Articles on Medical Diseases and Conditions

Tag: Hyponatremia

  • Laboratory Investigation of Hyponatremia

    When the serum sodium level is unexpectedly low, one must determine whether it is due to false (artifactual) hyponatremia, sodium depletion, hemodilution, the IADH syndrome, or the reset osmostat syndrome. The first step is to rule out artifactual causes. The serum sodium tests should be repeated and blood redrawn if necessary, avoiding areas receiving IV infusions. Then, other causes for artifact, such as hyperlipemia or myeloma protein (if a flame photometer is being used), should be excluded. Next, iatrogenic causes should be considered, including sodium-poor IV fluids (producing dilution) and diuretics (producing sodium depletion). If none of these possibilities is the cause, measurement of urine sodium excretion and serum or urine osmolality may be useful.

    Urine sodium. In hyponatremia, the kidney normally attempts to conserve sodium, so that the urine sodium level is low (<20 mEq/L, usually <10 mEq/L). If the patient has hyponatremia and is not receiving IV fluids containing sodium, and if the urine sodium concentration is normal or high (e.g., early morning random urine sodium >20 mEq/L), this suggests inappropriate sodium loss through the kidneys. Possible etiologies are (1) acute or chronic renal failure, such as diffuse, bilateral, renal tissue injury (blood urea nitrogen [BUN] and serum creatinine levels confirm or eliminate this possibility); (2) effect of diuretics or osmotic diuresis; (3) Addison’s disease; (4) IADH syndrome; and (5) the reset osmostat syndrome.

    A low urine sodium concentration is a normal response to a low serum sodium level and suggests (1) nonrenal sodium loss (sweating or GI tract loss), (2) the reset osmostat syndrome, and (3) ECF dilution. Presence of edema favors ECF dilutional etiology (e.g., cirrhosis, congestive heart failure, nephrotic syndrome). Measurement of certain relatively stable constituents of blood, such as hemoglobin and total protein, may provide useful information. However, one must have previous baseline values to assist interpretation. A significant decrease in hemoglobin and total protein levels possibly in other substances such as serum creatinine and uric acid suggests hemodilution. Similar changes in several blood constituents are more helpful than a change in only one, since any constituent could change due to disease that is independent of vascular fluid shifts. A significant increase in hemoglobin level and other blood constituents suggests nonrenal sodium loss with accompanying dehydration.

    The best way to determine hemodilution or hemoconcentration is by plasma volume measurement, most often by using albumin tagged with radioactive iodine. However, the diagnosis usually can be made in other ways.

    Serum and urine osmolality. Osmolality is the measurement of the number of osmotically active particles in a solution. It is determined by either the degree of induced freezing point change or measurement of vapor pressure in special equipment. Units are milliosmoles per liter of water. Therefore, osmolality depends not only on the quantity of solute particles but also on the amount of water in which they are dissolved. Sodium is by far the major constituent of serum osmolality. Plasma proteins have little osmotic activity and normally are essentially noncontributory to serum osmolality. Serum (or plasma) osmolality may be calculated from various formulas, such as:

    mOs m/L = 2Na + BG/20 + BUN/3

    where blood glucose (BG) and BUN are in mg/100 ml and Na (sodium) is in mEq/L. The adult reference range is 275-300 mOsm/L. The ratio of serum sodium concentration to serum osmolality (Na/Osm) is normally 0.43-0.50.

    Increased serum osmolality. Increased serum osmolality may be caused by loss of hypotonic (sodium-poor) water producing dehydration. Some etiologies include diabetes insipidus, fluid deprivation without replacing the daily insensible water loss of 0.5-1.0 L, and hypotonic fluid loss from skin, GI tract, or osmotic diuresis. It may also be caused by sodium overload, hyperglycemia (100 mg of glucose/100 ml increases osmolality about 5.5 mOsm/L), uremia (10 mg of urea/100 ml increases osmolality about 3.5 mOsm/L), unknown metabolic products, or various drugs or chemicals, especially ethyl alcohol. Ethanol is one of the more common causes for increased serum osmolality. Each 100 mg of ethanol/100 ml (equivalent to a serum concentration of 0.1%) raises serum osmolality about 22 mOsm/L. An “osmolal gap” (the difference between the calculated and the measured osmolality) of more than 10 mOsm/L provides a clue to the presence of unusual solutes. Osmolality is one of the criteria for diagnosis of hyperosmolar nonketotic acidosis and of the IADH syndrome (discussed previously). Renal dialysis units sometimes determine the osmolality of the dialysis bath solution to help verify that its electrolyte composition is within acceptable limits.

    Decreased serum osmolality. Serum osmolality is usually decreased (or borderline low) in true noncomplicated hyponatremia. Hyponatremia with definitely normal or elevated serum osmolality can be due to (1) artifactual hyponatremia, due to interference by hyperlipidemia or elevated protein with flame photometer methods; (2) the presence of abnormal quantities of normal hyperosmolar substances, such as glucose or urea; or (3) the presence of abnormal hyperosmolar substances, such as ethanol, methanol, lactic acid or other organic acids, or unknown metabolic products. In categories 2 and 3, measured osmolality is more than 10 mOsm/L above calculated osmolality (alcohol does not produce this osmolal gap when the vapor pressure technique is used). Most of the hyperosmolar substances listed here, with the exception of ethanol, are associated with metabolic acidosis and will usually produce an elevated anion gap.

    An appreciable minority of patients with hyponatremia (especially of mild degree) have serum osmolality results in the low-normal range, although theoretically the osmolality value should be decreased. Some of these patients may be dehydrated; others may have cardiac, renal, or hepatic disease. These diseases characteristically reduce the Na/Osm ratio, this being partially attributed to the effects of increased blood glucose, urea, or unknown metabolic substances. Especially in uremia, osmolality changes cannot always be accounted for by the effects of BUN alone. Patients in shock may have disproportionately elevated measured osmolality compared with calculated osmolality; again, this points toward circulating metabolic products. Besides elevating osmolality, these substances displace a certain amount of sodium from serum, thus lowering sodium levels.

    Urine osmolality. In patients with hyponatremia, urine osmolality is most helpful in diagnosis of the IADH syndrome (discussed previously). Otherwise, urine osmolality values parallel the amount of sodium excreted, except that osmolality values may be disproportionately increased when large quantities of hyperosmotic substances (glucose, urea, ethanol, etc.) are also being excreted, causing an increased urine osmolality gap.

    Summary of laboratory findings in hyponatremia

    1. When hyponatremia is secondary to exogenous hemodilution from excess sodium-deficient fluid (e.g., excess IV fluids or polydipsia), serum osmolality is low, urine osmolality is low, and the urine sodium level is low. There may be other laboratory evidence of hemodilution.

    2. When hyponatremia is secondary to endogenous hemodilution in cirrhosis, nephrotic syndrome, or congestive heart failure, serum osmolality is decreased and the urine sodium concentration is low. There may be other laboratory evidence to suggest hemodilution. The patient may have visible edema. The underlying condition (e.g., cirrhosis) may be evident.

    3. When hyponatremia is due to sodium loss not involving the kidney (skin or GI tract), serum osmolality is usually decreased (or low normal due to dehydration if there is water intake that is inadequate). The degree of dehydration would influence the serum osmolality value. The urine sodium concentration is low. There may be other laboratory and clinical evidence of dehydration.

    4. When hyponatremia is due to sodium loss through the kidneys (diuretics, renal failure, Addison’s disease), there is low serum osmolality and the urine sodium concentration is increased. Both BUN and serum creatinine levels are elevated in chronic renal disease (although they can be elevated from prerenal azotemia with normal kidneys).

    5. In IADH syndrome, serum osmolality is low, urine osmolality is normal or increased, and urine sodium concentration is normal or high. Serum AVP (ADH) level is elevated.

    6. In false hyponatremia due to marked serum protein or triglyceride elevation, serum sodium concentration is mildly decreased, serum osmolality is normal, and urine sodium concentration is normal.

    7. In hyponatremia secondary to marked hyperglycemia, serum osmolality is increased; this suggests the presence of hyperosmotic substances, of which glucose can be confirmed by a blood glucose measurement.

    The laboratory findings described earlier and summarized above apply to untreated classic cases. Diuretic or fluid therapy, or therapy with various other medications, may alter fluid and electrolyte dynamics and change the typical laboratory picture, or may even convert one type of hyponatremia into another. There is also a problem when two conditions coexist, for example, depletional hyponatremia from GI tract loss (which should produce dehydration and low urine sodium concentration) in a patient with poor renal function (whose kidneys cannot conserve sodium and who thus continues to excrete normal amounts of sodium into the urine despite dehydration).

    Certain other test results or clinical findings suggest certain diseases. Hyperkalemia with hyponatremia raises the possibility of renal failure or Addison’s disease. If the patient’s hyponatremia is at least moderate in degree and is asymptomatic, it may reflect chronic hyponatremia rather than acute. If the patient has the reset osmostat syndrome, water restriction does not correct the hyponatremia, whereas water restriction would correct the hyponatremia of the IADH syndrome. If the serum osmolality is well within reference range in a patient with hyponatremia, and the sodium assay was done using flame photometry, serum total protein measurement and examination of the serum for the creamy appearance of hypertriglyceridemia can point toward pseudohyponatremia. If ion selective electrodes were used to assay sodium, and serum osmolality is normal or elevated in hyponatremia, calculation of the osmolal gap can point toward the presence of unexpected hyperosmolal substances.

  • Disorders Simulating Inappropriate Antidiuretic Hormone

    Refractory dilutional syndrome is a moderately frequent condition in which many features of IADH are seen but the classic syndrome is not present. The dilutional hyponatremia of cirrhosis and congestive heart failure may sometimes be of this type, although usually other mechanisms can better account for hyponatremia, such as overuse of diuretics. However, in some cases, IADH syndrome seems to be contributory. These patients differ from those with the classic IADH syndrome in that edema is often present and the urine contains very little sodium. In other words, the main feature is water retention with dilutional hyponatremia. Treatment with sodium can be dangerous, and therapy consists of water restriction.

    Reset osmostat syndrome is another syndrome involving hyponatremia without any really good explanation, although, again, IADH syndrome may contribute in part. These persons have a chronic wasting illness such as carcinomatosis or chronic malnutrition or may simply be elderly and without known disease. Serum sodium levels are mildly or moderately decreased. As a rule, affected persons do not exhibit symptoms of hyponatremia and seem to have adjusted physiologically to the lower serum level. Treatment with salt does not raise the serum values. Apparently the only cure is to improve the patient’s state of nutrition, especially the body protein, which takes considerable time and effort. This condition has also been called the “tired cell syndrome.”

  • Hyponatremic Depletional Syndromes

    In protracted and severe vomiting, as occurs with pyloric obstruction or stenosis, gastric fluid is lost in large amounts and a hypochloremic (acid-losing) alkalosis develops. Gastric contents have a relatively low sodium content and water loss relatively exceeds electrolyte loss. Despite relatively low electrolyte content, significant quantities of electrolytes are lost with the fluid, leading to some depletion of total body sodium. The dehydration from fluid loss is partially counteracted by increased secretion of arginine vasopressin (AVP, or vasopressin; antidiuretic hormone, ADH) in response to decreased fluid volume. AVP promotes fluid retention. Whether hyponatremia, normal-range serum sodium values, or hypernatremia will develop depends on how much fluid and sodium are lost and the relative composition and quantity of replacement water and sodium, if any. Oral or parenteral therapy with sodium-free fluid tends to encourage hyponatremia. On the other hand, failure to supply fluid replacement may produce severe dehydration and even hypernatremia. Serum potassium values are most often low due to direct loss and to alkalosis that develops when so much hydrochloric acid is lost. Similar findings are produced by continuous gastric tube suction if continued over 24 hours.

    In severe or long-standing diarrhea, the most common acid-base abnormality is a base-losing acidosis. Fluid loss predominates quantitatively over loss of sodium, chloride, and potassium despite considerable depletion of total body stores of these electrolytes, especially of potassium. Similar to what occurs with vomiting, decrease in fluid volume by fluid loss is partially counteracted by increased secretion of AVP (ADH). Again, whether serum sodium becomes decreased, normal, or increased depends on degree of fluid and electrolyte loss and the amount and composition of replacement fluid (if any). Sufficient electrolyte-free fluids may cause hyponatremia. Little or no fluid replacement would tend toward dehydration, which, if severe, could even produce hypernatremia. The diarrhea seen in sprue differs somewhat from the electrolyte pattern of diarrhea from other causes in that hypokalemia is a somewhat more frequent finding.

    In extensive sweating, especially in a patient with fever, large amounts of water are lost. Although sweat consists mostly of water, there is a small but significant sodium chloride content. Enough sodium and chloride loss occurs to produce total body deficits, sometimes of surprising degree. The same comments previously made regarding gastrointestinal (GI) content loss apply here also.

    In extensive burns, plasma and extracellular fluid (ECF) leak into the damaged area in large quantities. If the affected area is extensive, hemoconcentration becomes noticeable and enough plasma may be withdrawn from the circulating blood volume to bring the patient close to or into shock. Plasma electrolytes accompany this fluid loss from the circulation. The fluid loss stimulates AVP (ADH) secretion. The serum sodium level may be normal or decreased, as discussed earlier. If the patient is supported over the initial reaction period, fluid will begin to return to the circulation after about 48 hours. Therefore, after this time, fluid and electrolyte replacement should be decreased, so as not to overload the circulation. Silver nitrate treatment for extensive burns may itself cause clinically significant hyponatremia (due to electrolyte diffusion into the hypotonic silver nitrate solution).

    Diabetic acidosis and its treatment provide very interesting electrolyte problems. Lack of insulin causes metabolism of protein and fat to provide energy that normally is available from carbohydrates. Ketone bodies and other metabolic acids accumulate; the blood glucose level is also elevated, and both glucose and ketones are excreted in the urine. Glucosuria produces an osmotic diuresis; a certain amount of serum sodium is lost with the glucose and water, and other sodium ions accompany the strongly acid ketone anions. The effects of osmotic diuresis, as well as of the accompanying electrolyte loss, are manifested by severe dehydration. Nevertheless, the serum sodium and chloride levels are often low in untreated diabetic acidosis, although (because of water loss) less often they may be within normal range. In contrast, the serum potassium level is usually normal. Even with normal serum levels, considerable total body deficits exist for all of these electrolytes. The treatment for severe diabetic acidosis is insulin and large amounts of IV fluids. Hyponatremia may develop if sufficient sodium and chloride are not given with the fluid to replace the electrolyte deficits. After insulin administration, potassium ions tend to move into body cells as they are no longer needed to combine with ketone acid anions. Also, potassium is apparently taken into liver cells when glycogen is formed from plasma glucose under the influence of insulin. In most patients, the serum potassium level falls to nearly one half the admission value after 3-4 hours of fluid and insulin therapy (if urine output is adequate) due to continued urinary potassium loss, shifts into body cells, and rehydration. After this time, potassium supplements should be added to the other treatment.

    Role of the kidney in electrolyte physiology

    In many common or well-recognized syndromes involving electrolytes, abnormality is closely tied to the role of the kidney in water and electrolyte physiology. A brief discussion of this subject may be helpful in understanding the clinical conditions discussed later.

    Urine formation begins with the glomerular filtrate, which is similar to plasma except that plasma proteins are too large to pass the glomerular capillary membrane. In the proximal convoluted tubules, about 85% of filtered sodium is actively reabsorbed by the tubule cells. The exchange mechanism is thought to be located at the tubule cell border along the side opposite the tubule lumen; thus, sodium is actively pumped out of the tubule cell into the renal interstitial fluid. Sodium from the urine passively diffuses into the tubule cell to replace that which is pumped out. Chloride and water passively accompany sodium from the urine into the cell and thence into the interstitial fluid. Most of the filtered potassium is also reabsorbed, probably by passive diffusion. At this time, some hydrogen ions are actively secreted by tubule cells into the urine but not to the extent that occurs farther down the nephron (electrolyte pathways and mechanisms are substantially less well known for the proximal tubules than for the distal tubules).

    In the ascending (thick) loop of Henle, sodium is still actively reabsorbed, except that the tubule cells are now impermeable to water. Therefore, since water cannot accompany reabsorbed sodium and remains behind in the urine, the urine at this point becomes relatively hypotonic (the excess of water over what would have been present had water reabsorption continued is sometimes called “free water” and from a purely theoretical point of view is sometimes spoken of as though it were a separate entity, almost free from sodium and other ions).

    In the distal convoluted tubules, three processes go on. First, sodium ions continue to be actively reabsorbed. (In addition to the sodium pump located at the interstitial side of the cell, which is pushing sodium out into the interstitial fluid, another transport mechanism on the tubule lumen border now begins actively to extract sodium from the urine into the tubule cells.) Intracellular hydrogen and potassium ions are actively excreted by the tubule cells into the urine in exchange for urinary sodium. There is competition between hydrogen and potassium for the same exchange pathway. However, since hydrogen ions are normally present in much greater quantities than potassium, most of the ions excreted into the urine are hydrogen. Second, the urinary acidification mechanisms other than bicarbonate reabsorption (NaHPO4 and NH4) operate here. Third, distal tubule cells are able to reabsorb water in a selective fashion. Permeability of the distal tubule cell to water is altered by a mechanism under the influence of AVP (ADH). There is a limit to the possible quantity of water reabsorbed, because reabsorption is passive; AVP (ADH) simply acts on cell membrane permeability, controlling the ease of diffusion. Therefore, only free water is actually reabsorbed.

    In the collecting tubules, the tubular membrane is likewise under the control of AVP (ADH). Therefore, any free water not reabsorbed in the distal convoluted tubules plus water that constitutes actual urine theoretically could be passively reabsorbed here. However, three factors control the actual quantity reabsorbed: (1) the state of hydration of the tubule cells and renal medulla in general, which determines the osmotic gradient toward which any reabsorbed water must travel; (2) the total water reabsorption capacity of the collecting tubules, which is limited to about 5% of the normal glomerular filtrate; and (3) the amount of free water reabsorbed in the distal convoluted tubules, which helps determine the total amount of water reaching the collecting tubules.

    Whether collecting tubule reabsorption capacity will be exceeded, and if so, to what degree, is naturally dependent on the total amount of water available. The amount of water reabsorbed compared to the degree of dilution (hypotonicity) of urine reaching the collecting tubules determines the degree of final urine concentration.

  • Hyponatremia. Iatrogenic Sources of Hyponatremia

    Diuretic therapy and administration of IV hypotonic fluids (dextrose in water or half-normal saline) form very important and frequent etiologies for hyponatremia, either as the sole agent or superimposed on some condition predisposing to hyponatremia. In several studies of patients with hyponatremia, diuretic use was considered to be the major contributing factor or sole etiology in about 30% of cases (range, 7.6%-46%). In two series of patients with severe hyponatremia (serum sodium <120 mEq/L), diuretics were implicated in 30%-73% of cases. Hyponatremia due to diuretics without any predisposing or contributing factors is limited mostly to patients over the age of 55 years. IV fluid administration is less often the sole cause for hyponatremia (although it occurs) but is a frequent contributing factor. In one study of postoperative hyponatremia, 94% of the patients were receiving hypotonic fluids. If renal water excretion is impaired, normal maintenance fluid quantities may lead to dilution, whereas excessive infusions may produce actual water intoxication or pulmonary edema. There may also be problems when excessive losses of fluid or various electrolytes occur for any reason and replacement therapy is attempted but either is not adequate or is excessive. The net result of any of the situations mentioned is a fluid disorder with or without an electrolyte problem that must be carefully and logically reasoned out, beginning from the primary deficit (the cause of which may still be active) and proceeding through subsequent events. Adequate records of fluid and electrolyte administration are valuable in solving the problem. In nonhospitalized persons a similar picture may be produced by dehydration with conscious or unconscious attempts at therapy by the patient or relatives. For example, marked sweating leads to thirst, but ingestion of large quantities of water alone dilutes body fluid sodium, already depleted, even further. A baby with diarrhea may be treated at home with water or sugar water; this replaces water but does not adequately replace electrolytes and so has the same dilutional effect as in the preceding example. On the other hand, the infant may be given boiled skimmed milk or soup, which are high-sodium preparations; the result may be hypernatremia if fluid intake is not adequate.

  • Serum Sodium Abnormalities

    The most frequent electrolyte abnormalities, both clinically and as reflected in abnormal laboratory values, involve sodium. This is true because sodium is the most important cation of the body, both from a quantitative standpoint and because of its influence in maintaining electric neutrality. The most common causes of low or high serum sodium values are enumerated in the box. Some of these conditions and the mechanisms involved require further explanation.

    Technical problems in sodium measurement may affect results. For many years the primary assay technique for sodium and potassium was flame photometry. Since 1980, instrumentation has been changing to ion-selective electrodes (ISEs). ISEs generate sodium results that are about 2% higher than those obtained by flame photometry (in patient blood specimens this difference is equivalent to 2-3 mEq/L [2-3 mmol/L]). Potassium values are about the same with both techniques. Many, but not all, laboratories automatically adjust their ISE sodium results to make them correspond to flame photometer values. Sodium concentration can be decreased in blood by large amounts of glucose (which attracts intracellular fluid, creating a dilutional effect). Each 62 mg of glucose/100 ml (3.4 mmol/L) above the serum glucose upper reference limit results in a decrease in serum sodium concentration of 1.0 mEq/L. Large amounts of serum protein (usually in patients with myeloma) or lipids (triglyceride concentration >1,500 mg/100 ml [17 mmol/L]) can artifactually decrease the serum sodium level when sodium is measured by flame photometry (values obtained by the ISE method are not affected). One report suggests a formula whose result can be added to flame photometry values to correct for severe

    Clinical Situations Frequently Associated With Serum Sodium Abnormalities

    I. Hyponatremia
    A. Sodium and water depletion (deficit hyponatremia)
    1. Loss of gastrointestinal (GI) secretions with replacement of fluid but not electrolytes
    a. Vomiting
    b. Diarrhea
    c. Tube drainage
    2. Loss from skin with replacement of fluids but not electrolytes
    a. Excessive sweating
    b. Extensive burns
    3. Loss from kidney
    a. Diuretics
    b. Chronic renal insufficiency (uremia) with acidosis
    4. Metabolic loss
    a. Starvation with acidosis
    b. Diabetic acidosis
    5. Endocrine loss
    a. Addison’s disease
    b. Sudden withdrawal of long-term steroid therapy
    6. Iatrogenic loss from serous cavities
    a. Paracentesis or thoracentesis
    B. Excessive water (dilution hyponatremia)
    1. Excessive water administration
    2. Congestive heart failure
    3. Cirrhosis
    4. Nephrotic syndrome
    5. Hypoalbuminemia (severe)
    6. Acute renal failure with oliguria
    C. Inappropriate antidiuretic hormone (IADH) syndrome
    D. Intracellular loss (reset osmostat syndrome)
    E. False hyponatremia (actually a dilutional effect)
    1. Marked hypertriglyceridemia*
    2. Marked hyperproteinemia*
    3. Severe hyperglycemia
    II. Hypernatremia
    Dehydration is the most frequent overall clinical finding in hypernatremia.
    1. Deficient water intake (either orally or intravenously)
    2. Excess kidney water output (diabetes insipidus, osmotic diuresis)
    3. Excess skin water output (excess sweating, loss from burns)
    4. Excess gastrointestinal tract output (severe protracted vomiting or diarrhea without fluid therapy)
    5. Accidental sodium overdose
    6. High-protein tube feedings

    *Artifact in flame photometry, not in ISE.

    hyperlipidemia (triglyceride >1,500 mg/100 ml): % that Na value should increase = 2.1 Ч [triglyceride (gm/100 ml) – 0.6]. There is an interesting and somewhat inexplicable variance in reference range values for sodium in the literature, especially for the upper end of the range. This makes it highly desirable for each laboratory to determine its own reference range. Another problem is a specimen drawn from the same arm that already has an intravenous (IV) line; this usually happens when the phlebotomist cannot find a vein in the opposite arm. However, this may lead to interference by the contents of the IV system.