Principles of Ambulatory Medicine, 7th Edition

Chapter 50

Hypokalemia

John E. Anderson

Hypokalemia, serum potassium concentration less than 3.5 mEq/L, occurs in less than 1% of normal, healthy people. It is, however, common in ambulatory practice, often as a consequence of drug therapy or disease (1). Severe hypokalemia may be life-threatening, but even mild hypokalemia may predispose to death. Hypokalemia may play an important role in the etiology of hypertension and cardiovascular, and cerebrovascular disease. Gastrointestinal (GI) and renal losses account for most cases seen in ambulatory practice, but less common causes are occasionally encountered. This chapter reviews the physiology of potassium homeostasis, the clinical consequences of potassium depletion, an approach to the differential diagnosis, and the management of hypokalemia.

Physiologic Background

Total body potassium, normally approximately 50 mEq/kg, is determined by the balance between the intake and excretion of potassium. In health, excretion matches intake so total body potassium remains constant (Fig. 50.1). The serum potassium concentration, however, depends on both the total body potassium content and the distribution between the intracellular and extracellular spaces. The internal balance or distribution of potassium between the intracellular and extracellular spaces thus may vary in the absence of changes in the external balance of potassium (2).

External Potassium Balance

The average intake of potassium is 1 mEq/kg body weight per day (range 35 to 110 mEq/day). Normally approximately 90% is absorbed from the GI tract and excreted in the urine, and the remainder is eliminated in the stool (Fig. 50.1). Hypokalemia caused by diet alone is rare in otherwise normal patients, although reduced intake may exacerbate other causes of hypokalemia (e.g., diuretic induced).

The kidney is the major regulator of potassium balance since the rate of urinary potassium excretion is adjusted in proportion to intake. In patients with hypokalemia, the normal kidney can reduce potassium excretion to a minimum of 5 to 25 mEq/day. Most renal excretion of potassium occurs by distal tubular secretion. Increased urinary flow rate, increased distal sodium delivery, aldosterone, and alkalosis have clinically important roles in sustaining potassium secretion in hypokalemic patients (Fig. 50.2).

Less than 5 mEq/day are lost through the skin unless sweating is profuse. Diarrhea and other GI disorders can cause loses of large amounts of potassium in stool.

Internal Potassium Balance

Nearly all of the body potassium is located intracellularly, with only a small portion (2%; 50 to 60 mEq) in the extracellular space. Small transcellular potassium shifts can, therefore, significantly affect the serum potassium concentration, even in the absence of changes in total body potassium. Such shifts are, in fact, critically important for the maintenance of extracellular potassium within a safe range during times of acute potassium loading (2,3). Cellular potassium uptake is increased and hypokalemia potentially produced by β₂-adrenergic stimulation, insulin, alkalosis, anabolism, and aldosterone.

In the absence of major alterations in internal potassium balance, there is a roughly linear inverse relationship between the decrement in the serum potassium concentration and the magnitude of the total body potassium deficit. For deficits up to approximately 500 mEq the serum potassium falls approximately 0.3 mEq/L for each 100 mEq of potassium depletion. With larger deficits, the serum potassium falls less for every 100 mEq of potassium lost. Thus even small decreases in serum potassium may mean substantial intracellular potassium deficits.

Consequences of Potassium Depletion

Hypokalemia itself is often asymptomatic so the only symptoms patients typically experience are those of the disorder causing potassium depletion, such as vomiting or

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diarrhea. Severe potassium depletion may, however, have serious symptoms and severe consequences (Table 50.1).

FIGURE 50.2. Factors influencing potassium secretion by the distal tubule. ADH, antidiuretic hormone. (Modified from  Giebisch G. Physiology of potassium metabolism. In: Whelton A, Walker WG, eds. Potassium in cardiovascular and renal medicine. New York: Marcel Dekker, 1986. )

Effects on the Cardiovascular System

Of greatest concern is the effect of hypokalemia on cardiac conduction and rhythm. Severe potassium depletion also rarely causes myocardial necrosis. During hypokalemia, characteristic pathologic electrocardiographic changes may be seen (Fig. 50.3). It is controversial whether mild to moderate hypokalemia per se can cause dangerous ventricular ectopy (4), but it seems certain that hypokalemia may be arrhythmogenic in patients with underlying heart disease (5,6). Hypokalemia also predisposes patients to arrhythmias due to digitalis intoxication. Hypokalemia also reduces the protective effect of diuretics on cardiovascular disease (7,8).

FIGURE 50.1. Balance of potassium (Adapted from  Klinger AS, Hayslett JP. Disorders of potassium. In: Brenner BM, Stein JH, eds. Acid-base and potassium homeostasis. New York: Churchilll Livingstone, 1978. )

Effects on the Neuromuscular System

Potassium depletion alters both smooth and skeletal muscle function. Severe hypokalemia can cause GI tract dysmotility and ileus. Proximal muscle weakness can progress to paralysis. Respiratory muscle involvement can result in respiratory failure. Hypokalemia may also predispose to rhabdomyolysis, at least in part by interfering with exercise-induced vasodilation. Rarely, tetany may be seen even in the absence of changes in serum calcium or pH.

Effects on Blood Pressure

Hypokalemia commonly occurs as a complication of the treatment of hypertension, but potassium balance is also important in the underlying pathophysiology and evolution of hypertension, and of cardiovascular and cerebrovascular diseases. Populations that consume a low-potassium diet, such as African Americans, have very high prevalences of hypertension and cardiovascular disease (9,10). Large studies have shown that blood pressure is partly potassium dependent (11,12). The risk of hypertension increases as the amount of potassium in the diet decreases, independent of sodium intake (13). While the mechanism(s) for the effect of potassium on blood pressure are unclear, simply increasing potassium intake may lower the likelihood of developing hypertension (14,15). Supplementation with 48 to 120 mEq/day of potassium can lower blood pressure (16,17). The correction of hypokalemia by dietary means or by pharmacologic

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supplementation can enhance the treatment of hypertension with minimal risk and expense (18). Increased dietary potassium may have a greater effect than equivalent potassium chloride supplementation, perhaps because dietary potassium is associated with citrate rather than chloride anions (19). In addition, beyond its effect on hypertension, potassium supplementation has been shown to reduce the risk of cerebrovascular disease and stroke (20).

TABLE 50.1 Clinical Sequelae of Hypokalemia

Cardiovascular Predisposition to digitalis intoxication Abnormal electrocardiogram Ventricular ectopic rhythms Cardiac necrosis Increased blood pressure Neuromuscular Gastrointestinal    Constipation    Ileus Skeletal muscle    Weakness, cramps    Tetany    Paralysis (including respiratory)    Rhabdomyolysis Renal Decreased renal blood flow Decreased glomerular filtration rate Renal hypertrophy Pathologic alterations (interstitial nephritis) Predisposition to urinary tract infection Fluid and Electrolyte Polyuria and polydipsia    Renal concentrating defect    Stimulation of thirst center    ADH release (?) Increased renal ammonia production    Predisposition to hepatic coma    Altered urinary acidification Renal chloride wasting Metabolic alkalosis Sodium retention Hyponatremia (with or without concomitant diuretic) Endocrine Decrease in aldosterone Increase in renin Altered prostaglandin metabolism Decrease in insulin secretion (carbohydrate intolerance) ADH, antidiuretic hormone. Modified from Tannen RL. Potassium disorders. In: Kokko J Fluids and electrolytes. Philadelphia: WB Saunders, 1986.

Effects on the Kidney

Hypokalemia impairs urinary concentrating ability. The defect is mild and the associated polyuria is also caused in part by direct stimulation of thirst. Prolonged, severe potassium depletion can produce reversible reductions in glomerular filtration rate and renal blood flow. Hypokalemia increases the risk of nephrotoxic renal failure (21) and rarely causes acute renal injury by itself (22). Hypokalemia-induced chronic tubulointerstitial disease can result in progressive chronic renal failure (23).

FIGURE 50.3. Electrocardiogram in assessment of potassium. (Adapted from  Burch GE, Winsor T. A primer of electrocardiography. 6th ed. Philadelphia: Lea & Febiger, 1972: 128. )

Effects on the Endocrine System

Hypokalemia inhibits aldosterone synthesis, increases plasma renin activity, and decreases insulin secretion as well as insulin action. The latter may worsen diabetic control. Renal ammonia production, directly stimulated by hypokalemia, may precipitate or aggravate hepatic encephalopathy.

Differential Diagnosis and Management

Diuretic use, vomiting, and diarrhea are the most common causes of hypokalemia. Typically these conditions are evident from the history. Less obvious causes can be diagnosed

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(Fig. 50.4) (24) by consideration of the fundamental mechanisms of potassium balance: reduced intake, transcellular shift into cells, and excessive loss. Surreptitious vomiting and diuretic abuse, along with Gitelman syndrome (see External Losses of Potassium, Normotensive Hypokalemia, and Bartter and Gitelman Syndromes), are the most common conditions associated with hypokalemia when the cause is difficult to ascertain (25).

FIGURE 50.4. Diagnostic approach to hypokalemia. RTA, renal tubular acidosis; DKA, diabetic keloacidosis; NG, nasogastric; CHF, congestive heart failure. (Modified from  Narins RG, Jones ER, Stom MC, et al. Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am J Med 1982;72:496.)

Deficient Potassium Intake

Potassium is present in many foods, especially fruits, raw vegetables, fish, and red meat (Table 50.2). Inadequate intake is an unusual cause of hypokalemia except in high-risk situations (dietary fads, pica, alcoholism, cachexia). Hypokalemia can also occur if dietary potassium intake is inadequate during anabolic states such as refeeding of malnourished patients and treatment of megaloblastic anemia. Dietary deficiency of potassium, particularly in the elderly, may also exacerbate diuretic-induced hypokalemia.

Transient Disorders of Internal Potassium Balance

β₂-Adrenergic agonists lower serum potassium concentrations by stimulating cellular uptake of potassium. This is commonly seen when β₂-adrenergic agonists (administered via any route) are used to treat asthma or premature labor. The decrease in potassium is usually mild, but significant hypokalemia can also occur. Resolution occurs within hours of discontinuing the drug. High levels of endogenous catecholamines released during stress may explain transient hypokalemia that resolves with or without supplementation during acute stressful illness (26,27).

Metabolic and respiratory alkalosis are associated with small shifts of potassium from the extracellular to the intracellular space.

Insulin stimulates potassium uptake in liver and skeletal muscle cells independent of effects on glucose transport. This action is the basis for using insulin to treat severe hyperkalemia. Insulin treatment of hyperglycemia may induce hypokalemia even if the serum potassium is normal (28).

Hypokalemic periodic paralysis is a rare familial disorder characterized by spontaneous episodes of paralysis often precipitated by stimuli, including insulin, glucose, and a high-carbohydrate meal (29). A similar syndrome occurs in hyperthyroidism, especially in Asian men (30). Both the serum potassium and urinary potassium excretion decrease dramatically, signifying an intracellular shift of potassium. In the thyrotoxic form, β-blocking agents may be effective in preventing attacks.

TABLE 50.2 Some Common Potassium-Rich Foods

Food Source Average Portion Potassium (mEq) Vegetables Artichoke 1 large 22.0 Beans    Cooked dried ½ cup 10.7    Lima 5/8 cup 10.8 Brussels sprouts 7 medium 7 Corn 1 ear 5.0 Potato    White 1 boiled 7.3    Sweet 1 boiled 7.7 Tomato    Fresh 1 medium 9.4    Canned ½ cup 5.6 Squash, winter ½ cup boiled 11.9 Meats Hamburger 1 patty 9.8 Rib roast 2 slices 11.2 Fish, haddock 1 medium fillet 8.0 Clams 4 large 6.0 Oysters 6 medium 3.1 Fruits Apple 1 medium 2.8 Applesauce 1/3 cup 1.7 Apricots 3 medium 7.2 Avocado ½ pitted 15.5 Banana 1 6-inch 9.5 Cantaloupe ¼ medium 6.4 Dates 10 pitted 16.6 Fruit cocktail ½ cup 4.3 Grapefruit ½ medium 3.5 Melon ¼ small 6.4 Orange 1 small 7.7 Peach 1 medium 5.2 Pear 1 medium 6.7 Plum 2 medium 7.7 Prunes, dried 10 medium 17.8 Raisins 1 tablespoon 2.0 Strawberries 10 large 4.2 Watermelon 1 slice 15.4 Juice Grapefruit 1 cup 10.4 Orange 1 cup 12.4 Pineapple 1 cup 9.2 Prune 1 cup 15.0 Tomato 1 cup 13.7 Vegetable 1 cup 14.1 Nuts Peanuts, roasted 1 tablespoon 2.0 Peanut butter 2 tablespoon 2.0 Mixed nuts 3.5 oz 2.0 Milk Buttermilk 9 oz 8.0 Skim milk 8 oz 8.5 Whole milk 8 oz 9.0

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Vitamin B₁₂ treatment of megaloblastic anemia may cause large intracellular shifts of potassium. Potassium supplementation and careful monitoring prevent this complication.

Rare causes of transient hypokalemia include hypothermia, which can increase potassium uptake into cells and barium poisoning, which can inhibit potassium potassium exit from cells.

External Losses of Potassium

If there is no evidence of a disorder of internal potassium balance, the patient is likely to be potassium depleted either via renal or GI losses. If unclear from the history, urine potassium measurement may help clarify the route of potassium loss. Potassium greater than 20 mEq/L on a spot urine specimen or greater than 20 mEq in a 24-hour collection despite hypokalemia suggests renal potassium loss is at least partially responsible for potassium depletion. Low urine potassium (<20 mEq/L on a spot urine) suggests an extrarenal loss of potassium with appropriate renal conservation. More sophisticated tests such as the calculation of the transtubular potassium concentration gradient (TTKG) (31) and referral to a nephrologist may be required in specific cases.

Gastrointestinal Losses Resulting in Potassium Deficiency

Diarrhea

High concentrations of potassium and bicarbonate are normally present in the stool. Diarrhea can produce significant hypokalemia, often associated with bicarbonate loss that results in a non–anion gap, hyperchloremic metabolic acidosis. While urinary potassium excretion should be low when potassium deficiency results from intestinal losses, this is true only when volume status is maintained. Secondary hyperaldosteronism induced by volume contraction may produce paradoxically high urine potassium losses. Even in the absence of diarrhea, hypokalemia may be a clue to the presence of a villous adenoma of the colon or surreptitious laxative abuse.

Loss of Gastric Fluid

Although gastric fluid contains only small amounts of potassium (approximately 5 to 10 mEq/L), hypokalemia frequently accompanies vomiting or gastric drainage because potassium is lost in the urine (32). The loss of gastric chloride induces metabolic alkalosis, chloride deficiency, extracellular volume depletion, and secondary hyperaldosteronism. The increased distal delivery of bicarbonate and high levels of aldosterone stimulate secretion of potassium. The urine will have high potassium concentrations and very low chloride concentrations.

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Correction of potassium depletion and metabolic alkalosis requires provision of adequate amounts of chloride, potassium, and sodium. Potassium administered with anions other than chloride is not retained but is excreted in the urine (33).

Renal Losses Resulting in Potassium Deficiency

Diuretics

Loop and thiazide diuretics accelerate potassium excretion by increasing sodium and water delivery to the potassium secretory sites in the distal nephron and by simultaneously stimulating aldosterone release. The nadir of serum potassium concentration typically is within 7 days after therapy begins (34). Increased sodium intake increases the degree of potassium depletion. At standard dosages, thiazide and thiazide-like diuretics induce an average fall in the serum potassium concentration of 0.6 mEq/L, and 7% to 50% of patients develop a serum potassium less than 3.5 mEq/L. Furosemide causes less potassium depletion, with an average fall in potassium concentration of only 0.3 mEq/L. The use of multiple kaliuretic diuretics acting at different nephron sites (e.g., furosemide and thiazide) is likely to cause hypokalemia that is greater than that produced by a single agent (35).

Levels below 3.0 mEq/L suggest either excessive sodium intake or an unrecognized potassium-wasting state such as primary or secondary hyperaldosteronism (36). Both should be considered when significant hypokalemia develops after the introduction of potassium-wasting diuretics, particularly if the potassium level before treatment was low.

Monitoring Potassium in Patients Receiving Diuretics

The serum potassium should be measured before administration of diuretics and, if normal, it should be measured again 1 and 4 weeks after initiation of, or an increase in the dosage of, a diuretic. Subsequently, semiannual assessment is probably adequate in nonedematous, stable, well-nourished patients. Patients at greater risk of serious consequences of hypokalemia such as those with heart failure on digitalis or with cirrhosis at risk of hepatic coma should have more frequent monitoring.

Prevention and Therapy of Diuretic-Induced Hypokalemia

While the risk of mild diuretic-induced hypokalemia remains controversial (1), simple measures can minimize its occurrence. Both the lowest effective dosage of a diuretic agent, and moderate salt restriction (75 to 100 mEq sodium per day or 2 to 2.5 g sodium or 4 to 6 g sodium chloride) should be used. Increased dietary potassium is easy to achieve, cost-effective, and may be associated with other benefits such as lower blood pressure and decreased risk of stroke, hypertension, and other cerebrovascular dis-eases.

TABLE 50.3 Indications for Potassium Maintenance Therapy

Digitalis therapy Predisposition to hepatic coma Serum potassium concentration <3.0 mEq/L Development of glucose intolerance Underlying cardiac disease Symptoms attributable to hypokalemia With permission from Tannen RL. Diuretic-induced hypokalemia. Kidney Int 1985;28:988.

Even with these measures, approximately 30% of diuretic-treated patients become hypokalemic in the range of 3.0 to 3.5 mEq/L (37). If a diuretic is required, a normal potassium is a prudent goal for those patients listed in Table 50.3. Either potassium supplements or potassium-sparing diuretics can be used. Potassium chloride (Table 50.4) is preferred as potassium with poorly absorbed anions increases potassium loss. Salt substitutes (50 to 65 millmole per teaspoon potassium chloride) are a cheap and effective alternative. Diuretic-induced hypokalemia may seem to be refractory even to large doses of potassium chloride because the renal clearance of potassium remains high during continued diuretic therapy. In one study, potassium chloride at dosages up to 96 milli-mole per day normalized the serum potassium in only

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8 of 16 hypertensive patients with diuretic-induced hypokalemia (38).

TABLE 50.4 Commonly Available Potassium Chloride Supplements

Product Amount (mEq) Extended-release tablets    Micro-K Extentabs, Slow K, Klor-Con 8 8    K-Dur, K-Norm, K-Tab, Ten-K, Micro-K 10 10    Extentabs, Klor-Con 10    K-Dur 20    Powders for solution (flavored)a    K-Lor (also 15 mEq), Kato, Klor-Con 20/packet       Klor-Con 125 (25 mEq) Suspension (no taste)    Micro-K LS 20/packet Efflorescent granules or tablets (flavored)a    Klorvess, Klor-Con/EF (25 mEq) 20 Solutions (flavored)a    Klorvess 10%, Rum-K 15% 20–30/15 mL aTaste is generally improved by chilling.

Potassium-sparing diuretics (spironolactone, triamterene, amiloride) reduce urinary potassium losses, minimize development of metabolic alkalosis by reducing acid excretion (spironolactone), and limit renal magnesium wasting. In one study conversion from hydrochlorothiazide (with or without potassium supplements) to hydrochlorothiazide plus amiloride or hydrochlorothiazide plus triamterene without potassium supplements increased the serum potassium by 0.5 to 0.7 mEq/L into the midnormal range (39). Measuring 24-hour urinary potassium excretion and serum potassium may help determine how much supplement to prescribe.

All patients should be assessed for risk of hyperkalemia before potassium supplements or potassium-sparing agents are prescribed. These risks are renal insufficiency (serum creatinine greater than 1.2 mg/dL or glomerular filtration rate less than 60 mL/minute), diabetes mellitus, age 75 or older, and the use of other agents known to interfere with potassium homeostasis such as angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, cyclosporine, and heparin. Even patients with normal renal function generally should not be given potassium supplements and potassium-sparing diuretics together with other drugs that interfere with potassium homeostasis. All patients beginning therapy to raise the serum potassium level should have their serum potassium measured after 1 and 4 weeks and then at least every 6 to 12 months.

Renal Potassium Wasting Unrelated to Diuretics or Gastric Losses

The blood pressure and acid-base status of the patient simplify the complex differential diagnosis of renal potassium wasting (Fig. 50.4) (24), but referral to a specialized center may still be necessary.

Hypokalemia Accompanied by Hypertension

Hypokalemia accompanied by an elevated blood pressure suggests renin/angiotensin, mineralocorticoid/glucocorticoid, or apparent mineralocorticoid excess (Table 50.5). Determination of plasma renin activity is the first step in the evaluation of renal potassium wasting in a hypertensive patient (Fig. 50.4). An elevated renin suggests renovascular disease, malignant hypertension, or a rare renin-producing tumor. A low renin level should be repeated along with a plasma aldosterone level. If both are low, either excess endogenous or exogenous steroids, other than aldosterone, are likely. Licorice, chewing tobacco, carbenoxolone (an agent derived from licorice root), and steroid-containing nasal sprays are rare exogenous causes of this syndrome. Liddle syndrome (hypertension with hypokalemia unresponsive to spironolactone but responsive to amiloride) is caused by an autosomal dominant increased activity of the amiloride-sensitive sodium channel (40). Finally, if the renin level is low but the simultaneous aldosterone level is high, primary aldosteronism is strongly suggested.

TABLE 50.5 Causes of Hypertension with Associated Renal Potassium Wasting

Hyperreninemic Forms Renovascular Renin tumor Malignant or accelerated essential hypertension Hyporeninemic Steroid-Dependent Forms Mineralocorticoid    Exogenous       Licorice, desoxycorticosterone, fludrocortisone, chewing tobacco, carbenoxolone    Endogenous       Adrenal adenoma       Adrenal glomerulose hyperplasia       Enzyme deficiency: 17-OHase; 11-OHase       Liddle syndrome    Glucocorticoid       Endogenous   Cushing syndrome, pituitary, ectopic ACTH, adrenal cortical       Exogenous ACTH, adrenocorticotropic hormone. With permission from Narins RG, Jones ER, Stom MC, et al. Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am J Med 1982;72:496.

Most patients with primary aldosteronism are asymptomatic. Although once thought to be an extremely rare disorder, the use of the plasma aldosterone to plasma renin activity ratio (41) as a screening test in hypertensive patients has resulted in greater detection of this condition and a higher apparent prevalence than previously believed (42). Clinical manifestations, in addition to hypertension, are related to potassium depletion and occur only when such depletion is severe. These include weakness, paralysis, tetany, arrhythmias, polyuria, and polydipsia. Edema is uncommon because adaptive factors diminish sodium retention. Only a minority of patients with primary hyperaldosteronism have hypokalemia but many of these patients manifest hypokalemia if challenged with potassium-wasting diuretics or with large intakes of sodium chloride (200 millmoles per day, approximately 4 to 5 g of sodium or 10 to 12 g sodium chloride). The development of severe hypokalemia after the initiation of thiazide therapy is sometimes a clue to a hypermineralocorticoid state.

Localization procedures (computerized tomography [CT] or magnetic resonance imaging [MRI]) are needed to distinguish adenomas from bilateral adrenal hyperplasia. Adenomas are usually treated surgically but surgery is seldom curative for bilateral hyperplasia. A spironolactone trial (up to 400 mg daily for several weeks) is useful

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in almost all patients. Failure of spironolactone to normalize the blood pressure while normalizing hypokalemia strongly suggests that surgery would probably not resolve the hypertension.

Normotensive Hypokalemia

The acid-base status of normotensive, hypokalemia patients with renal potassium wasting should be assessed (Fig. 50.4). Hypokalemia occurs in both renal tubular acidosis and diabetic ketoacidosis. Measuring urine chloride can help distinguish hypokalemic, metabolic alkalosis caused by GI losses from that due to renal losses (43). Upper GI fluid loss is typically associated with low urinary chloride concentration while a high urinary chloride concentration is seen during active diuretic use and with unusual disorders like Bartter syndrome (see Bartter and Gitelman Syndromes). The high urinary chloride concentration that is seen during active or recent diuretic use is typically followed by paradoxically low urine chloride after the drug has been discontinued. Diuretic abuse and self-induced vomiting are commonly concealed causes of hypokalemia and metabolic alkalosis.

Hypomagnesemia is a common finding in up to 40% of hypokalemic patients. Although the mechanism is incompletely understood, enhanced aldosterone secretion is believed to play a role by increasing the urinary excretion of magnesium. Hypomagnesemia of any cause can cause hypokalemia as a result of fecal as well as urinary losses. Serum magnesium therefore should be measured during the evaluation of any refractory hypokalemic patient.

Bartter and Gitelman Syndromes

Bartter syndrome consists of hypokalemic metabolic alkalosis, excessive urinary potassium losses, and normal blood pressure, without edema (40). Plasma renin activity and aldosterone levels are significantly elevated. This presentation is mimicked by diuretic abuse and surreptitious vomiting, from which Bartter syndrome must be differentiated. A urine screening test for surreptitious diuretic use should be done. Urinary chloride is elevated in Bartter syndrome and decreased in surreptitious vomiting. Hypokalemia is usually refractory to potassium supplementation but may be ameliorated by administration of prostaglandin synthesis inhibitors (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]) or by amiloride 5 to 10 mg/day.

Gitelman syndrome consists of hypokalemic metabolic alkalosis, excessive urinary potassium losses, and normal blood pressure, without edema but also with hypomagnesemia and hypocalciuria. A defect in the thiazide-sensitive sodium chloride transporter causes patients with this condition to appear as if they were taking thiazide diuretics (40).

Specific References*

For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.

1. Cohn JN, Kowey PR, Whelton PK, et al. New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice. Arch Int Med 2000;160:2429.
2. Sterns RH, Cox M, Feig PU, et al. Internal potassium balance and the control of the plasma potassium concentration. Medicine 1981;60:339.
3. McDonough AA, Thompson CB, Youn JH. Skeletal muscle regulates extracellular potassium. Am J Physiol Renal Physiol 2002;282:F967.
4. Siegel D, Hulley SB, Black DM, et al. Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. JAMA 1992;267:1083.
5. Kuller LH, Hulley SB, Cohen JD, et al. Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: a critical analysis. Circulation 1986;73:114.
6. Caralis PV, Materson BJ, Perez-Stable E. Potassium and diuretic-induced ventricular arrhythmias in ambulatory hypertensive patients. Miner Electrolyte Metab 1984;10:148.
7. Franse LV, Pahor M, Di Bari M, et al. Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension 2000;35:1025.
8. Cohen HW, Madhavan S, Alderman MH. High and low serum potassium associated with cardiovascular events in diuretic-treated patients. J Hypertens 2001;19:1315.
9. Langford HG. Dietary potassium and hypertension: epidemiological data. Ann Intern Med 1983;98(Suppl):770.
10. Linas SL. The role of potassium in the pathogenesis and treatment of hypertension. Kidney Int 1991;39:771.
11. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988;297:319.
12. McCarron DA, Morris CD, Henry HJ, et al. Blood pressure and nutrient intake in the United States. Science 1984;224:1392.
13. Frisancho AR, Leonard WR, Bollettino LA. Blood pressure in blacks and whites and its relationship to dietary sodium and potassium intake. J Chronic Dis 1984;37:515.
14. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997;336:1117.
15. Brancati FL, Appel LJ, Seidler AJ, et al. Effect of potassium supplementation on blood pressure in African Americans on a low-potassium diet. A randomized, double-blind, placebo-controlled trial. Arch Intern Med 1996;156:61.
16. Siani A, Strazzullo P, Giacco A, et al. Increasing the dietary potassium intake reduces the need for antihypertensive medication. Ann Intern Med 1991;115:753.
17. Siani A, Strazzullo P, Russo L, et al. Controlled trial of long term oral potassium supplements in patients with mild hypertension. BMJ 1987;294:1453.
18. Svetkey LP, Yarger WE, Feussner JR, et al. Double-blind, placebo-controlled trial of potassium chloride in the treatment of mild hypertension. Hypertension 1987;9:444.
19. Whelton PK, He J, Cutler JA, et al. Effects of oral potassium on blood pressure: metaanalysis of randomized controlled clinical trials. JAMA 1997;277:1624.
20. Khaw KT, Barrett-Connor E. Dietary potassium in stroke-associated mortality: a 12-year prospective population study. N Engl J Med 1987;316:235.
21. Bernardo JF, Murakami S, Branch RA, et al. Potassium depletion potentiates amphotericin-B-induced toxicity to renal tubules. Nephron 1995;70:235.
22. Menahem SA, Perry GJ, Dowling J, et al. Hypokalaemia-induced acute renal failure. Nephrol Dial Transplant 1999;14:2216.
23. Abdel-Rahman EM, Moorthy AV. End-stage renal disease (ESRD) in patients with eating disorders. Clin Nephrol 1997;47:106.
24. Narins RG, Jones ER, Stom MC, et al. Diagnostic strategies in disorders of fluid, electrolyte and acid–base homeostasis. Am J Med 1982;72:496.
25. Reimann D, Gross P. Chronic, diagnosis-resistant hypokalaemia. Nephrol Dial Transplant 1999;14:2957.
26. Sterns RH, Spital A. Disorders of internal potassium balance. Semin Nephrol 1987;7:399.
27. Morgan DB, Young RM. Acute transient hypokalemia: new interpretation of a common event. Lancet 1982;2:751.
28. Heller SR, Robinson RT. Hypoglycemia and associated hypokaelemia in diabetes: Mechanisms, clinical implications and prevention. Diabetes Obes Metab 2000;2:75.

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29. Ahlawat SK, Sachdev A. Hypokalaemic paralysis. Postgrad Med J 1999;75:193.
30. McFadzean AJ, Yeung R. Periodic paralysis complicating thyrotoxicosis in Chinese. BMJ 1967;1:451.
31. Ethier JH, Kamel KS, Magner PO, et al. The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J Kidney Dis 1990;15:309.
32. Kassirer JP, Schwartz WB. The response of normal man to selective depletion of hydrochloric acid. Am J Med 1966;40:10.
33. Kassirer JP, Berkman PM, Lawrenz DR, et al. The critical role of chloride in the correction of hypokalemic alkalosis in man. Am J Med 1965;38:172.
34. Morgan DB, Davidson C. Hypokalemia and diuretics: an analysis of publications. BMJ 1980;280:905.
35. Nader PC, Thompson JR, Alpern RJ. Complications of diuretic use. Semin Nephrol 1988;8:365.
36. Tannen RL. Diuretic-induced hypokalemia. Kidney Int 1985;28:988.
37. Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451.
38. Papademetriou V, Burris J, Kukich S, et al. Effectiveness of potassium chloride or triamterene in thiazide hypokalemia. Arch Intern Med 1985;145:1986.
39. Ridgeway NA, Ginn DR, Alley K. Outpatient conversion of treatment to potassium-sparing diuretics. Am J Med 1986;80:785.
40. Scheinman SJ, Guay-Woodford LM, Thakker RV, et al. Genetic disorders of renal electrolyte transport. N Engl J Med 1999;340:1177.
41. Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am 2002;31:619.
42. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89:1045.
43. Kamel KS, Ethier JH, Richardson RM, et al. Urine electrolytes and osmolality: when and how to use them. Am J Nephrol 1990;10:89.