Chloride is the most abundant extracellular anion. In general, chloride is affected by the same conditions that affect sodium (the most abundant extracellular cation) and in roughly the same degree. Thus, in the great majority of cases, serum chloride values change in the same direction as serum sodium values (except in a few conditions such as the hyperchloremic alkalosis of prolonged vomiting). For example, if the serum sodium concentration is low, one can usually predict that the chloride concentration will also be low (or at the lower edge of the reference range). To confirm this I did a study comparing sodium and chloride values in 649 consecutive patients. There were 37 discrepancies (5.7%) in the expected relationship between the sodium and chloride values. On repeat testing of the discrepant specimens, 21 of the 37 discrepancies were resolved, leaving only 16 (2.5%). Of these, 6 (1%) could be classified as minor in degree and 10 (1.5%) as significant. Thus, in 649 patients only 1.5% had a significant divergence between serum sodium and chloride values.
Month: December 2009
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Clinical Symptoms of Electrolyte Imbalance
Before I conclude the discussion of sodium and potassium, it might be useful to describe some of the clinical symptoms of electrolyte imbalance. Interestingly enough, they are very similar for low-sodium, low-potassium, and high-potassium states. They include muscle weakness, nausea, anorexia, and mental changes, which usually tend toward drowsiness and lethargy. The electrocardiogram (ECG) in hypokalemia is very characteristic, and with serum values less than 3.0 mEq/L usually shows depression of the ST segment and flattening or actual inversion of the T wave. In hyperkalemia the opposite happens: the T wave becomes high and peaked; this usually begins with serum potassium values more than 7.0 mEq/L (reference values being 4.0-5.5 mEq/L). Hypokalemia may be associated with digitalis toxicity with digitalis doses that ordinarily are nontoxic because potassium antagonizes the action of digitalis. Conversely, very high concentrations of potassium are toxic to the heart, so IV infusions should never administer more than 20.0 mEq/hour even with good renal function.
There is disagreement in the medical literature regarding preoperative detection and treatment of hypokalemia. On one hand, various reports and textbooks state that clinically significant hypokalemia (variously defined as less than 2.8, 3.0, or 3.2 mEq/L) produces a substantial number of dangerous arrhythmias. On the other hand, several investigators did not find any significant difference in intraoperative arrhythmias, morbidity, or mortality between those patients with untreated hypokalemia and those who were normokalemic.
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Hyperkalemia
High potassium values are not uncommon in hospitalized patients, especially in the elderly. One study reported serum potassium levels more than 5 mEq/L in 15% of patients over age 70. However, hyperkalemia is found in relatively few diseases.
Decreased renal potassium excretion. Renal failure is the most common cause of hyperkalemia, both in this category and including all causes of hyperkalemia.
Pseudohyperkalemia. Dehydration can produce apparently high-normal or mildly elevated electrolyte values. Artifactual hemolysis of blood specimens may occur, which results in release of potassium from damaged RBCs, and the laboratory may not always mention that visible hemolysis was present. In one series of patients with hyperkalemia, 20% were found to be due to a hemolyzed specimen, and an additional 9% were eventually thought to be due to some technical error. Rarely, mild hyperkalemia may appear with very marked elevation of platelets.
Exogenous potassium intake. Examples include excessive oral potassium supplements or parenteral therapy that either is intended to supplement potassium (e.g., potassium chloride) or contains medications (e.g., some forms of penicillin) that are supplied as a potassium salt or in a potassium-rich vehicle. Some over-the-countersalt substitutes contain a considerable amount of potassium.
Endogenous potassium sources. Potassium can be liberated from tissue cells in muscle crush injuries, burns, and therapy of various malignancies (including the tumor lysis syndrome), or released from RBCs in severe hemolytic anemias. In some cases where liberated potassium reaches hyperkalemic levels, there may be a superimposed element of decreased renal function.
Endocrinologic syndromes. As noted previously, hyperkalemia may be produced by dehydration in diabetic ketoacidosis. Hyperkalemia is found in about 50% of patients with Addison’s disease. In one series, hyporeninemic hypoaldosteronism was found in 10% of patients with hyperkalemia. Decreased renal excretion of potassium is present in most endocrinologic syndromes associated with hyperkalemia, with the exception of diabetic acidosis.
Drug-induced hyperkalemia. Some medications supply exogenous potassium, as noted previously. A few, including beta-adrenergic blockers such as propranolol and pindolol, digoxin overdose, certain anesthetic agents at risk for the malignant hyperthermia syndrome such as succinylcholine, therapy with or diagnostic infusion of the amino acid arginine, hyperosmotic glucose solution, or insulin, affect potassium shifts between intracellular and extracellular location. In the case of insulin, deficiency rather than excess would predispose toward hyperkalemia. Most other medications that are associated with increase in serum potassium produce decreased renal excretion of potassium. These include certain potassium-sparing diuretics such as spronolactone and triamterene; several nonsteroidal anti-inflammatory agents such as indomethacin and ibuprofen; angiotensin-converting enzyme inhibitors such as captopril; heparin therapy, including low-dose protocols; and cyclosporine immunosuppressant therapy.
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Hypokalemia
Hypokalemia has been reported in about 5% of hospitalized patients. Abnormalities in potassium have many similarities to those of sodium. Some conditions with potassium abnormalities are also associated with sodium abnormalities and were discussed earlier. Several different mechanisms may be involved.
Inadequate intake. Ordinarily, 90% of ingested potassium is absorbed, so that most diets are more than adequate. Inadequate intake is most often due to anorexia nervosa or to severe illness with anorexia, especially when combined with administration of potassium-free therapeutic fluids. Alcoholism is often associated with inadequate intake, and various malabsorption syndromes may prevent adequate absorption.
Gastrointestinal tract loss. Severe prolonged diarrhea, including diarrhea due to laxative abuse, can eliminate substantial amounts of potassium. One uncommon but famous cause is large villous adenomas of the colon.
Clinical Conditions Commonly Associated With Serum Potassium Abnormalities
Hypokalemia
Inadequate intake (cachexia or severe illness of any type)
Intravenous infusion of potassium-free fluids
Renal loss (diuretics; primary aldosteronism)
GI loss (protracted vomiting; severe prolonged diarrhea; GI drainage)
Severe trauma
Treatment of diabetic acidosis without potassium supplements
Treatment with large doses of adrenocorticotropic hormone; Cushing’s syndrome
Cirrhosis; some cases of secondary aldosteronismHyperkalemia
Renal failure
Dehydration
Excessive parenteral administration of potassium
Artifactual hemolysis of blood specimen
Tumor lysis syndrome
Hyporeninemic hypoaldosteronism
Spironolactone therapy
Addison’s disease and salt-losing congenital adrenal hyperplasia
ThrombocythemiaProtracted vomiting is another uncommon cause. Patients with ileal loop ureteral implant operations after total cystectomy frequently develop hypokalemia if not closely watched.
Renal loss. Twenty percent to 30% (range, 10%-40%) of hypertensive patients receiving diuretic therapy, particularly with the chlorothiazides, are reported to be hypokalemic. Combined with other conditions requiring diuretics, this makes diuretic therapy the most frequent overall cause of hypokalemia. Renal tubular acidosis syndromes might also be mentioned. Finally, there is a component of renal loss associated with several primarily nonrenal hypokalemic disorders. These include the various endocrinopathies (discussed next), diabetic ketoacidosis, and administration of potassium-poor fluids. The kidney is apparently best able to conserve sodium and to excrete potassium (since one way to conserve sodium is to excrete potassium ions in exchange), so that when normal intake of potassium stops, it takes time for the kidney to adjust and to stop losing normal amounts of potassium ions. In the meantime, a deficit may be created. In addition, renal conservation mechanisms cannot completely eliminate potassium excretion, so that 5-10 mEq/day is lost regardless of total body deficit.
Endocrinopathies. These conditions are discussed in detail elsewhere. Patients with primary aldosteronism (Conn’s syndrome) are hypokalemic in about 80% of cases. Patients with secondary aldosteronism (cirrhosis, malignant hypertension, renal artery stenosis, increased estrogen states, hyponatremia) are predisposed toward hypokalemia. Cirrhosis may coexist with other predisposing causes, such as poor diet or attempts at diuretic therapy. About 20%-25% of patients with Cushing’s syndrome have a mild hypokalemic alkalosis. Congenital adrenal hyperplasia (of the most common 11-b-hydroxylase type) is associated with hypokalemia. Hypokalemia may occur in Bartter’s syndrome or the very similar condition resulting from licorice abuse. Most of the conditions listed in this section, except for cirrhosis, are also associated with hypertension.
Severe trauma. In a review of three studies of trauma patients, hypokalemia was much more common (50%-68% of patients) than hyperkalemia. Hypokalemia usually began within 1 hour after the trauma and usually ended within 24 hours.
Diabetic ketoacidosis. Extracellular fluid (ECF) may lose potassium both from osmotic diuresis due to hyperglycemia and from shift of extracellular to intracellular potassium due to insulin therapy. Nevertheless, these changes are masked by dehydration, so that 90% of patients have normal or elevated serum potassium values when first seen in spite of substantial total body potassium deficits. These deficits produce overt hypokalemia if fluid therapy of diabetic acidosis does not contain sufficient potassium.
Hypokalemic alkalosis. Hypokalemia has a close relationship to alkalosis. Increased plasma pH (alkalosis) results from decreased ECF hydrogen ion concentrations; the ECF deficit draws hydrogen from body cells, leading to decreased intracellular concentration and therefore less H+ available in renal tubule cells for exchange with urinary sodium. This means increased potassium excretion in exchange for urinary sodium and eventual hypokalemia. Besides being produced by alkalosis, hypokalemia can itself lead to alkalosis, or at least a tendency toward alkalosis. Hypokalemia results from depletion of intracellular potassium (the largest body store of potassium). Hydrogen ions diffuse into body cells to partially replace the intracellular cation deficit caused by potassium deficiency; this tends to deplete ECF hydrogen levels. In addition, more hydrogen is excreted into the urine in exchange for sodium since the potassium that normally would participate in this exchange is no longer available. Both mechanisms tend eventually to deplete extracellular fluid hydrogen. As noted in Chapter 24, in alkalosis due to hypokalemia an acid urine is produced, contrary to the usual situation in alkalosis. This incongruity is due to the intracellular acidosis that results from hypokalemia.
Medication-induced hypokalemia. Certain non-diuretic medications may sometimes produce hypokalemia. Ticarcillin, carbenicillin, and amphotericin B may increase renal potassium loss. Theophylline, especially in toxic concentration, may decrease serum potassium to hypokalemic levels.
In one group of hospitalized patients with serum potassium levels less than 2.0 mEq/L, apparent etiology was potassium-insufficient IV fluids in 17%, diuretic therapy in 16%, GI loss in 14%, acute leukemia receiving chemotherapy in 13%, dietary potassium deficiency in 6%, renal disease with urinary potassium loss in 6%, diabetic acidosis in 5%, and all other single causes less than 5% each.
Urine potassium assay in hypokalemia
Measurement of urine potassium may sometimes be useful in differentiating etiologies of hypokalemia. Those conditions associated with decreased urine potassium include the following:
1. Loss from the GI tract (diarrhea, villous adenoma, ileal conduit). Vomiting, however, is associated with alkalosis, which may increase renal potassium excretion.
2. Shift of extracellular potassium to intracellular location (insulin therapy). However, hyperglycemic osmotic diuresis may confuse the picture.
3. Inadequate potassium intake, in the absence of conditions that increase urine potassium excretion.
4. Potassium deficiency associated with renal excretion of potassium (e.g., diuretic induced) after the stimulus for potassium loss is removed and renal loss ceases.Besides the first three categories, the other etiologies for hypokalemia usually demonstrate normal or increased urine potassium levels while active potassium loss is occurring.
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Serum Potassium Abnormalities
The potassium level in serum is about 0.4-0.5 mEq/L higher than the potassium level in whole blood or plasma (literature range, 0.1-1.2 mEq/L). This is attributed at least in part to potassium released from platelets during clotting. Serum specimens may have artifactual potassium level increase additional to that of normal clotting in patients with very high white blood cell (WBC) counts or platelet counts. The sodium concentration is about the same in serum, plasma, and whole blood. Potassium values increase 10%-20% if the patient follows the common practice of opening and closing his or her hand after a tourniquet is applied to the arm before venipuncture. Potassium can be increased in patient specimens by RBC hemolysis, sometimes considerably increased, which, unfortunately, is most often a laboratory artifact produced during venipuncture or when processing the specimen after venipuncture. Therefore, a pink or red color of plasma or serum usually means very inaccurate potassium values.
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Hypernatremia
Hypernatremia is much less common than hyponatremia. It is usually produced by a severe water deficit that is considerably greater than the sodium deficit and is most often accompanied by dehydration (see the box on this page). The water deficit can be due to severe water deprivation, severe hypotonic fluid loss (renal or nonrenal) without replacement, or a combination of the two. The serum sodium concentration and serum osmolality are increased. Urine volume is low and urine specific gravity or osmolality are high in water deprivation or in dehydration due to nonrenal water loss. Urine volume is high and urine specific gravity or osmolality is low in dehydration due to water loss through the kidneys. Other laboratory test values may suggest dehydration, and clinical signs of dehydration may be present. Although the serum sodium level is increased, the total body sodium level may be normal or even decreased, the sodium deficit being overshadowed by the water deficit. Occasionally, hypernatremia is caused by excess intake of sodium, which is usually not intentional.
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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.
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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.”
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Inappropriate ADH Syndrome (IADH Syndrome)
This is another syndrome involving AVP (ADH) that is now well recognized. It results from water retention due to secretion of AVP (ADH) when AVP (ADH) would not ordinarily be secreted. The criteria for IADH syndrome include (1) hyponatremia, (2) continued renal excretion of sodium despite hyponatremia, (3) serum hypoosmolality, (4) urine osmolality that shows a significant degree of concentration (instead of the maximally dilute urine one would expect), (5) no evidence of blood volume depletion, and (6) normal renal and adrenal function (this criterion is necessary to rule out continuous sodium loss due to renal disease or Addison’s disease; diuretic-induced urine sodium loss should also be excluded). These criteria attempt to demonstrate that AVP (ADH) is secreted despite hemodilution, decreased serum osmolality, or both. The reason for increased sodium excretion is not definitely known; it is thought that increase of interstitial fluid volume by water retention may lead to suppression of sodium reabsorption (in order not to reabsorb even more water). Most patients with IADH syndrome do not have edema, since interstitial fluid expansion is usually only moderate in degree.
In the diagnosis of IADH syndrome a problem may arise concerning what urine osmolality values qualify as a significant degree of concentration. If the serum and urine specimens are obtained at about the same time and the serum demonstrates significant hyponatremia and hypoosmolality, a urine osmolality greater than the serum osmolality is considered more concentrated than usual. However, in some cases of IADH syndrome the urine need not be higher than the serum osmolality for the diagnosis to be made, if it can be demonstrated that water retention is taking place despite a hypotonic plasma. With significant serum hypoosmolality, urine osmolality should be maximally dilute. This value is about 60-80 milliosmoles (mOsm)/L. A urine osmolality greater than 100 mOsm/L (literature range, 80-120 mOsm/L) can be considered a higher osmolality than expected under these circumstances. The urine sodium level is usually more than 20 mEq/L in patients with IADH syndrome, but can be decreased if the patient is on sodium restriction or has volume depletion. In patients with borderline normal or decreased urine sodium levels, the diagnosis of IADH may be assisted by administering a test dose of sodium. In IADH syndrome, infusion of 1,000 ml of normal saline will greatly increase urine sodium excretion but will not correct the hyponatremia as long as the patient does not restrict fluids (fluid restriction will cause sodium retention in IADH syndrome). Water restriction is the treatment of choice and may provide some confirmatory evidence. However, water restriction is not diagnostic, since it may also benefit patients with extracellular fluid (ECF) excess and edema. Uric acid renal clearance is increased in IADH syndrome, resulting in decreased serum uric acid levels in most, but not all, patients. Decreased serum uric acid levels in a patient with hyponatremia is another finding that is nondiagnostic but that raises the question of IADH syndrome.
In some patients, assay of serum AVP (ADH) levels may be helpful to confirm the diagnosis. The AVP (ADH) levels should be elevated in IADH syndrome. However, AVP (ADH) assay is expensive, technically very difficult, and is available only in a few reference laboratories. The specimen should be placed immediately into a precooled anticoagulant tube, centrifuged at low temperature, frozen immediately, and sent to the laboratory packed in dry ice.
IADH syndrome may be induced by a variety of conditions, such as: (1) central nervous system neoplasms, infections, and trauma; (2) various malignancies, most often in bronchogenic carcinoma of the undifferentiated small cell type (11% of patients); (3) various types of pulmonary infections; (4) several endocrinopathies, including myxedema and Addison’s disease; (5) certain medications, such as antineoplastics (vincristine, cyclophosphamide), oral antidiabetics (chlorpropamide, tolbutamide), hypnotics (opiates, barbiturates), and certain others such as carbamazepine; and (6) severe stress, such as pain, trauma, and surgery.
Normal physiologic response to surgery is a temporary moderate degree of fluid and electrolyte retention, occurring at least in part from increased secretion of AVP (ADH). In the first 24 hours after surgery there tends to be decreased urine output, with fluid and electrolytes remaining in the body that would normally be excreted. Because of this, care should be taken not to overload the circulation with too much IV fluid on the first postoperative day. Thereafter, adequate replacement of normal or abnormal electrolyte daily losses is important, and excessive hypotonic fluids should be avoided. In certain patients, such as those undergoing extensive surgical procedures and those admitted originally for medical problems, it is often useful to obtain serum electrolyte values preoperatively so that subsequent electrolyte problems can be better evaluated.
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Disorders of Arginine Vasopressin (Antidiuretic Hormone) Secretion
Arginine Vasopressin (AVP, also called vasopressin; originally known as antidiuretic hormone or ADH) has been mentioned as one regulator of plasma volume by its ability to concentrate urine via its action on renal distal tubule water reabsorption. It is produced by the posterior pituitary under the influence of centers in the anterior hypothalamus. Several factors influence production: blood osmotic changes (concentration and dilution, acting on osmoreceptors in the hypothalamus), blood volume changes, certain neural influences such as pain, and certain drugs such as morphine and alcohol. The two most important syndromes associated with abnormal AVP (ADH) are diabetes insipidus and the “inappropriate ADH” syndrome.
Diabetes Insipidus (DI) is a syndrome manifested by hypotonic polyuria. In spite of the name “diabetes,” it is not associated with diabetes mellitus, which produces a hypertonic polyuria (due to overexcretion of glucose). In general, there are three major etiologies of DI: neurogenic (hypothalamus unable to produce AVP [ADH] normally), renal (end-organ inability to respond normally to AVP [ADH], and temporary overpowering of the vasopressin system (ingestion of large quantities of water; sometimes called primary DI). Patients with DI are usually thirsty.
Before starting a test sequence to determine etiology, it has been recommended that the following preliminary tests be done—24-hour urine collection for volume, osmolality, and solute excretion and serum sodium, potassium, calcium, and osmolality—all under basal conditions (unrestricted diet and water intake). The goals are to determine if polyuria exists (urine output over 2000 ml/day); if so, whether the urine is hypotonic (urine osmolality below 300 mosm/kg; literature range, 200-300 mosm/kg). If results show excess urine output that is hypotonic, the patient could have DI. Then the solute content per day should be measured. If the solute excretion is not increased (i.e., is less than 20 mosm/kg/day) the patient does not have a solute-induced diuresis and definitely qualifies for the diagnosis of DI. However, other relatively common etiologies for polyuria should be excluded, such as osmotic diuresis (glucose, NaC1, mannitol,) diuretics, hypokalemia, hypercalcemia, drug-induced (lithium, chlorpromazine, thioridazide), sickle cell disease, pregnancy-induced DI, severe chronic renal disease, or after acute tubular necrosis or renal transplantation. If the serum sodium or calcium level is high, this condition should be corrected before doing provocative tests. It is also necessary to stop any medications affecting AVP (ADH) secretion, all tobacco or alcohol use, and all caffeine-containing beverages at least 24 hours before and during the test. One investigator recommends blood osmolality measurement be done on plasma collected with heparin anticoagulant and tested using the freezing point depression method for best accuracy.
The standard diagnostic procedure in DI is the water deprivation (dehydration) test. Although the basic procedure is followed throughout the literature, some details vary (such as the exact criteria for maximum dehydration, the minimum urine osmolality value acceptable as a response to maximal fluid-restriction dehydration, and the details of preparation for and starting the test. There are other test protocols in the literature to disclose etiology of DI; two of these will be presented, as well as the water deprivation test.
1. Baseline serum osmolality and sodium levels that are high normal or elevated—serum osmolality over 295 mosm/kg (some investigators use 288 or 290) or sodium level over 143 mEq/L (mmol/L), with low urine osmolality (less than 300 mOsm/kg; literature range, 200-300)—are strong evidence against primary water-intake DI. The next step recommended is to inject subcutaneously either 1 µg of DDAVP (desmopressin, a synthetic analog of AVP) or 5 IU of AVP (vasopressin or ADH) and collect urine samples 30, 60, and 120 minutes afterward. If the highest urine osmolality after vasopressin is less than 50% higher than the baseline urine osmolality value, this suggests nephrogenic DI. If the result shows increase equal to or greater than 50%, this suggests neurogenic DI.
2. It is also possible to differentiate between neurogenic, nephrogenic, and primary water intake etiologies for DI using administration of DDAVP for 2-3 days in a hospital with close observation. In patients with hypothalamic (neurogenic) DI there should be substantial decrease in thirst and urine output. In renal (nephrogenic) DI (primary polydipsia), there should be substantial decrease in urine output but increasing hyponatremia and body weight (due to continued high fluid intake). Although the simplicity of this test is attractive, it may be hazardous (especially in patients with primary polydipsia) and results are not always clear-cut.
3. In the water deprivation test, the duration of water restriction is based on the degree of polyuria. The greater the output, the greater need for close supervision of the patient to prevent overdehydration. Patients with urine output less than 4000 ml/24 hours undergo restricted fluid after midnight; those with output greater than 4000 ml/24 hours begin fluid restriction at the time the test begins. Body weight and urine osmolality are measured hourly from 6 A.M. to noon or until three consecutive hourly determinations show urine osmolality increase of less than 30 mosm/kg (of H2O). The procedure should be terminated if body weight loss becomes more than 2 kg. When urine osmolality becomes stable, plasma osmolality is obtained. Osmolality should be greater than 288 mosm/kg for adequate dehydration. If this has occurred, 5 units of aqueous vasopressin (or 1 µg DDAVP) is administered subcutaneously. A urine specimen for osmolality is obtained 30-60 minutes after the injection. In central DI, there should be a rise in urine osmolality more than 9% of the last value before administration of vasopressin. In polyuria from nephrogenic DI, hypokalemia, or severe chronic renal disease, there is usually little increase in osmolality either during the dehydration test or after vasopressin administration. Patients with primary polydipsia frequently take longer than usual to dehydrate to a serum osmolality over 288, and urine osmolality rises less than 9% after vasopressin administration.