Hyponatremia in the Elderly: Risk Factors, Clinical Consequences, and Management
Alterations associated with the normal aging process may compromise homeostatic systems involved in the regulation of fluid balance including thirst perception that govern fluid intake, the kidney, regulation of secretion of arginine vasopressin (AVP) or antidiuretic hormone, atrial natriuretic hormone, and the renin–angiotensin–aldosterone system. Clinicians involved in the care of the elderly recognize that disturbances of water and electrolyte balance, especially hyponatremia, are common in this age group.1
Despite wide ranges in intake of sodium and water in normal persons, serum sodium concentration is tightly maintained within the range of 136-144 mEq/L. Hyponatremia is usually defined as a serum sodium concentration of 135 mEq/L or less. It appears when there is an excess of water relative to sodium in the extracellular body fluid compartment and can be the consequence of either a decrease in extracellular sodium content (ie, sodium depletion) or an increase in extracellular water (ie, dilutional hyponatremia). In the elderly person, dilutional hyponatremia is the more common mechanism and most frequently is due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The altered relationship of sodium to water can occur in the setting of decreased (hypovolemic), normal (euvolemic), or increased (hypervolemic) intravascular volume. Hypovolemic hyponatremia can result from increased sodium loss from the gastrointestinal tract, from increased urinary loss, and from sweat. Euvolemic hyponatremia is characteristic of SIADH. Hypervolemic hyponatremia is seen in edematous states such as congestive heart failure, cirrhosis with ascites, and nephrotic syndrome. Both euvolemic and hypervolemic hyponatremia are mediated by the secretion of AVP, resulting in increased water reabsorption by the kidney.2
Dilutional versus Depletional Hyponatremia
A key determination in evaluating the patient with hyponatremia is whether hyponatremia is of dilutional, depletional, or mixed origin, and can generally be made by history, physical examination, and commonly available laboratory measurements (Table I). The characteristic features of dilutional hyponatremia and SIADH are hyponatremia and serum hypoosmolality with clinical euvolemia and absence of edema, failure of the urine to be appropriately dilute, excretion of sodium in the urine at a concentration of more than 20 mEq/L, and the absence of other hyponatremia-producing disease states such as hypothyroidism, adrenal insufficiency, congestive heart failure, cirrhosis, or renal disease.
Depletional hyponatremia typically results from a prolonged period of inadequate sodium intake and/or from increased gastrointestinal tract or urinary sodium loss. Extracellular fluid volume depletion is often present with physical findings and laboratory values related to hypovolemia.
Hyponatremia is a common finding in elderly persons. Analysis of plasma sodium values in healthy individuals has shown an age-related decrease of approximately 1 mEq/L per decade from a mean value of 141 ± 4 mEq/L in young subjects. In a population of individuals older than age 65 years who were living at home and who were without acute illness, a 7% incidence of serum sodium concentration of 137 mEq/L or less was observed. Similarly, there was an 11% incidence of hyponatremia in the population of a geriatric medicine outpatient practice.3 In hospitalized patients, hyponatremia is even more common, with an incidence of approximately 1% and a prevalence of 3-4%, increasing to as high as 30% in patients in the Intensive Care Unit.4 A high prevalence of hyponatremia has been found in patients hospitalized for a variety of acute illnesses, with the risk being greater with increasing age of the patient.5
Elderly residents of long-term care institutions appear to be especially prone to hyponatremia. In a study of patients with a mean age of 72 years who resided in a chronic disease hospital, 22.5% had repeated serum sodium determinations of less than 135 mEq/L.6 Of patients admitted to an acute geriatric unit, 11.3% were found to have serum sodium concentrations of 130 mEq/L or lower.7 A survey of nursing home residents over age 60 years revealed a prevalence of 18% with serum sodium less than 136 mEq/L. When this population was observed on a longitudinal basis over a 12-month period, 53% were observed to experience one or more episodes of hyponatremia. Persons with central nervous system (CNS) and spinal cord disease were at highest risk, and water load testing indicated that most patients with hyponatremia had features consistent with SIADH.8
Vasopressin System in Normal Aging
The magnocellular neurons of the hypothalamus where AVP is synthesized do not appear to undergo age-related degenerative changes. There is no evidence of the cell destruction, neuronal dropout, or loss of dendritic arborization found in other segments of the aged brain. Moreover, neurosecretory material in supraoptic nuclei and paraventricular nuclei in elderly persons does not appear to differ in amount from that in younger subjects. Morphologic data obtained from subjects ranging from 10-93 years of age provide evidence that these nuclei, in fact, become more active with age above 60 years, suggesting that AVP production increases in senescence.9
There are conflicting data regarding basal concentration of AVP in the blood during normal aging. Some studies indicate that basal plasma levels of AVP did not differ among young, middle-aged, and elderly healthy individuals. In contrast are reports of elevated basal vasopressin levels in healthy elderly persons as compared with younger individuals. Healthy human subjects age 20-80 years have been observed to exhibit a progressive rise in plasma AVP concentration with age, which becomes most evident in subjects older than age 60 years.10
The major physiologic stimulus for vasopressin secretion in humans, plasma osmolality, is regulated by hypothalamic osmoreceptors. Hypertonic saline infusion raises plasma osmolality with a consequent increase in plasma AVP in both young and elderly subjects, but the hormone concentrations in the older subjects were almost double those in the younger subjects, suggesting that aging results in osmoreceptor hypersensitivity.11 Use of water deprivation as a stimulus for vasopressin secretion has supported the concept of an age-related enhancement in vasopressin secretion.
Metoclopramide can stimulate vasopressin secretion in persons through cholinergic mechanisms. Intravenous metoclopramide administration to normal elderly subjects age 65-80 years and to normal young subjects age 16-35 years produced significantly higher plasma AVP concentrations in the older group. The stimulation studies indicate that, in aging, AVP response to osmotic and pharmacologic stimuli is increased and can increase the risk of elderly persons for hyponatremia by impairing their ability to excrete excess water promptly.
Risk Factors for Hyponatremia
The physiologic changes in water regulatory systems that occur as part of normal aging make the older person more susceptible to the development of hyponatremia12 (Table II). A major risk for the development or worsening of hyponatremia is the administration of hypotonic fluid, either as an increase in oral water intake or as intravenous 0.45% saline solution or 5% glucose in water, a finding in 78% of nursing home residents with hyponatremia.8
Low sodium intake coupled with age-associated impaired renal sodium-conserving ability can, over time, lead to sodium depletion with hyponatremia. Many patients whose nutritional support is primarily or entirely provided by tube feeding develop either intermittent or persistent hyponatremia. The underlying cause appears to be sodium depletion because of the low sodium content of most tube-feeding diets. The hyponatremia usually resolves in response to increasing the dietary sodium intake.
Advanced age itself may be a risk factor for hyponatremia. SIADH has been described in elderly individuals, generally older than age 80 years, in whom no identifiable cause for hyponatremia could be found, suggesting that there is an idiopathic form of SIADH that may represent the clinical expression of physiologic changes that take place in the regulation of water balance during aging. Race may play a role because African Americans appear to be at lower risk than whites or Hispanics.3
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Many diseases that are common in the elderly population can cause SIADH13,14 (Table III). Almost all CNS disorders can lead to dysfunction of the hypothalamic system involved in the normal regulation of AVP secretion with resultant increased secretion of the hormone and consequent risk for water retention and hyponatremia. Such CNS disorders include vascular injury (thrombosis, embolism, hemorrhage, vasculitis), trauma with subdural hematoma, tumor, and infection.15 Psychiatric disorders such as schizophrenia and psychogenic polydipsia may be accompanied by increased fluid ingestion with consequent hyponatremia.
Malignancies can cause SIADH as a result of autonomous release of AVP from cancer tissue where it is synthesized, stored, and discharged in the absence of known stimuli. The malignancy most commonly associated with SIADH in the elderly population is small-cell carcinoma of the lung, in which as many as 68% of patients have been found to have evidence of impaired water excretion and elevated blood AVP concentration.16 Other malignancies include pancreatic carcinoma, thymoma, pharyngeal carcinoma, lymphosarcoma, and Hodgkin’s disease. Inflammatory lung diseases can also cause SIADH, perhaps as a result of AVP production by diseased pulmonary tissue, and include such entities as bronchiectasis, pneumonia, lung abscess, and tuberculosis.
Numerous drugs taken by elderly persons can affect water balance by direct action on the kidney or by altering AVP release from the neurohypophyseal system or its action on the kidney (Table IV). Hyponatremia with the characteristics of SIADH is recognized as a side effect of several older antipsychotic agents, such as fluphenazine, thiothixene, and pheno-thiazine, and the tricyclic antidepressants. There is evidence that the selective serotonin reuptake inhibitor (SSRI) antidepressants can also induce SIADH, with a reported incidence of 3.5-6.3 per 1000 people treated per year.17 Although fluoxetine is the SSRI most commonly reported to produce hyponatremia, other SSRIs including paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram have also been involved. Individuals at highest risk for SSRI-induced hyponatremia are those older than age 65 years in whom the onset of hyponatremia typically occurs within 2 weeks after initiation of drug therapy.18 More recently, there is evidence that drugs with combined SSRI/norepinephrine reuptake inhibitor (SNRI) activity, such as venlafaxine and duloxetine, and drugs capable of raising brain serotonin levels, such as mirtazapine, are also capable of producing SIADH-type hyponatremia.19
Angiotensin-converting enzyme (ACE) inhibitor use in the elderly population is associated with the development of hyponatremia.20 In most of the cases, the level of hyponatremia has been clinically significant, with serum sodium concentrations as low as 101 mEq/L and with symptoms ranging from confusion to seizures and coma. Although initial reports indicated that the risk was greatest when ACE inhibitors were used in combination with thiazide diuretics, it now appears that ACE inhibitors alone can precipitate hyponatremia. The hyponatremia appears to be dilutional with features of SIADH. Discontinuing the ACE inhibitor is associated with rapid resolution of the hyponatremia.
Diuretics, both of the loop and thiazide types, can produce hyponatremia.21 Loop diuretics appear to have a greater natriuretic effect in older persons than in younger persons. Hyponatremia can occur when diuretic-induced sodium and water loss are replaced by hypotonic fluids, resulting in a combined depletional and dilutional hyponatremia. With thiazide diuretics, the induced sodium loss is often accompanied by loss of total body potassium with consequent decrease in intracellular solute content and decreased cell volume. This circumstance can activate hypothalamic pathways leading to increased AVP discharge, water retention, and SIADH. This form of thiazide-induced hyponatremia occurs almost entirely in the elderly population and can be reversed by correcting the underlying potassium depletion.
Other drugs associated with development of hyponatremia in the elderly population include the sulfonylurea chlorpropamide, the anticonvulsant carbamazepine, and the antineoplastic agents vincristine, vinblastine, and cyclophosphamide. Analgesics, particularly the narcotics, may be responsible for the occurrence of hyponatremia in the elderly postoperative patient.
Mild chronic hyponatremia may appear to be asymptomatic. However, recent evidence from a case-control study suggests that mild chronic hyponatremia may have serious consequences in the elderly, even when symptoms appear to be absent.22 This study examined the frequency of falls in patients (mean age, 72 yr) with chronic hyponatremia (serum sodium 115-132 mEq/L) admitted to a medical Emergency Department. The frequency of reported falls was significantly greater among patients with hyponatremia (21.3%) than among control subjects (5.3%) and was unrelated to the level of hyponatremia. Alterations in gait and attention were detected in patients with hyponatremia and suggest that these impairments may have contributed to the higher incidence of falls in this group. The data suggest that prompt recognition of even apparently asymptomatic hyponatremia and early initiation of appropriate treatment may be important for preventing hyponatremia-related consequences.
The clinical severity of hyponatremia is dependent on both the magnitude of the hyponatremia and the rate at which the serum sodium level has declined.23 There is often a poor correlation between serum sodium concentration and severity of symptoms. Serum sodium levels less than 125 mEq/L may be accompanied by lethargy, fatigue, anorexia, nausea, and muscle cramps. With worsening hyponatremia, overt CNS symptoms predominate and range from confusion to coma to seizures. There is substantial risk of death in severely symptomatic patients with serum sodium less than 110 mEq/L who also have underlying disease with cachexia. Hyponatremia often is a marker for severe underlying disease with poor prognosis and high mortality.24 The presence of hyponatremia in patients with congestive heart failure is an independent risk factor for death.25 Hyponatremia is common in patients with liver cirrhosis, in whom it is associated with a significantly worse prognosis.26,27 It is unclear whether hyponatremia is the direct cause of death in these patients, but its prompt diagnosis and effective treatment are important in improving patient outcomes.
Treatment of hyponatremia is based on the absence or presence of symptoms and their severity, whether the onset is acute or chronic, and if acute, the rapidity of onset.23 Hyponatremia due to sodium depletion is often accompanied by extracellular fluid volume depletion, and treatment is directed at correcting the volume deficit with intravenous 0.9% saline. Milder depletional hyponatremia, such as that which occurs in persons whose nutrition is predominantly from enteral feedings, can be corrected by adding saline solution or crushed sodium chloride tablets to the enteral feedings.
For euvolemic patients thought to be asymptomatic, conservative management is appropriate with fluid restriction and an attempt to identify and correct the underlying cause, if possible.28 Mildly symptomatic patients with serum sodium greater than 125 mEq/L can be treated with fluid restriction to a level of 800-1000 mL/24 per hour. The patient with acute onset of symptomatic dilutional hyponatremia requires prompt intervention and is best managed in an Intensive Care Unit setting and treated with intravenous 3% saline infusion at a rate sufficient to raise serum sodium by 0.5-1 mEq/L per hour. The goal is a maximum increase in serum sodium of no more than 12 mEq/L in the first 24 hours, and to a value no higher than 125 mEq/L, in order to avoid central pontine myelinolysis.29 Occasionally, patients either with fluid overload and pulmonary edema or with symptoms of coma or seizures who have very low serum sodium levels may require initial treatment with intravenous furosemide in a dose of 1 mg/kg body weight along with the 3% saline. In this circumstance, attention will need to be given to possible diuretic-induced potassium and magnesium depletion.
Strategies currently used for the treatment of chronic stable, asymptomatic, or mildly symptomatic hyponatremia include mainly fluid restriction and occasionally demeclocycline. Demeclocycline in doses of 600-1200 mg daily blocks AVP effect on the renal distal and collecting tubules with production of a mild state of nephrogenic diabetes insipidus, thus promoting an increase in urine production and a corresponding increase in serum sodium.30 Both chronic fluid restriction and demeclocycline administration are limited by poor compliance, inconsistent or delayed response, and, in the case of demeclocycline, renal and hepatotoxicity.
Aquaretic Treatment of Hyponatremia
AVP receptor antagonists, a new class of drugs called “aquaretics,” promote electrolyte-free excretion of water and may provide a more effective approach to the treatment of both acute and chronic hyponatremia.31-33 AVP promotes renal water reabsorption by increasing the water permeability of epithelial cells in the renal collecting ducts through the binding of AVP to V2 receptors on these cells.
Excess or inappropriate secretion of AVP acting on renal V2 receptors causes the retention of water and can lead to dilutional hyponatremia. The blockade of these AVP V2 receptors by nonpeptide molecules, which can bind to AVP receptors, thus represents a novel approach to the treatment of hyponatremia. The nonpeptide AVP receptor antagonists currently in use or in clinical trials—conivaptan, tolvaptan, lixivaptan, and satavaptan—exhibit a long half-life and no agonist activity33,34 (Table V).
At the present time, conivaptan and tolvaptan are the only agents in this class to be approved by the Food and Drug Administration and are limited to the treatment of euvolemic hyponatremia in hospitalized patients. Conivaptan is administered intravenously and blocks the action of AVP at both the V2 receptor that mediates renal excretion of water and the V1A receptor located on smooth muscle that mediates systemic vasoconstriction. Tolvaptan, lixivaptan, and satavaptan are effective by oral administration and bind to V2 receptors in the renal tubules to block the action of AVP. In clinical trials, these drugs have been demonstrated to promote aquaresis within several hours of administration in patients with SIADH and in patients with hyponatremia due to congestive heart failure or cirrhosis, and also to maintain improvement in serum sodium for up to 12 months of chronic treatment.35,36
The AVP receptor antagonists may provide a more direct approach to the treatment of both acute and chronic euvolemic and hypervolemic hyponatremia than currently available therapies. Preliminary experience with the AVP receptor antagonists suggests that these agents are effective and well tolerated both acutely and following prolonged administration.36,37 Continued investigation should further define the role of AVP receptor antagonists in the treatment of acute and chronic hyponatremia in the elderly. The ability of the drugs to normalize serum sodium in patients who have chronic and apparently asymptomatic hyponatremia will help determine the clinical significance of this common electrolyte disturbance, especially the role of hyponatremia on worsening cognitive function in persons who already have underlying disorders of cognition. The potential ability of long-term treatment with AVP antagonists to alter diminished quality of life and mortality of persons with hypervolemic hyponatremia, such as occurs in congestive heart failure and in cirrhosis with ascites, remains an area for future investigation.
The author reports that he is a member of the speakers bureaus of Astellas Pharma US and Otsuka America Pharmaceutical. From the Department of Medicine, Johns Hopkins University School of Medicine, and the Department of Medicine, Sinai Hospital of Baltimore, Baltimore, MD.