Slide Lecture with Audio

Thank you for attending today's lecture, Current Trends in Hyponatremia in the Elderly. I am Dr. Myron Miller.

Among the most common disturbances of fluid and electrolyte balance is that of hyponatremia, a disorder of multiple causes that is highly prevalent in the elderly patient. If we look at the second slide, hyponatremia is generally defined as a serum sodium concentration of 135 mEq/L or less and occurs when there is an excess of extracellular water relative to sodium. Extracellular fluid volume can be increased with normal or increased total body sodium resulting in dilutional hyponatremia, the most common form of the disorder. This form of hyponatremia is often referred to as the syndrome of inappropriate antidiuretic hormone secretion (or SIADH) and is the leading cause of dilutional hyponatremia in the elderly. SIADH is characterized by the consistent release of antidiuretic hormone (ADH) along with body fluid dilution and increased extracellular fluid volume. Fluid volume can also be normal or decreased in the presence of sodium depletion, which results in depletional hyponatremia. It is not uncommon for a patient with hyponatremia to have both dilutional and depletional components contributing to the presence of hyponatremia.

If we look now at slide 3, the key points for this discussion, this presentation will deal with the magnitude of the problem and will review the circumstances that put the elderly individual at increased risk. Further, there will be discussion of the clinical consequences of hyponatremia and a review of current concepts in its management.

If we look at slide 4, hyponatremia in the elderly is a common and often unrecognized or unappreciated problem. The elderly are the age group at highest risk of developing hyponatremia because of the interaction of several events, which occur with increasing age. First, there are changes associated with normal aging, which affect the systems regulating water and sodium. Second, there are a number of diseases, which are common with increasing age. And third is the influence of drugs that are commonly prescribed in the elderly. The confluence of these events can result in the development of clinically significant hyponatremia.

Turning to slide 5, I will review some data on the prevalence of hyponatremia. A number of studies have been carried out during the past 15 to 20 years, which have established that hyponatremia is a common finding in the elderly. If one looks at ambulatory, community-residing elderly, approximately 7% to 10% have been found to have hyponatremia. If one looks at a sicker segment of the elderly population, that is individuals who are hospitalized, a prevalence of 10% to 20% has been identified. If one looks at the oldest, frailest component of the elderly population, those who reside in nursing homes, it has been shown that as many as 18% to 20% of individuals will have hyponatremia. If that population is looked at on a longitudinal basis over a period of 12 months, more than 50% have been shown to have one or more episodes of hyponatremia occurring in that time period.

Now look at slide 6. Why is it then that these older individuals are so likely to develop hyponatremia? One factor has to do with physiologic changes of aging, which increase the risk for hyponatremia. A number of these changes are listed, and these are changes, which occur as part of the normal aging process. First, there is a decrease in total body water and the extracellular fluid compartment. A consequence of this is that exposure of the individual to hypotonic fluid results in an increased risk for developing a dilutional form of hyponatremia. Second, there is a decrease in renal blood flow, and third, there is a decrease in glomerular filtration rate. Both of these events are associated with an increase in passive water reabsorption in the distal part of the renal tubule. Next we see that there is impaired renal diluting capacity and impaired renal sodium conservation. The impaired renal sodium conservation results in an increased risk of sodium loss and, therefore, can contribute to a depletional hyponatremia. Hormonal changes occur in association with the aging process, which can affect the sodium and water regulation. There is an increase in the production of atrial natriuretic hormone, which, as its name implies, acts on the kidney to cause an increase in sodium excretion. In addition, there is a decrease in activity of the renin-angiotensin-aldosterone system, so that aldosterone, a hormone involved in sodium retention, is present in lesser amounts and, therefore, can be a factor contributing to the sodium losing state characteristic of older individuals. Finally, there is an increase in ADH secretion in response to osmotic and some other stimuli. The consequence of this is that the action of ADH on the kidney can lead to increased water reabsorption and the development of dilutional hyponatremia.

If we look at slide 7 now, there are several considerations that need to be made in the evaluation of the patient with hyponatremia. First is the determination of whether the picture of hyponatremia is more compatible with a dilutional or depletional form. Secondly, the individual needs to be evaluated for the presence of diseases that are associated with hyponatremia, both of the SIADH type and non-SIADH type. Third, a careful history must be taken looking for the possible role of drugs that may be associated with hyponatremia. Fourth, one must look for the possibility that iatrogenic causes may contribute to the hyponatremia. Finally, there is the possibility that an older person with hyponatremia may have idiopathic SIADH of the elderly, a syndrome, which is now being appreciated.

I will now review each of these in more detail. If you will look at slide 8, here are shown features that help to differentiate dilutional from depletional hyponatremia. If you will look first at the column labeled dilutional, an important component is history, looking particularly for history of increased fluid intake, which can be oral or intravenous (IV) fluid. We also look for a history of clinical disorders that may underlie dilutional hyponatremia, and in particular, a history of malignancy or central nervous system (CNS) disorders. Next, a careful drug history must be taken, and we will see in a few moments, which drugs in particular are of concern. On physical examination, one could make a judgment as to whether the individual is euvolemic or has edema. In general, individuals with SIADH as the mechanism for dilutional hyponatremia do not have edema. Also on physical examination, one looks for evidence of CNS disorders, pulmonary disease, and malignancy. If we now turn to the laboratory, one looks for evidence of dilution, particularly as reflected by a decrease in hematocrit, blood urea nitrogen (BUN), and creatinine. Uric acid levels are often low in dilutional hyponatremia because an increase in intravascular volume results in an increase in uric acid excretion. An important measure to obtain is the urine sodium concentration, which can be obtained on a random urine specimen. In general, individuals with dilutional hyponatremia have an increase in sodium excretion, generally more than 20 mEq/L. Let's now look at the column labeled depletional. Again, the history is important, and in particular one looks for evidence of a decrease in sodium intake, perhaps as a result of an individual having been put on a low sodium diet. One also looks for evidence of sodium loss, most commonly through the gastrointestinal (GI) tract in the form of vomiting or diarrhea. We also look for a history of renal disorders or adrenal disease, both of which can be associated with sodium loss. We also must take a careful history for drug use, particularly diuretics, which can lead to sodium loss. On physical examination, one looks for features compatible with volume depletion, which often accompanies sodium depletion and may be clinically manifested by the presence of drawn mucous membranes, decreased skin turgor, hypotension, and orthostatic tachycardia. Turning to the laboratory, we often find an increase in hematocrit, BUN, and creatinine. When significant sodium depletion has occurred, urinary sodium excretion tends to be low, generally less than 20 mEq/L.

Let's now look at slide 9 at some of the diseases associated with hyponatremia. Among the most common are CNS disorders. Almost any form of CNS disease can be associated with hyponatremia and generally are due to the SIADH type. Virtually any vascular disease, including thrombosis, embolism, hemorrhage, or vasculitis, can result in SIADH-type hyponatremia. Head trauma, particularly that associated with the development of subdural hematoma, subarachnoid hemorrhage, or intracranial hemorrhage, is commonly accompanied by the development of hyponatremia. CNS tumors may also be a cause of hyponatremia. Most of the infections that involve the CNS, including meningitis, encephalitis, and brain abscess can be accompanied by hyponatremia. Perhaps second most important in terms of diseases are malignancies in which ectopic ADH is produced. By far the most common of these is small cell carcinoma of the lung, which makes up approximately 80% of the malignancies associated with SIADH. Other malignancies include pharyngeal carcinoma, pancreatic carcinoma, thymoma, lymphoma, Hodgkin's disease, and reticulum cell sarcoma. There have also been reports that bladder carcinoma may be associated with SIADH. As you would appreciate, most of these malignancies have an increased prevalence in older individuals.

If we now look at slide 10 at additional diseases associated with hyponatremia, we note that inflammatory or nonmalignant pulmonary diseases can be associated with hyponatremia, usually of the SIADH type. Bacterial pneumonias of any form can be associated with hyponatremia, and in particular Legionella pneumonia is commonly accompanied by hyponatremia. Other pulmonary diseases include lung abscess, bronchiectasis, and tuberculosis. There are several endocrine disorders in which hyponatremia may occur. Pituitary tumors can affect the production of ADH and lead to SIADH, but this is an extremely rare presentation. Hypothyroidism and adrenal insufficiency are often accompanied by impairments in water excretion, leading to the development of hyponatremia. There are several other disorders that can lead to hyponatremia. It has been well recognized in recent years that AIDS often is accompanied by hyponatremia. Diabetes mellitus with marked hyperglycemia can lead to hyponatremia due to increased intravascular volume and response to osmotic-induced movement of water into the intravascular space. In this circumstance, the hyponatremia is transient and resolves when blood sugar returns to normal. A useful correction factor for the effect of hyperglycemia on serum sodium is that each 100 mg/dL rise in glucose can decrease serum sodium by 1.6 mEq/L. And, finally, it should be pointed out that individuals who are on positive pressure ventilation are at increased risk for hyponatremia.

If we now look at slide 11, drugs associated with dilutional hyponatremia, another factor associated with the development of hyponatremia, particularly SIADH type in the elderly, is the exposure to a number of drugs. Among the most common drugs are those that have effect on CNS function. These include the antipsychotics, the antidepressants, including both the tricyclic antidepressants and selective serotonin reuptake inhibitor (SSRI) type of antidepressants. Typically, hyponatremia develops within 3 weeks of initiation of SSRI therapy. The anticonvulsive carbamazepine has also been associated with hyponatremia. Narcotics, particularly when administered in the acute, postoperative period, are often accompanied by the development of hyponatremia, particularly if fluid intake is high. There have been a number of reports that hallucinogenics, particularly the drug known as Ecstasy, can be accompanied by severe and sometimes fatal hyponatremia. Although this is not commonly seen in the elderly, it is possible that an older individual could gain exposure to this, and questioning with regard to the use of elicit drugs should be part of the evaluation of the individual with otherwise unexplained hyponatremia. It is becoming increasingly recognized that all of the angiotensin converting enzyme inhibitors (or ACE inhibitors) can be associated with hyponatremia, which has the characteristics of SIADH. Another category of drugs are the antineoplastic agents, particularly vincristine, vinblastine, and cyclophosphamide, which are commonly associated with hyponatremia, generally occurring somewhere between 7 to 10 days after administration of the drugs and subsequently resolving. In some circumstances, the hyponatremia may be severe enough to produce major symptomatology. The antidiuretic analog desmopressin, or DDABP as it's commonly known, is now being used more commonly not only for its initial indication in the treatment of diabetes insipidus, but for treatment of other polyuric disorders. Approximately 20% of individuals who are given desmopressin will develop hyponatremia and, therefore, warrant careful observation whenever this drug is to be initiated. The older sulfonylurea, chlorpropamide, which is now rarely used, has been associated with the development of hyponatremia in the past, and individuals who might still be receiving this drug should be transferred to a different and more appropriate sulfonylurea. Similarly, an older hypolipidemic agent, clofibrate, has been associated with hyponatremia, and, again, individuals receiving this drug should be considered for transfer to a different agent.

There are also drugs, which are associated with depletional hyponatremia, as we'll see on slide 12. The most common of these are the thiazide diuretics and loop diuretics. In some individuals taking thiazide diuretics, the hyponatremia can be of mixed type. In individuals taking thiazide who develop significant hypokalemia a component of the hyponatremia has been shown to be due to SIADH, as well as to sodium depletion. In these circumstances the hyponatremia will often improve when the individuals are potassium repleted. Other agents that can cause depletional hyponatremia are osmotic diuretics, which include glucose, mannitol, and urea.

If we now look at slide 13, in recent years, an entity has been identified called iatrogenic hyponatremia. In this circumstance, the cause of hyponatremia is something that has been done to the patient who has an underlying, predisposing set of circumstances, which allows that patient to become hyponatremic. The most common factor is fluid overload with hypotonic fluid. This can be in the form of hypotonic IV fluids given as half normal saline or as oral fluids when orders have been written to push fluids without specifying the quantity to be administered. Another form of iatrogenic hyponatremia is that occurring as a consequence of low sodium intake. This can occur in conjunction with nasogastric or percutaneous endoscopic gastrostomy (or PEG) tube feedings. Most of the tube-feeding diets are extremely low in sodium, and over a period of time, individuals will develop sodium depletion. In addition, individuals who were put on a low sodium diet will often end up with sodium depletion and hyponatremia.

On the next slide, number 14, data are shown that were obtained in a study of residents in a nursing home who had developed hyponatremia. What we see here is that the most common circumstance for the development of hyponatremia was an increase in fluid intake, both as IV and as oral fluid, so that 78% of the residents with hyponatremia had their hyponatremia due to increased fluid intake. As you will note, the numbers add up to greater than 100%, and that is because in many of the individuals, more than one factor was identified as a causative event in the development of hyponatremia. Low sodium diets also contributed to hyponatremia in 32% of the individuals. Tube feeding was a factor in 14%, pneumonia in 14%, and drugs in 11%. I want to call your attention to the last category, no evident cause, which was found in 6% of the nursing home residents. I will come back to this in a moment.

If you look at the next slide, number 15, here we see the impact of tube feeding on the development of hyponatremia. Twelve individuals in this nursing home population received their nutritional support solely through tube feeding. Of these 12 individuals, 11 developed hyponatremia, six in whom the hyponatremia was persistent and five in whom it was intermittent.

As I mentioned on slide 14, a small segment of older individuals with hyponatremia will not have an identifiable cause for the development of the disorder after extensive clinical evaluation. If you look at slide 16, what is shown here are the characteristics of individuals who have been identified as having idiopathic SIADH of the elderly. The general characteristics are that it is hyponatremia of the SIADH type in the absence of an identifiable cause, generally occurring in individuals older than 80 years of age, and for reasons, which are unclear, occurring predominantly in races other than black.

Now look at slide 17. Why is it then that there is such concern about the development of hyponatremia in older individuals? As we look at slide 17, we see that there are a number of effects of hyponatremia on the brain. When hyponatremia develops acutely, there is an increase in brain water content and an increase in intracranial pressure. With chronic hyponatremia, there is a decrease in brain sodium, potassium, chloride, and amino acid content, which is related to impaired energy metabolism, ultimately resulting in impaired neurotransmitter release from CNS neurons.

If we now look at slide 18, we see at the clinical level, the manifestations of hyponatremia may range from none to severe. Milder forms of hyponatremia will often present with nonspecific symptoms, including anorexia, headache, and muscle cramps. With more severe levels of hyponatremia, the symptoms are related predominantly to alterations in CNS function, and these are nausea and vomiting, confusion, and personality change. With more severe hyponatremia, the manifestations are seizures, coma, and in some patients, death.

If we now look at slide 19, we will see some data attempting to relate serum sodium level with the magnitude of symptoms. Although there is a rough relationship between serum sodium and symptoms, there is a wide spread in serum sodium values, so that some individuals with higher serum sodium levels had severe symptoms and some individuals with lower serum sodium levels had relatively mild symptoms. If we look at the mean serum sodium concentrations, however, we see that the absence of symptoms in the alert group occurs with a mean serum sodium of about 124 mEq/L. Confusion is present when the mean serum sodium is about 119 mEq/L. Stupor and coma occur with serum sodium levels in the 110 mEq/L range, and similarly, seizures with a mean serum sodium of around 110 mEq/L.

If we now look at slide 20, hyponatremia not only is capable of causing significant symptomatology, but also there is a significant mortality associated with it. On this slide, we see the influence of hyponatremia, defined in this study as serum sodium less than 130 mEq/L on mortality in hospitalized individuals. The death rate in hospitalized individuals with hyponatremia is 8.7% compared with 1.1% in individuals with a serum sodium level greater than 130 mEq/L for an odds ratio of 7.33. After discharge, hyponatremia continued as a risk factor for death, with a mortality rate of 13.1% postdischarge for patients with hyponatremia versus 6.7% for individuals with higher serum sodium levels. If we look at overall mortality, both in hospital and after discharge, there is a 21.5% mortality rate in individuals with hyponatremia versus 7.9% in individuals with higher serum sodium levels. Given this background, we recognize that it becomes important to appropriately manage hyponatremia when it is identified.

If we now look at slide 21, we see here guidelines for the acute management of dilutional hyponatremia. If the individual is asymptomatic or exhibits only mild symptoms compatible with hyponatremia, fluid restriction alone should be sufficient. Symptomatic patients, though, should be placed in an intensive care unit setting where monitoring of fluid intake and output and of serum electrolytes can be done on a regular basis. The critical element of therapy is the administration of hypertonic saline in the form of 3% saline given IV at a rate sufficient to raise the serum sodium by 0.5 to 1 mEq/L per hour, by no more than 12 mEq/L over the ensuing 24 hours, and to a maximum level not to exceed 125 mEq/L. Proceeding at a faster rate or taking the serum sodium level beyond 125 mEq/L can predispose the patient to the development of central pontine myelinolysis. In an occasional patient, the response to hypertonic saline may be slow, and in that circumstance, one can consider giving IV furosemide or another loop diuretic at a dose of 1 mg/kg body weight to induce a prompt diuresis. This class of diuretics produces hypotonic urine, ridding the body of more water than salt. Diuretics affecting the distal tubules, such as those of thiazide type, are not as effective because they induce isotonic urine. In all of these circumstances, serum sodium levels must be monitored at 1- to 2-hour intervals to assure that the rate and magnitude of increase in serum sodium levels do not exceed the previously mentioned guidelines. Once the serum sodium has been increased to greater than 125 mEq/L, the IV fluid should be changed to 0.9% saline in an attempt to maintain the serum sodium levels at around 125 mEq/L or slightly higher. In addition, fluid restriction is usually required to maintain the serum sodium level.

If we now look at slide 22, for individuals who have chronic hyponatremia, the approach is to try to correct the underlying cause, if possible. In the case of malignancy, it may mean appropriate surgery or chemotherapy; for infectious disorders, appropriate antimicrobial treatment. If the hyponatremia is related to a drug, then the drug should be discontinued. Some degree of fluid restriction is often required, and this may mean fluid intake of no more than 800 to 1000 mL per 24 hours. For individuals who fail to respond to fluid restriction, in whom the underlying cause cannot be corrected, and who continue to have significant chronic hyponatremia one can use demeclocycline in a dose of 600 to 1200 mg daily.

If we now turn to slide 23, here is some background information on the use of demeclocycline. Demeclocycline is in the tetracycline class of antibiotics and has been shown to block the affect of ADH on the kidney and cause an increase in water excretion. This effect was uncovered in a 1973 study by Singer, et al., during which renal-concentrating defects were found in eight of 24 patients being treated with demeclocycline for acne. In three patients, a dose-dependent defect in ADH responsiveness was found. The impact of demeclocycline in the treatment of SIADH has been evident in multiple small studies, including a 1979 study by Perks, et al. In that study, which was published in Thorax, demeclocycline was shown to have a normalizing effect on serum sodium levels in 14 patients with SIADH.

If we turn now to slide 24, this slide illustrates the effectiveness of demeclocycline in the treatment of a patient with persistent hyponatremia in whom the hyponatremia was due to lung cancer with inappropriate ADH syndrome. In the upper panel, we see that this individual required fluid restriction to approximately 600 mL per day, and even in the face of fluid restriction of this magnitude, serum sodium remained low. It was extremely difficult to have the patient comply with this level of fluid restriction over a prolonged period of time. As we see in the middle portion of the figure, demeclocycline was started at a dose of 300 mg four times daily. Within approximately 4 days, urine osmolality, which had been in the range of 700 to 900 mOsm, dropped to approximately 300 mOsm, and this was accompanied by a gradual rise in serum sodium. With this, fluid intake was liberalized, and after approximately 1 week, fluid restriction was removed. Even on ad libitum fluid intake, serum sodium remained stable in the range of 135 to 140 mEq/L, clearly demonstrating the beneficial effect of demeclocycline in the management of this individual. When the demeclocycline was discontinued, urine osmolality again began to rise.

Now on slide 25, I would like to review some of the information that has developed in the past several years on the use of ADH antagonists. These agents are nonpeptides that have been given the name aquaretics. They act by blocking the action of ADH in the kidney and by binding to the ADH receptors, thereby preventing native ADH from acting. In this slide is illustrated the acute effect of an investigational drug given the name OPC-31260 given IV to a group of patients with SIADH. Three doses were administered, and as we see in the top left figure, with the higher doses, there is a prompt increase in urine volume, which persists for approximately 3 hours. In the figure at the bottom left, drug administration is accompanied by a prompt, significant decrease in urine osmolality, dropping from a baseline of approximately 550 mOsm to a low point of approximately 150 to 200 mOsm, with the effect lasting for 3 to 4 hours. In the figure on the right, we can see the effect of the drug on serum sodium. If we look at the line made up of solid circles, we see that the serum sodium level rose from 126 to approximately 132 mEq/L within 3 hours of administration of the drug.

In slide 26 are data from the use of another of these aquaretic agents, this one given orally in a dose of 50 or 100 mg twice daily to a group of six patients with SIADH. As you will see from the table, urine volume increased from 0.84 to 1.46 mL per minute in the 24-hour period following administration of the drug, and urine osmolality decreased by almost half from 414 to 209 mOsm. The aquaretics are currently undergoing investigation in phase III clinical trials. The hope is that in the not too distant future they will be available and will add to our capability of treating patients with significant hyponatremia.

Now turn to slide 27. In the treatment of patients with hyponatremia, one has to be careful that the treatment itself does not result in significant adverse consequences. Shown here is a list of some of the concerns in monitoring patients who are being treated for hyponatremia. The administration of hypertonic saline, if given too rapidly, can result in too great a rise in serum sodium and can lead to the development of central pontine myelinolysis, a devastating brain disorder that is almost always fatal. In older individuals who have a history of congestive heart failure, a high rate of fluid and sodium administration could lead to the precipitation of congestive heart failure. In the circumstance of a patient who has a known history of congestive heart failure, careful monitoring needs to be carried out and consideration should be given to the concomitant use of IV furosemide. Furosemide itself can be associated with both hypokalemia and hypomagnesemia, and if this agent is used, careful monitoring of blood electrolytes is essential.

Now look at slide 28. There are also potential adverse consequences with chronic treatment of hyponatremia. Fluid deprivation can lead to thirst stimulation, which will make it difficult for the individual to continue to comply with the fluid deprivation regimen. In addition, significant fluid deprivation can be accompanied by volume depletion, and this, in turn, can lead to a decline in renal blood flow and glomerular filtration rate, with subsequent increased renal water reabsorption. This may compound the problem then of trying to maintain an improvement in serum sodium. Demeclocycline has been associated with photosensitivity, azotemia, and nephrotoxicity in patients with hepatic disease or congestive heart failure. Generally, these problems have been reversible with cessation of the demeclocycline, and it requires then that individuals who are being treated with this drug be monitored carefully for changes in renal and liver function tests.

Now turn to slide 29. With an understanding of the factors that can result in hyponatremia, it is possible to consider the concept of primary prevention in the elderly. First, excessive hypotonic fluid intake should be avoided, either as IV hypotonic fluid or as oral push fluid orders without specific quantification. Low sodium diets should be advised only when there is clear, clinical justification for low sodium intake. Tube-feeding diets should be reviewed for their sodium content, and if the sodium content is low, sodium should be added to the tube-feeding regimen. This can easily be done by flushing the feeding tube periodically with normal saline. When individuals are started on drugs that are capable of affecting serum sodium, particularly ACE inhibitors, SSRIs, and diuretics, serum sodium must be monitored at relatively frequent and regular intervals to detect the onset of hyponatremia, which can become significant if not recognized. With these measures in mind, it should be possible to reduce the development of hyponatremia in the older population, or when it does occur, to initiate early effective management and reduce the morbidity and mortality, which can be associated with this disorder.

If we now turn to slide 30, the conclusions, in summary, the elderly patient is at increased risk of development of hyponatremia, which can be associated with significant morbidity and mortality. Understanding of the factors that put the older person at increased risk can lead to reduction in the development of hyponatremia and early recognition of its presence. Effective therapeutic interventions are available for the management of patients with acute symptomatic hyponatremia and for the long-term management of those with chronic hyponatremia. This concludes today's lecture. I thank you for your attention.