing hypovolemia, kidney hypoperfusion, activation of the renin–angiotensin–aldosterone system, and secondary renal sodium retention. The overfill hypothesis is simply that primary renal sodium retention leads to edema.

Patients with cirrhosis initially develop ascites as a result of splanchnic vasodilation resulting in an increase in the pressure in the portal circulation (i.e., portal hypertension). The combination of portal hypertension and splanchnic vasodilation increases capillary pressure and permeability and facilitates the accumulation of ascites (fluid in the abdominal cavity; third spacing). Ascites can cause a decrease in effective circulating ECF volume and activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system, leading to secondary hyperaldosteronism. The subsequent renal sodium retention leads to worsened ascites and edema.72

Clinical Presentation

Edema is usually first detected in the feet or pretibial area of ambulatory patients and in the presacral area of bed-bound individuals. Edema is described as “pitting” when a depression created by exerting pressure for several seconds over a bony prominence such as the tibia does not rapidly refill. The severity of the edema should be rated on a semi-quantitative scale of 1+ to 4+ depending on the depth of the pit: 1+ = 2 mm; 2+ = 4 mm; 3+ = 6 mm; and 4+ = 8 mm.

The extent of the edema should also be quantified according to the areas involved. Pretibial edema, for example, should be quantified according to how far it extends up the lower leg (e.g., one-third up the lower leg). Pulmonary edema, an increase in lung interstitial and alveolar water, is often evidenced by crackles (rales) upon auscultation. Rales should be quantified according to how far the crackles extend from the dependent portion of the lung(s). So, for example, edema limited to the ankles and feet would indicate less severe edema than edema that extends halfway up the lower legs, and crackles limited to the base of both lungs in an upright person would indicate less severe pulmonary edema than crackles throughout both lung fields.

TREATMENT

General Approach to Treatment

The goals of therapy for hypervolemic hypernatremia are to minimize edema and to improve organ function, as well as to relieve accompanying symptoms (e.g., dyspnea, abdominal distention). Importantly, the presence of edema does not always dictate the need for pharmacologic (diuretic) therapy. Severe pulmonary edema requires immediate pharmacologic treatment because it is life-threatening. Other forms of edema may be treated gradually, with a comprehensive approach that includes not only diuretics but also sodium and water restriction and treatment of the underlying disease. Sodium intake should generally be restricted to 1,000 to 2,000 mg/day. A slow, more judicious approach in non-life–threatening situations will help to minimize complications of diuretic therapy and excessive diuresis, including impaired perfusion, azotemia, and impaired cardiac output due to a fall in the left ventricular end-diastolic filling pressure.

Pharmacologic Therapy

Images Diuretics are the primary pharmacologic therapy for edema management when treatment of the underlying disease and sodium and water restriction are insufficient to reduce the expanded ECF volume and relieve edema. Diuretics can be categorized according to the site in the nephron where sodium reabsorption is inhibited. Loop diuretics (furosemide, bumetanide, torsemide and ethacrynic acid) inhibit the sodium–potassium–chloride (Na+–K+–2Cl) carrier in the loop of Henle, while thiazide diuretics (hydrochlorothiazide, chlorthalidone, and metolazone) inhibit the Na+–Cl carrier in the distal tubule. Potassium-sparing diuretics inhibit the sodium channel in the cortical collecting duct either directly (triamterene and amiloride) or by interfering with aldosterone activity (spironolactone and eplerenone). A diuretic’s efficacy depends on: (a) the amount of filtered sodium normally reabsorbed at its site of action; (b) the amount of sodium reabsorbed distal to its site of action; (c) adequate delivery of the drug to its site of action; and (d) the amount of sodium reaching its site of action in a given patient.

All diuretics act by inhibiting sodium reabsorption in the renal tubules; thus increase fractional excretion of sodium (FeNa). Loop diuretics are the most potent diuretics, as evidenced by the fact that they increase peak FeNa from normal of 1% (0.01) or less to 20% to 25% (0.20 to 0.25). Thiazide- and potassium-sparing diuretics are less potent and increase peak FeNa only to 3% to 5% (0.03 to 0.05) and 1% to 2% (0.01 to 0.02), respectively.19 Although a large portion of the filtered sodium is reabsorbed in the proximal nephron, the efficacy of proximal-acting diuretics (e.g., acetazolamide) is limited by reabsorption of excess fluid and sodium in the loop of Henle. Furthermore, sodium reabsorption by the distal tubule can compensate for reduced reabsorption in the loop of Henle when sodium intake is high.

The effectiveness of thiazide and loop diuretics is dependent on drug concentration in the tubular lumen. These diuretics are delivered to the tubular lumen via active transport by the proximal tubular cells. Osmotic diuretics are freely filtered into the tubular lumen in the proximal tubule; whereas, spironolactone gains access to mineralocorticoid receptors in the cortical collecting duct through diffusion from the systemic circulation.

A threshold concentration of loop or thiazide diuretic must be delivered to the respective site of action to achieve a natriuresis.19 Once this concentration is achieved, a further diuretic dose increase will not elicit an increase in diuretic response. Thus, a “ceiling dose” for these diuretics is recognized. Administration of 40 mg of IV furosemide to a normal subject will result in excretion of 200 to 250 mEq (200 to 250 mmol) of sodium in 3 to 4 L of urine over a 3- to 4-hour period.19

Loop diuretics except torsemide have a rapid action but short half-life requiring administration every 2 to 3 hours while thiazide diuretics have a longer half-life allowing for less frequent (once daily) dosing. Table 34-9 lists the maximal effective doses and dosing intervals for loop diuretics in patients with cirrhosis, HF, nephrotic syndrome, and those with reduced kidney function.

TABLE 34-9 Maximal Effective Dose a and Dosing Interval for Edema Management with Loop Diuretics

Images

Patients with kidney insufficiency often require larger diuretic doses to achieve adequate drug concentrations at the site of action. The natriuretic response is decreased in patients with kidney insufficiency because the filtered sodium load falls proportionately as GFR declines. This decrease in the GFR can be partially overcome by administering diuretics more frequently or by using a continuous infusion, a method commonly used in critically ill patients. The latter will limit the effect of postdiuretic sodium retention in the distal nephron. Table 34-10 lists initial continuous infusion rates for patients based on their creatinine clearance. Patients with diuretic-resistant edema can be treated with both a loop and a thiazide-type diuretic.

TABLE 34-10 Continuous Infusion Rates for Loop Diuretics

Images

Loop diuretic resistance can be caused by pronounced sodium reabsorption in the distal sites of the nephron when sodium absorption in the loop of Henle is blocked. If sodium intake is not restricted, this distal sodium reabsorption can compensate entirely for the loop-diuretic induced sodium loss. Another mechanism of diuretic resistance is impaired diuretic delivery to the site of action. Patients with HF and a normal GFR may have impaired oral furosemide absorption. An adequate diuresis is most readily sustained by increasing the frequency of diuretic administration, but a higher dose may also be effective (Fig. 34-4). Absorption of orally administered loop diuretics can be compromised by GI edema, gastroparesis, and delayed gastric emptying, findings often seen in critically ill patients. Inadequate drug concentrations at the site of action can also be caused by decreased perfusion as might be seen in patients with decompensated HF or those with decreased kidney perfusion. Due to extensive binding to serum albumin (more than 95%), very little of these agents reach the tubule lumen by filtration, and they are almost exclusively transported into the proximal tubule lumen by active secretion via the organic acid secretory pathway.19 Human studies, however, have demonstrated that when albumin binding is inhibited by concurrent sulfasoxazole administration, diuretic resistance persists, suggesting a decrease in intrinsic tubular sensitivity to loop diuretics.75 This impaired natriuretic response can be overcome by using higher diuretic doses to increase the delivery of free drug to the secretory site in the nephron.76Decreased intrinsic diuretic activity with repeated dosing may also play a role in the development of diuretic resistance. Whether this is mediated by the first two mechanisms or as a mechanism to prevent hypovolemia is not well understood. Combinations of loop diuretics with distally acting diuretics are generally necessary to promote a natriuresis that exceeds distal tubular sodium reabsorption for those with nephrotic syndrome (Fig. 34-5).

Images

FIGURE 34-4 Therapeutic algorithm for diuretic use in patients with heart failure. (GFR, glomerular filtration rate [50 mL/min is equivalent to 0.84 mL/s]; HCTZ, hydrochlorothiazide.)

Images

FIGURE 34-5 Therapeutic algorithm for diuretic therapy in patients with nephrotic syndrome. Albumin concentration of 2 g/dL is equivalent to 20 g/L. (HCTZ, hydrochlorothiazide.)

Secondary hyperaldosteronism from activation of the renin–angiotensin–aldosterone system plays a major role in the pathogenesis of edema in patients with cirrhosis. Therefore, these patients should initially be treated with an aldosterone antagonist (e.g., spironolactone) in the absence of impaired GFR and hyperkalemia (Fig. 34-6). Thiazides can then be added for patients with a creatinine clearance greater than 50 mL/min (0.84 mL/s). For those whose edema remains diuretic resistant, a loop diuretic can be used instead of the thiazide. Patients with impaired GFR (creatinine clearance less than 40 mL/min [0.67 mL/s]) can require a loop diuretic, with addition of a thiazide in those who do not achieve adequate diuresis.73,75

Images

FIGURE 34-6 Therapeutic algorithm for diuretic use in patients with cirrhosis. (CLcr, creatinine clearance [50 mL/min is equivalent to 0.84 mL/s]; HCTZ, hydrochlorothiazide.)

Complications of loop and thiazide diuretic therapy include hypokalemia, excess ECF volume loss, calcium imbalance, hyponatremia, hypomagnesemia, metabolic alkalosis, and hyperuricemia. Patients with refractory edema treated with high-dose synergistic combinations are at high risk for developing hypokalemia.8 Thiazides can also cause hypercalcemia, particularly in patients with mild subclinical hyperparathyroidism. Loop diuretics cause hypercalciuria and can lead to bone disorders when used chronically. Chronic therapy with potassium-sparing diuretics (i.e., triamterene, amiloride, and spironolactone) can cause a mild metabolic acidosis and hyperkalemia. Patients with moderate to severe kidney dysfunction or those receiving nonsteroidal antiinflammatory drugs (NSAIDs), ACEIs, or angiotensin receptor blockers are at highest risk for hyperkalemia. In addition, spironolactone can cause reversible gynecomastia in about 10% of men receiving it, and in about 50% of men receiving 150 mg/day or more. This side effect, however, has not been associated with eplerenone, another aldosterone antagonist.77

EVALUATION OF THERAPEUTIC OUTCOMES

Patients should be monitored by careful history and intermittent physical examinations to detect signs and symptoms of edema as well as adverse effects of treatment. Physical examination should include measurement of blood pressure and pulse in either supine or seated positions and after standing for 2 to 3 minutes. ECF volume can be estimated based on the height of the jugular venous pressure, extent of edema, auscultation of the heart and lungs, and skin turgor. Follow-up monitoring (10 to 14 days after therapy initiation) should include determinations of serum sodium, potassium, chloride, bicarbonate, magnesium, calcium, BUN, serum creatinine, and uric acid. A new steady state will have developed over that time period and further fluctuations in ECF volume and electrolyte balance generally do not occur in the absence of a change in clinical status, diuretic dosage, or dietary intake. Repeated blood tests are not necessary at every visit unless there is a change in the patient’s clinical status.

ABBREVIATIONS

Images

REFERENCES

    1. Androgué HJ, Madias NE. The challenge of hyponatremia. J Am Soc Nephrol 2012;23:1140–1148.

    2. Schrier RW. The science behind hyponatremia and its clinical manifestations. Pharmacotherapy 2011;31(5 Pt 2):9S–17S.

    3. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med 2006;119(7A):S30–S35.

    4. Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia. Semin Nephrol 2009;29(3):227–238.

    5. Patterson JH. The impact of hyponatremia. Pharmacother 2011;31 (5 Pt 2):5S–8S.

    6. Hoorn EJ, Geary D, Robb M, Halperin ML, Bohn D. Acute hyponatremia related to intravenous fluid administration in hospitalized children: an observational study. Pediatr 2004;113:1279–1284.

    7. Hawkins RC. Age and gender as risk factors for hyponatremia and hypernatremia. Clin Chim Acta 2003;337:169–172.

    8. Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part II: Electrolyte and acid-base disorders complicating diuretic therapy. Expert Opin Drug Saf 2010;9:259–273.

    9. Chow KM, Szeto CC, Wong, TY-H, et al. Risk factors for thiazide-induced hyponatremia. Q J Med 2003;96:911–917.

   10. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin reuptake inhibitors in older adults. Ann Pharmacother 2006;40:1618–1622.

   11. Meulendijks D, Mannesse CK, Jansen PA, et al. Antipsychotic-induced hyponatremia: A systematic review of the published evidence. Drug Saf 2010;33:101–114.

   12. Almond CSD, Shin AY, Fortescue EB, et al. Hyponatremia among runners in the Boston Marathon. N Engl J Med 2005;352:1550–1556.

   13. Koczmara C, Wade AW, Skippen P, et al. Hospital-acquired acute hyponatremia and reports of pediatric deaths. Dynamics 2010;21:21–26.

   14. Asadollahi K, Beeching N, Gill G. Hyponatremia as a risk factor for hospital mortality. Q J Med 2006;99:877–880.

   15. Kacprowicz RF, Lloyd JD. Electrolyte complications of malignancy. Emerg Med Clin North Am 2009;27:257–269.

   16. Nzerue CM, Baffoe-Bonnie H, You W, et al. Predictors of outcome in hospitalized patients with severe hyponatremia. J Natl Med Assoc 2003;95:335–343.

   17. Kurtz I, Nguyen MK. Evolving concepts in the quantitative analysis of the determinants of the plasma water sodium concentration and the pathophysiology and treatment of dysnatremias. Kidney Int 2005;68:1982–1993.

   18. Reynolds RM, Seckl JR. Hyponatremia for the clinical endocrinologist. Clin Endocrinol 2005;63:366–374.

   19. Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part I: Mechanisms of action, pharmacological effects and clinical indications of diuretic compounds. Expert Opin Drug Saf 2010;9:243–257.

   20. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008;52:144–153.

   21. Reynolds RM, Padfield PL, Seckl JR. Disorders of sodium balance. BMJ 2006;332:702–705.

   22. Decaux G. Is asymptomatic hyponatremia really asymptomatic? Am J Med 2006;119(7A):S79–S82.

   23. Kinsella S, Moran S, Sullivan MO, et al. Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin J Am Soc Nephrol 2010;5:275–280.

   24. Ayus JC, Morits ML. Bone disease as a new complication of hyponatremia: Moving beyond brain injury. Clin J Am Soc Nephrol 2010;5:167–168.

   25. Sterns RH, Silver SM. Brain volume regulation in response to hypoosmolality and its correction. Am J Med 2006;119(7A):S12–S16.

   26. Fisher SK, Heacock AM, Keep RF, Foster DJ. Receptor regulation of osmolyte homeostasis in neural cells. J Physiol 2010;18:3355–3364.

   27. Ayus JC, Arrief AI. Chronic hyponatremic encephalopathy in post-menopausal women—Association of therapies with morbidity and mortality. JAMA 1999;281:2299–2304.

   28. Murase TM, Sugimura Y, Takefuji S, et al. Mechanisms and therapy of osmotic demyelination. Am J Med 2006;119(7A): S69–S73.

   29. Nguyen MK, Kurtz I. A new quantitative approach to the treatment of the dysnatremias. Clin Exp Nephrol 2003;7:125–137.

   30. Ellison DH. Core curriculum in nephrology: Disorders of sodium and water. Am J Kidney Dis 2005;46:356–361.

   31. Decaux G, Soupart A. Treatment of symptomatic hyponatremia. Am J Med Sci 2003;326:25–30.

   32. Kraft MD, Btaiche IF, Sacks GS, Kudsk KA. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Health Syst Pharm 2005;62:1663–1682.

   33. Liamis G, Kalogirou M, Saugos V, Moses E. Therapeutic approach in patients with dysnatremias. Nephrol Dial Transplant 2006;21:1564–1569.

   34. Cawley MJ. Hyponatremia: current treatment strategies and the role of vasopressin antagonists. Ann Pharmacother 2007;41:840–850.

   35. Curtis NJ, van Heyningen C, Turner JJ. Irreversible nephrotoxicity from demeclocycline in the treatment of hyponatremia. Age Ageing 2002;31:151–152.

   36. Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006;69:2124–2130.

   37. Palm CP, Pistrosch F, Herbrig K, Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Am J Med 2006;119(7A):S87–S92.

   38. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099–2112.

   39. Oghlakian G, Klapholz M. Vaospressin and vasopressin receptor antagonists in heart failure. Cardiol Rev 2009; 17:10–15.

   40. Costello-Boerrigter LC, Boerrigter G, Burnett JC. Pharmacology of vasopressin antagonists. Heart Fail Rev 2009;14:75–82.

   41. Shoaf SE, Graumer SL, Briemont P, et al. Pharmacokinetic and pharmacodynamic interaction between tolvaptan, an ono-peptide AV antagonist and furosemide or hydrochlorthiazide. J Cardiovasc Pharmacol 2007;50:213–222.

   42. Shoaf SE, Ohzone Y, Ninomiya S, et al. In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan and digoxin in healthy subjects. J Clin Pharmacol 2011:51:761–769.

   43. Hauptman PJ, Zimmer C, Udelson J, et al. Comparison of two doses and dosing regimens of tolvaptan in congestive heart failure. J Cardiolvasc Pharmacol 2005;46:609–614.

   44. Ambrosy A, Goldsmith SR, Gheorghiade M. Tolvaptan for the treatment of heart failure: A review of the literature. Exp Opin Pharmacother 2011;12:961–976.

   45. McNeely EB, Talameh JA, Adams Jr KF, et al. Relative bioavailability of tolvaptan administered via nasogastric tube and tolvaptan tablets swallowed intact. Am J Health-Syst Pharm 2013;70:1230–1237.

   46. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. NEJM 2012;367:2407–2418.

   47. Elisaf M, Theodorou J, Pappas C, Siamopoulos K. Successful treatment of hyponatremia with angiotensin-converting enzyme inhibitors in patients with congestive heart failure. Cardiology 1995;86:477–480.

   48. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevation of creatinine: Is this a cause for concern? Arch Intern Med 2000;160:685–693.

   49. Baldasseroni S, Urso R, Orso F, et al. Relation between serum sodium levels and prognosis in outpatients with chronic heart failure: neutral effect of treatment with beta-blockers and angiotensin-converting enzyme inhibitors: data from the Italian network on congestive heart failure (IN-CHF database). J Cardiovasc Med 2011;12:723–731.

   50. Gerbes AL, Gulberg V, Gines P, et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial. Gastroenterology 2003;124:933–939.

   51. Berl T, Quittnet-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010;21:705–712.

   52. Dixon MB, Lien YH. Tolvaptan and its potential in the treatment of hyponatremia. Therapeut Clin Risk Management 2008;4:1149–1155.

   53. Gheorghaide M, Niazi I, Quyang J, et al. Vasopressin V2-receptor blockage with tolvaptan in patients with chronic heart failure: Results from a double-blind randomized trial. Circulation 2003;107:2690–2696.

   54. Gheorghaide M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA 2004;291:1963–1971.

   55. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST Clinical Status Trials. JAMA 2007;297:1332–1343.

   56. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST Outcome Trial. JAMA 2007;297:1319–1331.

   57. Udelson JE, Orlandi C, Quyang J, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: an international, multicenter, randomized, placebo-controlled trial. J Am Coll Cardiol 2008;52:1540–1545.

   58. Udelson JE, McGrew FA, Flores E, et al. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J Am Coll Cardiol 2005;49:2151–2159.

   59. Costello-Boerrigter LC, Smith WB, Boerrigter G, et al. Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol 2005;290:F273–F278.

   60. Al-Absi A, Gosmanova EO, Wall BM. A clinical approach to the treatment of chronic hypernatremia. Am J Kidney Dis 2012;60:1032–1038.

   61. Waite MD, Fuhrman SA, Badawi O, Zuckerman IH, Franey CS. Intensive care unit-acquired hypernatremia is an independent predictor of increased mortality and length of stay. J Crit Care 2013;. http://dx.doi.org/10.1016/j.jcrc.2012.11.013.

   62. Palevsky PM, Bhagrath R, Greenberg A. Hypernatremia in hospitalized patients. Ann Intern Med 1996;124:197–203.

   63. Aiyagari V, Deibert E, Diringer MN. Hypernatremia in the neurologic intensive care: How high is too high? J Crit Care 2006;21:163–172.

   64. Hoom EJ, Betjes MG, Weigel J, Zietse R. Hypernatremia in critically ill patients: Too little water and too much salt. Nephrol Dial Transplant 2008;23:1562–1568.

   65. Moritz ML, Ayus JC. The changing pattern of hypernatremia in hospitalized children. Pediatrics 1999;104:435–439.

   66. Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care 2012. http://dx.doi.org/10.1016/j.jcrc.2012.05.001.

   67. Buckley MS, Leblanc JM, Cawley MJ. Electrolyte disturbances associated with commonly prescribed medications in the intensive care unit. Crit Care Med 2010;38:S253–S264.

   68. Chassagne P, Druesne L, Capet C, Menard JF, Bercoff E. Clinical presentation of hypernatremia in elderly patients: A case control study. J Am Geriatr Soc 2006;54:1225–1230.

   69. Moritz ML. A water deprivation test is not indicated in the evaluation of hypernatremia [letter]. Am J Kidney Dis 2005;46:1150–1151.

   70. Sands JM, Bichet DG. Nephrogenic diabetes insipidus. Ann Intern Med 2006;144:186–194.

   71. Garofeanu CG, Weir M, Rosas-Arellano P, et al. Causes of reversible nephrogenic diabetes insipidus: A systematic review. Am J Kidney Dis 2005;45:626–637.

   72. Siddall EC, Radhakrishnan J. The pathophysiology of edema formation in the nephrotic syndrome. Kidney Int 2012;82:635–642.

   73. Somberg JC, Molnar J. Therapeutic approaches to the treatment of edema and ascites: The use of diuretics. Am J Ther 2009:16:98–101.

   74. Asare K. Management of loop diuretic resistance in the intensive care unit. Am J Health-Syst Pharm 2009;66:1635–1640.

   75. Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol 2000;11:1100–1105.

   76. Ellison DH. Edema and the clinical use of diuretics. In: Greenberg A, ed. Primer on Kidney Diseases, 5th ed. Philadelphia, PA: WB Saunders, 2009:135–147.

   77. Nappi JM, Sieg A. Aldosterone receptor antagonists in patients with chronic heart failure. Vasc Heal Risk Manag 2011;7:353–363.