Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section D – Metabolic and Paraneoplastic Syndromes

Chapter 49 – Hyponatremia

Richard L. Heideman,Nancy H. Heideman





Hyponatremia is a common problem in many malignancies.



It occurs in at least 30% of patients in hospitalized, outpatient hospital, and community-based care settings.



Hyponatremia is present in 10% to 30% of patients with small cell lung cancer.




Hyponatremia has many causes; primary extrarenal sodium loss associated with several medications, as well as cardiac, renal, and hepatic dysfunction. However, diarrhea, vomiting, and hemorrhage are the most common.



The syndrome of inappropriate antidiuretic hormone (SIADH) is associated with several malignancies, particularly small cell lung cancer.



Pseudohyponatremia is associated with hyperglycemia, hyperproteinemia, or hyperlipidemia.



Water overload at surgery, low-sodium intravenous fluids, or polydipsia are other causes.



Additional causes include edematous states such as malignant peritonitis, heart failure, hepatic tumor, or cirrhosis.



Thyroid and adrenal deficiencies can result in hyponatremia.



Renal sodium loss is mediated by diuretics or natriuretic peptides (with central nervous system tumors or injury), the effect of arginine vasopressin (AVP) on the distal tubules, and the renin-angiotensin-aldosterone system.

Evaluation of the Patient



Start by assessing plasma osmolality and extracellular fluid (ECF) volume.



SIADH is a common cause but must be a diagnosis of exclusion.

Grading of the Complication



Many patients are asymptomatic.



Sodium concentrations below 125 mEq/L and those developing rapidly are most likely to be symptomatic.



Symptomatic hyponatremia is a medical emergency.




Isotonic saline (0.9%) is an appropriate fluid for most patients.



Correction of sodium should occur slowly and at a rate that approximates its development; 10 to 12 mEq/L over the first 24 hr is considered safe.



Overly rapid correction is associated with severe neurologic morbidity.



Hypertonic saline is appropriate only in symptomatic patients with very low sodium concentrations; discontinue once serum sodium becomes 120 to 125 mEq/L.



Water restriction is the primary approach to SIADH.


Hyponatremia is among the most common electrolyte disturbances faced in clinical medicine. Recent reports show 30% to 43% of a group of hospitalized, ambulatory hospital, and community-based care patients had hyponatremia (serum sodium below 136 mEq/L), and an additional 3% to 6% had concentrations of 126 mEq/L or less. [1] [2] This is particularly sobering in light of the substantial morbidity and mortality that can be associated with hyponatremia. Current studies suggest that the mortality associated with hyponatremia in hospitalized patients is as high as 27%, in comparison with 9% in other patients.[3] Even relatively mild and presumably “asymptomatic” hyponatremia (128±3 mEq/L) is associated with attention deficits and a high incidence of accidental falls and injury.[4] Among patients with cancer, clinical experience suggests that the overall incidence of hyponatremia is perhaps even higher than in other populations. This is because many tumors predispose to the development of hyponatremia (i.e., small cell lung cancer with an incidence as high as 30%) as well as the influences of polypharmaceutical treatments, and chronically ill, debilitated patients.[5]

Sodium (Na+) is the dominant ion of the extracellular fluid (ECF) and thus the prime contributor to osmolality. Sodium and water balance are tightly linked, and disturbances of one are also generally reflected in the other. This balance is the result of many homeostatic feedback loops that revolve around protection of intravascular volume. Components of this integrated homeostatic system include the hypothalamic osmoreceptors; the adrenals (via the renin-angiotensin-aldosterone cascade); the cardiac, glomerular, and carotid baroreceptors; and changes in renal tubular permeability to water and sodium in response to antidiuretic hormone (ADH, or arginine vasopressin), and natriuretic peptides released from the heart and brain. Thus, there are many paths to hyponatremia.


Hyponatremia and hypernatremia are conditions of altered tonicity. To put the physiology of the problem into perspective, it is important to understand the difference between osmolality and tonicity. Osmolality is the concentration of all particles in a fluid. Particles are either “effective” or “ineffective” osmoles. Ineffective osmoles are solutes that can cross the cell membrane freely and distribute equally in the intracellular fluid (ICF) and ECF yet produce no net movement of water. Examples of physiologically ineffective osmoles include urea and ethanol; their addition to the ECF produces no change in osmolality, because they equilibrate rapidly with the ICF.

Solutes that do not cross the membrane freely or that are kept predominantly to one side by a transporter are referred to as effective osmoles. Only effective osmoles contribute to tonicity. In the physiologic setting, sodium is the major effective osmolar solute. It is relatively restricted to the ECF and is thus the major determinant of ECF tonicity. Other examples of physiologically effective osmoles are glucose and mannitol, two large molecules that are also relatively restricted to the ECF. Potassium and a host of organic compounds that are dominantly restricted to the intracellular milieu are the major osmolar solutes of the ICF and the major determinants of ICF tonicity. Despite the differences in tonicity of these compartments, the osmolality of the ECF and ICF are quite similar as a result of water movement. Even so, the distribution of water in these two spaces is not at all similar; 60% to 75% of total body water resides within the ICF and the remainder in the ECF. Within the ECF, approximately 65% is apportioned to plasma, and the rest is interstitial fluid between cells.


From the perspective of sodium, the job of the osmoregulatory system is to prevent either hyper- or hyponatremia and the secondary movement of water that can change cell volume and disrupt function. Under normal circumstances, plasma osmolality is kept within a relatively constant osmolar range of 275 to 290 mOsmol/kg. The maintenance of this narrow range is primarily the result of ADH, thirst, and renal function.

ADH provides the most sensitive control mechanism. Changes in serum osmolality of as little as 1% to 2% can be sensed by the hypothalamic osmoreceptors and can trigger ADH secretion from the posterior pituitary.[6] At the renal level, ADH acts on receptors in the collecting ducts to initiate a passive reabsorption of water. The threshold for ADH release occurs at a plasma osmolality of 280 to 290 mOsmol/kg; below 280 mOsmol/kg, the secretion of ADH is suppressed. [4] [5] Although there is a roughly linear rise in ADH with increases in osmolality, a plateau in its effect occurs at an osmolality of 295 mOsmol/kg or greater. Thus, there is a limit to the ability of ADH to reduce hypertonicity.

Another group of osmoreceptors located in the anterior hypothalamus stimulate thirst; this group is recruited at or near the serum osmolality where ADH begins to show its plateau in effect. Thirst can also be recruited by changes in plasma volume sensed by carotid and cardiac baroreceptors.

Carotid baroreceptors responding to a decrease in effective blood volume can also stimulate ADH release. The sensitivity of this system is significantly less than that of the hypothalamic osmoreceptors, and a change in vascular volume of 8% to 10% or more is required to initiate this nonosmotic stimulus for ADH release. In situations characterized by decreased effective circulating volume or arterial vasodilation (e.g., in anthracycline-induced congestive heart failure, sepsis, or third-space fluid accumulations from malignant ascites or hepatic cirrhosis), nonosmotic baroreceptor-mediated stimulation of ADH can override the osmotic suppression of ADH release that would otherwise be expected as a result of the expanded hypotonic ECF space.[6] The net result can be a spiraling decrease in sodium as more water is retained, and effective volume continues to decline even further.

Although most osmoregulation is affected by water as described previously, sodium also has an active regulatory mechanism. Reabsorption of sodium in the renal tubule is the dominant mechanism of regulation; under normal conditions, about 70% of filtered sodium is reabsorbed. Active excretion of sodium also occurs and is mediated through the actions of a group of related natriuretic peptides that inhibit sodium reabsorption. [7] [8] The best described of these, atrial and brain-derived natriuretic peptides, are released from cells in the atrial chambers in response to central volume overload or from the brain as a result of injury. Although there remains much to be learned about the complex physiologic effects of these peptides, their actions in medullary collecting tubules and their inhibitory effect on the renin-angiotensin-aldosterone system result in a sodium diuresis.

Cellular Adaptations to Hyponatremia

In response to hypotonic conditions, water moves from the ECF into the ICF causing an expansion of cell volume that, if unopposed, would eventually lead to cell lysis. Normally, the Na+,K+ ATPase pump in the cell membrane maintains cell volume by pumping out the small amounts of sodium that “leak” into cells in exchange for potassium. In the setting of acute hypotonicity, additional mechanisms must come into play; cells adjust initially by losing sodium, potassium, and chloride across stretch-activated membrane channels. However, this process reaches its limit within several hours. In the setting of more slowly developing or chronic hypotonic states, loss of intracellular organic molecules is part of the compensation process. [9] [10] In the reverse setting of hypertonicity, adaptations include new synthesis and an increased concentration of these organic osmoles. Because this change requires several days to be complete, these adaptations are not effective in acute events.

The brain is particularly sensitive to changes in tonicity. Hypotonic stresses that lead to cell swelling are tolerated poorly in the central nervous system (CNS) because of the constraints that the skull places on increased volume. The most feared change is increased intracranial pressure; coma and death can occur with as little as a 10% increase in brain volume. Another debilitating and potentially lethal complication is the osmotic demyelination syndrome. This is an uncommon but devastating result of an overly rapid correction of hyponatremia, which leads to demyelination in the pons and extrapontine white matter. [11] [12] Thus, both the initiating process and the interventions for hyponatremia can be associated with significant morbidity and mortality.


Hyponatremia is defined as a serum sodium less than 135 mEq/L. Although hyponatremia is seen most frequently in association with a low plasma osmolality (hypotonic hyponatremia), it also can occur in settings of high or low osmolality. Similarly, hyponatremia can also be associated with normal, increased, or decreased ECF. Identification of the probable etiology and proper approach to hyponatremia begins with evaluating plasma osmolality and ECF volume ( Fig. 49-1 ). In the sections that follow, hyponatremia is characterized and and addressed by these parameters. A graphic representation of many hyponatremic states is shown in Figure 49-2 .


Figure 49-1  A clinical algorithm for determining causes of hyponatremia using plasma osmolality and extracellular fluid volume. *May be accompanied by increased AVP in some patients.  Rest osmostat usually associated with low plasma osmolality and normal ECF volume. See Table 49-1 for associated etiologies.




Figure 49-2  Extracellular and intracellular fluid (ECF, ICF) compartments under normal conditions and during states of hyponatremia. A, Normally the ECF and ICF make up 40% and 60% of total body water, respectively. B, With the syndrome of inappropriate secretion of antidiuretic hormone, the volumes of ECF and ICF expand (although a small element of sodium and potassium loss, not shown, occurs during inception of the syndrome). C, Water retention can lead to hypotonic hyponatremia with the anticipated hypo-osmolality in patients who have accumulated ineffective osmoles, such as urea. D, A shift of water from the ICF compartment to the ECF compartment, driven by solutes confined in the ECF, results in hypertonic (translocation) hyponatremia. E, Sodium depletion (and secondary water retention) usually contracts the volume of ECF but expands the ICF compartment. At times, water retention can be sufficient to restore the volume of ECF to normal or even above normal levels. F, Hypotonic hyponatremia in sodium-retentive states involves expansion of both compartments but predominantly the ECF compartment. G, Gain of sodium and loss of potassium in association with a defect of water excretion, as they occur in congestive heart failure treated with diuretics, lead to expansion of the ECF compartment but contraction of the ICF compartment. In each panel: red circles, sodium; yellow circles, potassium; large squares, impermeable solutes other than sodium; small squares, permeable solutes; broken line, cell membrane; shading, intravascular volume.




There are two situations in which sodium can be fictitiously low as a result of the presence of substances that alter the volume of plasma water in which sodium is measured.

Pseudohyponatremia is common in the setting of hyperglycemia or the use of some other restricted solute that causes high plasma osmolality. These situations cause a shift of water from the ICF to the ECF, resulting in sodium dilution. As a general rule, each 100 mg/dL increase in glucose reduces serum sodium by 1.6 mEq/L. The presence of some other nonglucose, active substance (e.g., mannitol) is identified by finding a 10-point or greater difference in the measured vs. the calculated osmoloality ( Box 49-1 ). This “osmolar gap” can also be increased in azotemia and in ethanol and methanol intoxications. Although the plasma osmolality is increased by the addition of these ineffective osmolar substances, there is no shift in water; the true sodium is normal.

Box 49-1 


Note that measured osmolality is generally 10 mOsm/kg higher than calculated osmolality because of the effect of minor solutes such as magnesium, calcium, protein, phosphates, and amino acids. Normal osmolality is 287 ±4, with a normal range extending from 280 to 290 mOsm/kg.

Pseudohyponatremia also can occur as a result of an increase in relatively high-molecular-weight substances, such as occurs with Bence-Jones proteins in multiple myeloma or in hyperlipidemia. In these situations, plasma osmolality is normal, but the volume of plasma in which sodium is measured is expanded as a result of compensatory water shifts into the ECF. Thus, if sodium is normalized to the volume of sampled plasma, it will be reported as artificially low. However if sodium is measured using an ion-selective electrode that measures sodium only in the aqueous phase of plasma, its concentration will be reported as normal. Thus, it is important to know how a given laboratory determines sodium concentration.

Patients with pseudohyponatremia are not at risk for complications of low sodium and do not require sodium correction. Their true plasma sodium is normal.

Hypotonic Hyponatremia

Hyponatremia in the setting of hypotonic plasma (hypotonic hyponatremia) is the most common type of low serum sodium and represents a process in which there is an excess of water in relation to sodium.[13] [14] Several potential causes of this problem are outlined in the ensuing discussion and summarized in Table 49-1 . Most such situations are also characterized by the relative inability to excrete water. Although many patients might be “asymptomatic,” even mild hyponatremia is now known to be associated with increased morbidity.[2] Perhaps the most dangerous situation is when hyponatremia develops fairly rapidly (within 48 hours) and in which rapid changes in osmolality may lead to serious and potentially deadly neurologic sequelae.

Table 49-1   -- Causes of Hypotonic Hyponatremia




Extrarenal sodium loss



Diarrhea, vomiting, hemorrhage, fluid sequestration (third space), excessive sweating



Renal sodium loss



Diuretics, osmotic diuresis (use of mannitol with cisplatin over multiple days)



Renal tubular acidosis



Salt-losing nephropathy



Interstitial nephritis, urinary tract obstruction, Bartter's syndrome






Adrenal insufficiency (mineralocorticoid deficiency; most common as a late effect of cranial irradiation)



Cerebral salt wasting syndrome



Edematous states



Congestive heart failure, nephrotic syndrome, malignant ascites, cirrhosis, renal failure


Distal tubule diuretics

Loop diuretics (furosemide, ethacrynic acid)

Hypothyroidism (early effect of cranial and/or craniospinal irradiation) adrenal insufficiency (glucocorticoid deficiency; most commonly a late effect of cranial irradiation)





Small cell carcinoma of lung, Hodgkins disease, leukemia, lymphoma, adenocarcinoma of pancreas and duodenum, breast, and many others



CNS lesions



Tumor, stroke, subarachnoid bleed, hemorrhage, infection



Selected drugs



Opiates, phenothiazines, vincristine, cyclophosphamide, ifosfamide, cisplatin, carbamazipine, tricyclics, NSAIDs, selective serotonin reuptake inhibitors, desmopressin, nicotine, chlorpropamide



Increased intrathoracic pressure



Mediastinal tumor, positive pressure ventilation, pneumonia

Reset osmostat[*]

Trauma, pain, and stress (postoperative state)



Primary polydipsia[†]

Excessive dilute or sodium-free irrigants during surgery

Tap water enemas

AIDS, acquired immunodeficiency syndrome; AVP, arginine vasopressin; CNS, central nervous system; NSAIDs, nonsteroidal anti-inflammatory drugs; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

Common cancer-associated causes are italicized.



Normal volume accompanied by low plasma osmolality.

May also be accompanied by decreased water excretion as a result of AVP stimulation.



Hyponatremia developing in the setting of either decreased ECF or hypovolemia is a result of both sodium loss and water loss. As adaptations to volume loss occur, however, a relative excess of water over sodium develops.

The most common causes of decreased ECF are a result of extrarenal fluid losses such as diarrhea, vomiting, or third-space sequestrations of body fluid, as in malignant peritonitis. The net effect of these problems is the stimulation of ADH secretion and thirst in an effort to enhance water retention and restore ECF volume. The decreased circulating volume, renal hypoperfusion, and ADH-mediated water retention combine to limit renal water excretion and produce dilutional hyponatremia. The hyponatremia could be made worse by the concomitant depletion of potassium in severe diarrhea or vomiting and by the secondary migration of sodium into cells to compensate. Because the major pathology in these situations is nonrenal, these patients should have a low urine sodium excretion. As a rule of thumb, a urine sodium of less than 20 mEq/L suggests renal sodium conservation. The management of these patients is primarily saline volume expansion. Potassium may be added as necessary.

Hyponatremia associated with the use of thiazide diuretics is a result of sodium, potassium, and volume depletion. Secondary water retention can occur as a result of ADH response to volume loss. Urine sodium is characteristically elevated (>20 mEq/L) in these patients, reflecting increased renal sodium loss. This form of hyponatremia is characterized by hypovolemia or euvolemia with little decrease in effective plasma volume. In contrast, the loop diuretics (e.g., furosemide) rarely cause significant hyponatremia, because they inhibit sodium reuptake and reduce renal interstitial tonicity, which, in turn, limits passive water reabsorption. The management of these patients involves cessation of diuretic medication and volume expansion with saline.

Another cause of hypotonic hyponatremia is salt wasting associated with renal dysfunction. [13] [14] This can occur as a result of obstructive uropathy from abdominal and retroperitoneal tumors, loss of renal structure as in polycystic disease, or tubular damage associated with interstitial nephritis. The latter can occur as a result of several chemotherapeutic agents (especially cisplatin, aminoglycosides, or amphotericin) or infection, all of which can limit sodium reabsorption and diminish free-water excretion. As expected, urine sodium is high (>20 mEq/L) in these situations. The management of these situations relies on addressing the underlying problem and on replacing volume with saline.


In the disease states listed in this discussion, hyponatremia develops even though total body sodium is generally increased. This is a result of physiologic adaptations to disease that cause an even larger increase in total body water (particularly in the ECF), thus driving sodium down.

Congestive heart failure, ascites associated with malignant peritonitis or cirrhosis, and nephrotic syndrome are edematous states with increased ECF. Despite the edema, however, these diseases are usually associated with decreased effective circulating volume. In these situations, atrial and carotid baroreceptors stimulate ADH release and volume expansion as a compensatory (but physiologically inappropriate) event. [6] [13] The management of these situations is centered on improving effective circulating volume by addressing the underlying problem and restricting both sodium and water.

Hypotonic hyponatremia occurring in the setting of volume expansion can also develop in patients with renal failure. [13] [14] Accumulation of ineffective osmols (e.g., urea) leads to increased osmolality in both the ICF and ECF, with consequent water retention and an increase in the volume of both compartments. Thus, a dilutional hyponatremia occurs in the setting of increased ECF. As with the edematous states described previously, management is centered on treatment of the primary disease (dialysis) and on restriction of both sodium and water.

Hyponatremic states that are a result of excessive water intake, such as psychogenic polydipsia or low-sodium intravenous or enteral fluids, are examples of hypotonic hyponatremia in the setting of increased ECF. [13] [14] Although renal water excretion is usually normal in these patients, the volume of water intake overwhelms the normal ability of the kidney to excrete the maximum of 26L/1.73 m2per day of free water. A moderate to significantly increased ECF usually accompanies these problems. Characteristic of these states is the excretion of large volumes of maximally dilute urine, indicating intact renal function. Depending on how rapidly the problem has evolved, the degree of hyponatremia, and the presence of symptoms, treatment is aimed at net water loss or sodium replacement.


Patients who develop hyponatremia in the setting of normal or near-normal ECF volume generally have a modest increase in water relative to sodium. This condition generally signals the syndrome of inappropriate antidiuretic hormone secretion (SIADH). [6] [15] It is noteworthy, however, that increased ADH by itself is generally insufficient to cause significant hyponatremia; water intake is necessary for the dilutional effect to occur. Although SIADH is often classified as an isovolemic hyponatremia because of the lack of edema and overt signs of volume expansion, most patients have expansion of their ECF, diminished urine output and weight gain. Despite the hyponatremia, an atrial natriuretic peptide-mediated natriuresis can occur in response to the volume expansion. This, and the diminished sodium reabsorption associated with volume expansion, further decrease plasma sodium and limit the formation of edema. Eventually, a new equilibrium between sodium intake and excretion occurs, such that intake and output are matched. Thus, attempts to correct SIADH with the addition of sodium alone are rarely successful; water restriction remains the primary method of management in asymptomatic patients. SIADH is a diagnosis of exclusion. To make the diagnosis, the following criteria should be met:



Other causes of hyponatremic hyponatremia, particularly hormone deficiencies (e.g., thyroid and adrenal) and a reset osmostat are absent (see related topics covered later in this chapter).



The patient should be clinically isovolemic or only mildly hypervolemic. The presence of edema or clinical volume overload is not compatible with SIADH.



The plasma osmolality should be 280 mOsm/kg or less. Higher osmolality does not support the “inappropriate” nature of ADH secretion.



Urine osmolality must be greater than plasma (≥500 mOsm) and urine sodium must be in excess of 20 to 30 mEq/L; concentrations of 40 mEq/L or greater are not uncommon.

SIADH is associated with a wide variety of clinical settings (see Table 49-1 ). The most common cause in clinical oncology is the ectopic production of ADH by tumor. Although small cell anaplastic carcinoma of the lung is the most frequent cause, several other neoplasms also can be associated with the problem (see Table 49-1 ). [1] [2] Even though serum ADH is increased in as many as 40% of patients with small cell lung carcinoma, the clinical manifestations may occur in only 10% of such patients. The latter have latent SIADH, which might become evident only in the setting of water loading. It should be noted that ectopic ADH secretion is not steady, nor is it usually at a level that approaches the maximal release by the hypothalamus. Thus, an episode of volume depletion still can produce a nonosmotic ADH release.

Several pharmaceutical products, including several antineoplastic compounds, are also associated with SIADH. Most notable among these is vincristine, which has been associated with acute and severe SIADH. The problem generally develops 2 to 3 days after vincristine administration, is associated with increased ADH levels, and can persist for days to weeks. High-dose (2 g/m2) cyclophosphamide is also capable of inducing hyponatremia through direct renal tubular effects and possible enhancement of ADH activity.[13] In contrast to hyponatremia due to vincristine, the hyponatremia associated with cyclophosphamide occurs within several hours of administration, and is not associated with ADH secretion. Curiously, we have not identified SIADH associated with the use of ifosfamide, which is structurally similar to cyclophosphamide. Ifosfamide has, however, been associated with significant renal toxicity and a Fanconi-like tubulopathy characterized by the wasting of multiple electrolytes, glucose, and protein. The platinating agents, cisplatin and (less commonly) carboplatin, have also been associated with hyponatremia, although the mechanisms of these agents are probably related in part to direct renal toxicity and not to SIADH. Several other drugs listed in Table 49-1 also can cause SIADH.

The management of SIADH depends on how rapidly the problem has evolved and the degree of hyponatremia; it must include treatment aimed at the underlying disease process. In the asymptomatic patient with SIADH who has a serum sodium greater than 125 mEq/L, water restriction is the primary mode of management. The use of furosemide is appropriate for patients who do not respond well to fluid restriction alone. In the symptomatic patient, partial correction with 3% hypertonic saline and furosemide is indicated (see ensuing discussion). [13] [16] Even in these cases, however, treatment must eventually rely on water restriction.

Cerebral salt wasting (CSW) is a cause of hyponatremia associated with intracranial disease or injury. [7] [17] It is important to differentiate this process from SIADH, which it can closely resemble and for which it is often mistaken. The approaches to treatment for CSW and SIADH are quite different from one another. CSW is mediated by not yet fully defined physiologic circumstances and is characteristically associated with volume depletion rather than the isovolemic or modestly expanded state of SIADH. At a basic level, primary CNS tumors, subarachnoid hemorrhage, and increased intracranial pressure all seem to be associated with the release of natriuretic peptides from brain, cardiac foci, or both, causing a sodium diuresis and ECF volume loss. Water restriction, the typical approach to SIADH, is contraindicated in CSW, which requires both volume and sodium replacement.

Reset Osmostat

Resetting of the hypothalamic osmostat is generally associated with chronic hyponatremia and has been seen in a variety of malignancies as well as in cachexia, malnutrition, and pregnancy. [6] [18] Another common setting is in patients with hypothalamic tumors or hypothalamic injury from trauma or surgery. The mechanism seems to be one in which the set point for ADH release is adjusted downward. Such individuals might have stable plasma sodium concentrations in the range of 125 to 135 mEq/L and are generally asymptomatic. Treatment is unnecessary and even if attempted is generally unsuccessful, because thirst and ADH maintain sodium at the new set point. In isolation, this is a relatively benign problem unassociated with neurologic sequelae. In association with other central water and sodium problems, however (e.g., diabetes insipidus or loss of thirst that could accompany hypothalamic/pituitary tumor or injury), a reset osmostat can become a challenge.


Hyponatremia also can occur in the setting of a number of primary or secondary hormone deficiencies, such as hypothroidism or hypocortisolism. [7] [8] [16] Although these are generally associated with a euvolemic state, hypervolemia may occur also. It is important to keep the hyponatremia associated with these deficiencies in mind, because they can be slow to evolve after organ injury and can easily be mistaken for SIADH.

Although the mechanism of hyponatremia in hypothyroidism is not fully understood, the relatively low cardiac output, a decrease in renal perfusion, impaired water excretion, and ADH secretion all seem to be involved. Patients with milder forms of hypothroidism might be euvolemic and have only modestly decreased sodium. Settings commonly associated with hypothyroidism occur in those patients who have received head and neck or craniospinal irradiation. It can take 1 to 2 years for clinically evident hypothyroidism to develop after such events. The treatment of this problem relies largely on thyroid replacement. In patients with advanced disease, temporary sodium, with or without water restriction, may also be helpful.

In the setting of adrenal insufficiency, hyponatremia can be a result of mineralocorticoid deficiency, glucocorticoid deficiency, or both. The mechanisms of hyponatremia in these two settings are entirely independent of each other. Primary and metastatic tumors to the adrenal can reduce both hormones. Isolated glucocorticoid deficiency can occur as a result of hypothalamic or pituitary tumors, surgery, or CNS radiation therapy. Of note, central adrenocorticotropic hormone regulation is relatively radioresistant and generally requires doses exceeding 50 Gy and typically has a 3- to 5-year latency before becoming evident. Glucocorticoid deficiency is generally characterized by hyponatremia in the setting of normal or modestly expanded ECF. Cortisol is necessary for maximum urinary dilution and free water excretion, thus a deficiency results in water retention from increased permeability in the renal collecting tubules. This action seems to be independent of ADH, in that patients with panhypopituitarism who are given cortisol replacement soon exhibit diabetes insipidus. In the setting of an otherwise intact hypothalamic/pituitary axis, cortisol deficiency is also associated with some increase in ADH secretion. Thus, management might require not only cortisol replacement but also desmopressin acetate to control the diabetes insipidus that cortisol has “unmasked.”

In mineralocorticoid deficiency the renin-angiotensin system is compromised, and there is generally a contraction of effective circulating volume because of diminished capacity by the kidney to reabsorb sodium. In response to diminished volume, baroreceptor-mediated ADH release and water retention can drive sodium lower.


Most patients with hyponatremia are relatively asymptomatic, and treatment can be aimed at the underlying disease. Symptomatic hyponatremia should be considered a medical emergency. In the absence of infections and issues related to tumors, congestive failure, and the other edematous states, the symptoms associated with hyponatremia depend on the depth of the sodium concentration and the rapidity of its onset. When hyponatremia develops within a matter of several hours as a result of an acute hypotonic volume load, neurologic findings related to evolving cerebral edema dominate. Those patients in whom hyponatremia develops over an extended period (≥48 hr) might have only mild lethargy, muscular symptoms, and anorexia even though their serum sodium might be the same or even lower than that of patients who develop the problem acutely.

Mild symptoms characterized by vomiting, malaise, and even agitation are usually seen in patients with sodium concentrations above 125 mEq/L. As sodium falls further, muscle cramps and weakness, as well as neurologic symptoms including lethargy, headache, and confusion can occur. Sodium levels below 120 mEq/L are associated with seizures and coma.

In all but the unequivocal acute volume overload state and patients with neurologic signs, it is wise to assume that hyponatremia is a chronic process that has developed over several days. The rationale for this assumption is that chronic hyponatremia must be corrected slowly. Too rapid a correction is associated with severe, life-threatening CNS complications from osmotic demyelination syndrome.

Osmotic demyelination is related to an overly aggressive sodium correction. Rapid but relatively modest degrees of sodium correction can cause ECF to appear hypertonic to the cell (even though sodium is still low). Thus, correction should be limited to no more than 12 mEq/L in 24 hr and 18 to 24 mEq/L in 48 hr. [5] [12] [19] It should be noted that there is typically a delay of 2 to 4 days (and sometimes as long as 6 days) before the signs of brain injury and demyelination occur. Thus, it is possible to see patients improve initially but have a subsequent neurologic decline some days after the start of correction. Patients with acute hyponatremia have significantly less risk of developing this problem than do those with chronic hyponatremia.[16]

Treatment of Asymptomatic Hyponatremia

Hypovolemic hyponatremia is generally associated with the symptoms of volume depletion, and these patients are not at risk for the neurologic complications related to cerebral edema that accompany acute hyponatremia. They might, however, be subject to osmotic demyelinating syndrome associated with rapid sodium correction. The management of patients with mild hypovolemic hyponatremia from chronic renal sodium loss or overuse of diuretics is best performed by giving isotonic (0.9%) saline or, if tolerated, oral salt tablets. A rate of correction aimed at no more than 12 mEq/L per day over a period of 2 to 3 days is generally sufficient.

In the isovolemic hyponatremias that commonly result from SIADH, treating the underlying disease, stopping any potentially offending drugs, and water restriction are the methods of choice. Rigorous restriction of free water to as little as 30% to 70% of maintenance needs might be necessary and could take 2 to 3 days to become effective. The often attempted use of isotonic saline at a lower than maintenance rate is a doomed strategy, because an isotonic load is excreted quickly with little or no net change in serum sodium. In patients who do not tolerate or who are noncompliant with water restriction or in whom furosemide is contraindicated or ineffective, democycline may be used to induce a nephrogenic diabetes insipidus-like state with increased free-water excretion. Lithium carbonate can produce the same result but is generally not well tolerated.

In relatively asymptomatic hypervolemic hyponatremic patients, modest fluid restriction, sodium restriction, and the use of a loop diuretic to promote renal free-water excretion are appropriate measures. These measures will be ineffective, however, without management aimed at the underlying edematous disease state.

Treatment of Acute Symptomatic Hyponatremia

Acute hyponatremia—most frequently the result of volume overload with hypotonic fluids—generally manifests by the presence of some neurologic findings as a result of evolving cerebral edema. These patients generally have a serum sodium below 120 mEq/L and are generally hospitalized individuals with iatrogenic hyponatremia ( Box 49-2 ). Common characteristics include: menstruating women (who are more susceptible than males), excessive hypotonic intravenous fluids, recent use of diuretics, particularly thiazides, or seratonin reuptake inhibitors, which can lead to SIADH. Another group are patients who have undergone transurethral prostatectomy with excessive absorption of hypotonic fluids across the organ bed, and those with colonoscopic preparation–induced losses.[12] The goal of treatment for these patients should be to raise the serum sodium sufficiently to stop any seizure activity and to correct cerebral edema; changes in serum sodium of as little as 5% can diminish cerebral edema, and increases of as little as 3 to 6 mEq/L can stop most seizures.[13] With this in mind, a rate of correction of about 1 to 1.5 mEq/hr during the first 4 to 6 hr is often sufficient to manage the acute neurologic problems. Anticonvulsants might be necessary for those with seizures. This initial correction might use 3% hypertonic saline ( Box 49-3 ). Acute, symptomatic hyponatremia is the only condition in which the use of a hypertonic saline solution is unequivocally an appropriate intervention. Although patients with acute hyponatremia have a lower risk of osmotic demyelination than those who develop low sodium on a more chronic basis (>48 hr), the use of hypertonic saline should be limited to achieving an initial increase of 3 to 6 mEq/L or a serum sodium of 120 to 125 mEq/L. After the initial period of correction, the rate of sodium rise should be limited to 0.5 mEq/L using 0.9% (isotonic) saline. Correction rates of 10 to 12 mEq/L during the first 24-hr period and 18 mEq/L over the first 48 hr are safe. [5] [12] [19]

Box 49-2 



*  Use 0.5 in elderly and frail.

Box 49-3 



Na+ (mEq/L)

Na+ (mEq/mL)

3% saline



0.9% saline



Ringer's lactate




The addition of furosemide during the initial correction period has been advocated as a method of encouraging free-water excretion by the kidney. Furosemide diminishes interstitial renal medullary tonicity, impairs urinary concentrating ability, and leads to a hypotonic urine with a concentration of about 0.45% saline (75 mEq/L). Although this often seems to be helpful, it should probably be limited to a single dose, thus minimizing too rapid a correction. Furosemide is particularly useful in a frail patient with diminished cardiac reserve, in whom the use of hypertonic saline could incite congestive failure.

Management of Chronic Hyponatremia and SIADH

The management of these patients relies on treating the underlying disease. Examples include the treatment of malignancies, hormone replacement, removal of drugs associated with SIADH, providing adequate sodium (and water) needs for patients receiving enteral feeding, and compensating for disordered thirst. Preventive measures, such as the preference for the use of isotonic saline in “at risk” patients (malignancy, chemotherapy, positive pressure ventilation, and other states noted in Table 49-1 ) who require hydration, are equally important. It is important to remember that correction of chronic hyponatremia must be executed slowly to avoid the potential of osmotic demyelination. Asymptomatic patients who have slowly developed sodium concentrations as low as 105 to 110 mEq/L have been corrected successfully using an initial rate of 0.5 mEq/L/hr or less to bring them to serum levels of 120 mEq/L. After this, the rate of correction may be liberalized, keeping in mind the risk factors for demyelination noted earlier. Although it is permissible to initiate treatment with 3% saline solutions in these severely hyponatremic patients, the need to do so and the potential risks of too rapid a correction in a relatively asymptomatic patient suggest isotonic saline as a safer alternative. For unstable patients and those with neurologic symptoms, the approach to treatment should be similar to that noted earlier for acute symptomatic hyponatremia, but at a slower pace; a planned initial rise in sodium of 4 to 6 mEq/L over 12 hr, followed by a more gradual correction at a rate not to exceed 12 mEq/L during the first 24 hr, is considered safe (including the initial 4- to 6-mEq/L correction). During the second 24 hr, the rate of correction should be even more gradual than for the acutely symptomatic patient. A rate of 0.5 mEq/L or less, with the plan of limiting sodium rise to no more than 18 mEq/L over the initial 48 hr, is appropriate. Some authors suggest an even slower rate of correction, limiting sodium rise to no more than 8 mEq/L in any 24-hr period.[13] Furosemide may be used during the initial correction phase but should probably be limited to a single dose to minimize too rapid a correction, particularly in the setting of hypertonic saline use.

A more challenging situation is that of a patient with severe hyponatremia associated with a malignancy. Such patients should have at least a partial correction to a serum sodium above 125 mEq/L (and preferably above 130 mEq/L) before proceeding with chemotherapy and hydration.

A caution is that the correction of a hypovolemic hyponatremia associated with excessive use of thiazide diuretics might occur more rapidly than anticipated. As volume is replaced, these patients might quickly regain the ability to excrete a hypotonic urine that could cause an unintended acceleration of sodium correction. Likewise, other hypovolemic patients are at risk for rapid correction. As their volumes are expanded and the nonosmotic stimulus of ADH decreases, accelerated sodium correction can occur. Again, the use of isotonic rather than hypertonic saline for correction, as well as frequent evaluations of volume and sodium status, limits the potential for too rapid a rate of correction.

An important, more elegant and selective treatment of hyponatremia is now emerging as a result of the development of antagonists to the renal arginine vasopressin (ADH) receptors. Some amount of impaired water excretion is common in virtually all the hypervolemic and isotonic hyponatremic states. Thus, antagonists to the renal AVP receptors (V2 receptor antagonists; tolvapatan and conivaptan) which mediate free-water reabsorption from the distal tubules can promote free-water excretion. These agents have no effect on the excretion of sodium or other electrolytes; the effect is pure aquaresis. Though not yet in common use outside of the management of congestive heart failure, these agents will undoubtedly become a part of the primary treatment of hyponatremias, as adjuvants or replacements for management by water restriction. [20] [21] [22]


Postoperative Symptomatic Hyponatremia

A 56-year-old woman who had an uncomplicated resection of a breast tumor 48 hr ago is reported by her family to be more lethargic and somewhat confused compared with the day before. She has a tonic-clonic seizure that is controlled rapidly with lorazepam. Serum chemistries reveal a serum sodium of 115 mEq/L, a serum potassium of 3.3 mEq/L, and a serum osmolality of 245 mOsm/kg. Her urine osmolality is 125 mEq/L, and urine sodium is 20 mEq/L. On examination, she has a heart rate of 90 beats/min, is normotensive, and has no peripheral edema. Her preoperative weight was 65 kg. Based on the foregoing data, a probable diagnosis is hypotonic hyponatremia in what seems to be a euvolemic patient. The differential diagnosis includes SIADH from the pain and stress of surgery and/or from the use of morphine for postoperative discomfort, or dilutional hyponatremia from hypotonic volume overload. SIADH would be expected to be associated with a more concentrated urine and a urine sodium well in excess of 20 mEq/L. Her record indicates that she received 2.5L of D5W during surgery. Additionally, it is noted that she has had several glasses of water over the last 12 hr, the exact amount unknown. The highly dilute urine, the relatively low urine sodium in the setting of a low serum osmolality, and her history are characteristic of acute hypotonic fluid overload. Because the patient is symptomatic, the initial plan should be to increase her serum sodium by 3 to 6 mEq/L over the course of 3 to 6 hr. Based on her weight and gender, the appropriate factor for determining the volume of ECF in need of correction is 0.5, thus giving a volume of 32.5L (0.5×65 kg). An initial correction of 5 mEq/L over the course of 6 hr is planned using 3% saline. The total amount of sodium needed is 163 mEq (32.5 kg×5 mEq/L). Given over 6 hr, this equates to 27 mEq/hr. Using 3% saline, which contains 0.513 mEq/mL of sodium, her hourly fluid rate becomes

If furosemide is given at the start of the initial correction, the time to correction might be somewhat longer as a result of both free-water and sodium loss (furosemide produces a roughly 0.45% saline diuresis). Thus, sodium should be monitored every 2 hr, and the infusion rate should be adjusted accordingly ( Box 49-4 ).

Box 49-4 



At the end of the initial 6 hr the serum sodium is 119 mEq/L, and there have been no further seizures. The patient remains unresponsive, however. Based on this, an additional 5 mEq/L sodium correction is planned. Even though patients with acute volume overload are not at high risk for osmotic demyelination associated with rapid correction, it is wise to assume that the problem occurred slowly to minimize the potential for development of this condition. Thus, the second-phase correction should be done at a much slower rate of 0.5 mEq/L/hr, with the goal of not exceeding a total correction of more than 12 mEq/L over the first 24 hr. Another 163 mEq of sodium will be required (32.5 kg×5 mEq/L) over the next 18 hr. Because the patient is still unresponsive, it is appropriate to use 3% saline for correction. The hourly rate of correction now changes to 163 mEq/18 hr, or 9 mEq/hr. Using 3% saline, this becomes

At the end of 24 hr, the patient's serum sodium is 125 mEq/L, and she is somewhat lethargic but arousable. At this point, it is appropriate to switch to isotonic saline (0.9%) for further correction. The goal is now to continue correction, limiting the total amount of correction in the first 48 hr to 18 mEq/L. Thus, an additional 8 mEq/L of sodium will be given over the second 24-hr period, for a total of 260 mEq of sodium (8 mEq/L×32.5L) or 11 mEq/hr. Using isotonic saline, the rate becomes

At the end of the first 48 hr the patient's serum sodium is 132 mEq/L, and she is alert and responsive. Further correction with 0.9% saline at a rate of no more than 0.5 mEq/L/hr over the next 12 to 24 hr will result in a normal serum sodium having been achieved over a period of time long enough and at a slow enough rate to minimize the potential for CNS demyelination.

Hypotonic Hyponatremia Associated with Euvolemia

A 72-year-old man with recently diagnosed small cell lung carcinoma is noted to have become increasingly confused and lethargic over the last 72 hr. He has not yet started chemotherapy. Notably, he has been on replacement therapy for hyperthyroidism for several years. His wife is not sure whether he has been taking his thyroid replacement over the last several days. Laboratory evaluation reveals a serum sodium of 112 mEq/L, serum potassium at 3.6 mEq/L, and a serum osmolality of 225 mOsm/kg. The urine osmolality is 590 mOsm/kg. His blood pressure and heart rate are normal, and there is no evidence of edema, suggesting that he is euvolemic. His urine sodium is 50 mEq/L. His weight is 66 kg. Although the temptation to make the diagnosis of tumor-related SIADH is strong, this must be a diagnosis of exclusion. Other possible causes of euvolemic hypotonic hyponatremia include overuse of a diuretic and glucocorticoid or thyroid deficiency (see Fig. 49-2 ). He has not been taking any diuretics, and cortisol deficiency seems unlikely because his potassium is normal and he has been an otherwise healthy, active man except for recent events. Although known to have primary hypothyroidism, it is unlikely that missing 2 to 3 days of replacement therapy would put him at risk for hyponatremia. Thus, tumor-related SIADH is the most likely diagnosis. He is given 1L of normal saline (0.9%), and 2 hr later his serum sodium is 110 mEq/L and his urine osmolality remains at 590 mOsm/kg. Although this might initially be surprising, recall that patients with SIADH have a relatively fixed urine osmolality due to tonic ADH secretion, and they retain the ability to excrete sodium despite their hyponatremia. Thus, the net effect of isotonic saline was to produce further dilution of serum sodium, as a concentrated sodium-containing urine is excreted, leaving a relative free-water gain.

The approach to this symptomatic patient involves raising his sodium to a level of 120 mEq/L and then restricting free water. The goal is to provide an initial sodium increase of 3 to 6 mEq/L. Knowing that the hyponatremia has developed over a period of at least 72 hr based on the patient's history, the rate of correction should be similar to minimize the potential for osmotic demyelination, for which he is at significant risk. Based on this information, the goal is an increase in serum sodium of no more than 10 to 12 mEq/L over the first 24 hr at a rate of no more than 0.5 mEq/L/hr. Because he is an elderly man, the factor for determining his total body water is 0.5, thus making his total ECF volume 33L (0.5×66 kg). Although the use of isotonic saline is often a better plan for correcting hyponatremia in patients who have developed the disorder chronically, 3% saline is acceptable for this patient because he is symptomatic.

Raising his sodium by 10 mEq/L to 120 mEq/L over the next 24 hr requires 10 mEq/L of sodium by 23L, for a total of 230 mEq of sodium.

This correction rate is only 0.4 mEq/L/hr and within the guidelines for minimizing the risk of osmotic demyelination discussed earlier in the chapter. Also, keep in mind that the rate of correction should be limited to 18 mEq/L within the first 48 hr. If furosemide is used at the start of the initial correction, the rate of correction might even be somewhat slower, as noted in the previous case example. At 24 hr, the patient's serum sodium is 119 mEq/L; he is lethargic but arousable and less confused, and the objective of bringing his sodium close to 120 mEq/L has been achieved. If he had not been clinically improved, it might have been prudent to increase his sodium another 5 mEq/L over the next 12 hr, to about 125 mEq/L. At this point, with signs of improvement in the patient and a serum sodium of 119 mEq/L, it is appropriate to begin water restriction, limiting water and anything that becomes water at body temperature (e.g., gelatin and ice cream) to 1L/day. Over the next 48 to 72 hr, one should expect to see his sodium increase to 130 mEq/L or more. At this point, it is appropriate to begin management of his tumor.

Hyponatremia with Diminished Extracellular Fluid

A 12-year-old 50-kg male underwent resection of a large temporal lobe tumor 48 hr previously; the tumor has been associated with significantly increased intracranial pressure. He is irritable but lucid, complaining of leg cramps; he has a moderate hypotension of 100/60 mmHg and a moderate sinus tachycardia of 120 beats/min and has developed significantly increased urine output of 6 mL/kg/hr over the last 12 hr. Serum chemistries reveal a sodium of 124 mEq/L, potassium of 4.5 mEq/L, blood urea nitrogen (BUN) of 17, and creatinine of 1.2. His serum osmolality is 300 mOsm/kg, urine osmolality is 350 mOsm/L, and urine sodium is 155 mEq/L. Review of his record shows that he received 0.5 g/kg dose of mannitol before surgery and 1 L of normal saline during surgery. Over the last 24 hr he has been drinking ad lib and seems to have increased thirst. His examination suggests some degree of hypovolemia, and the elevated urine sodium is compatible with either a primary salt-wasting process or SIADH. The urine sodium and moderate urine concentration are not consistent with diabetes insipidus. The latter is unlikely given his increased serum osmolality, excessive urine output, and signs of hypovolemia. A hypovolemic hyponatremia characterized by excessive renal sodium loss in a neurosurgical setting is characteristic of cerebral salt wasting.

Recognizing that the serum sodium has probably developed acutely and is likely to quickly drop even further given the amount of sodium he is excreting and the fact that he is developing some mild symptoms (irritability and muscle cramps), the decision is to make a partial correction of his sodium to diminish the potential of more severe symptoms. At the same time, his hypovolemia must be treated, and his ongoing losses must be replaced. The plasma volume for this adolescent male is 30 L (0.6×50 kg). Because the sodium loss has been rapid, the decision is taken to raise his sodium by 4 mEq/L over 6 hr. Thus, a total of 120 mEq of sodium over 6 hr will be needed at a rate of 20 mEq/hr using 3% saline.

Simultaneously, it is necessary to replace his urine output, volume for volume, with isotonic saline. To this it is necessary to add an amount calculated to represent his current volume deficit with the intent of correcting it over 24 hr. After 24 hr, the patient appears euvolemic with a normal blood pressure and heart rate. Having replaced his volume deficit, it is now prudent to decrease the rate of isotonic saline correction to match urine output. The natriuresis continues for several days, but isotonic saline keeps the serum sodium at 138 mEq/L. At this point the patient is stable, is able to drink, and appears to have a normal thirst. He can be discharged on oral NaCl supplements approximating his renal sodium loss. Two weeks later he appears well, and his urine output has diminished to 3 mL/kg/day. He is on a normal diet, and urine osmolality has increased to 550 mEq/L with 50 mEq/L of sodium. The serum sodium is 138 mEq/L. At this point NaCl supplements are stopped, and the patient's serum sodium remains normal.


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