Donald F. Brophy
Potassium regulates many biochemical processes in the body and is a key cation for electrical action potentials across cellular membranes.
In patients with concomitant hypokalemia and hypomagnesemia, it is imperative to correct the hypomagnesemia before the hypokalemia.
Potassium chloride is the preferred potassium supplement for the most common causes of hypokalemia.
Hyperkalemia is a common occurrence in patients with acute or chronic kidney disease.
Hypomagnesemia is commonly caused by excessive GI or renal magnesium wasting.
Hypermagnesemia is predominantly observed in patients with acute or chronic kidney disease.
Potassium and magnesium are electrolytes that are responsible for numerous metabolic activities. Disorders of these electrolytes are frequently seen in both the acute care and community ambulatory care settings. Therefore, clinicians need a firm understanding of the etiology, pathophysiology, symptoms, pharmacotherapy, and monitoring of these disorders. This chapter describes the homeostatic mechanisms that are responsible for the maintenance of normal potassium and magnesium serum concentrations. The clinical disorders responsible for the development of hyperkalemia, hypermagnesemia, hypokalemia, and hypomagnesemia are also reviewed.
Potassium is the most abundant cation in the body, with estimated total-body stores of 3,000 to 4,000 mEq (3,000 to 4,000 mmol).1 Ninety-eight percent of this amount is contained within the intracellular compartment, and the remaining 2% is distributed within the extracellular compartment. The sodium-potassium adenosine triphosphatase (Na+-K+-ATPase) pump located in the cell membrane is responsible for the compartmentalization of potassium. This pump is an active transport system that maintains increased intracellular stores of potassium by transporting sodium out of the cell and potassium into the cell at a ratio of 3:2. Consequently, the pump maintains a higher concentration of potassium inside the cell.
The normal serum concentration range for potassium is 3.5 to 5 mEq/L (3.5 to 5 mmol/L), whereas the intracellular potassium concentration is usually approximately 150 mEq/L (150 mmol/L).2Approximately 75% of the intracellular potassium is located in skeletal muscle; the remaining 25% is located in the liver and red blood cells. Extracellular potassium is distributed throughout the serum and interstitial space. Potassium is dynamic in that it is constantly moving between the intracellular and extracellular compartments according to the body’s needs. Thus, the serum potassium concentration alone does not accurately reflect the total-body potassium content.
Potassium has many physiologic functions within cells, including protein and glycogen synthesis and cellular metabolism and growth. It is also a determinant of the electrical action potential across the cell membrane.1 The ratio of the intracellular-to-extracellular potassium concentration is the major determinant of the resting membrane potential across the cell membrane. Thus, the resting membrane potential is greatly affected by variations in extracellular potassium concentration. Serum potassium concentrations outside the normal range can have disastrous effects on neuromuscular activity, in particular cardiac conduction. Hypo- and hyperkalemia are both associated with potentially fatal cardiac arrhythmias, along with other neuromuscular disturbances. Finally, potassium is integral to maintaining healthy blood pressure balance, prevention of stroke, and potentially other cardiovascular diseases.3 Both the National High Blood Pressure Education Program and the Institute of Medicine recommend potassium supplementation as strategies for preventing and treating hypertension.4–6
Control of Potassium Homeostasis
Potassium homeostasis, the maintenance of serum potassium within the normal range, is affected by dietary intake, GI and urinary excretion, hormones, acid-base balance, body fluid tonicity, and a highly integrated feedback mechanism.7,8 The recommended daily allowance for dietary potassium intake in the United States is approximately 50 mEq/day (50 mmol/day); however, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines recommends a daily intake of 100 mEq (100 mmol) for prevention of hypertension and other cardiovascular complications.9 Potassium is found in abundance in fruits, vegetables, and meats. The typical American ingests approximately 50 to 150 mEq (50 to 150 mmol) of potassium daily. Nearly all of this is absorbed, with only 10 to 20 mEq/day (10 to 20 mmol/day) eliminated in feces. The amount eliminated in the feces increases, however, in patients with diarrhea and in those with chronic kidney disease (CKD).8
The kidney is the primary route of potassium elimination. Potassium is freely filtered, but almost all of it is reabsorbed passively in the proximal tubule and the thick ascending limb of the loop of Henle.10Therefore, urinary potassium excretion is primarily determined by potassium secretion from the luminal cells of the distal tubule and collecting duct. Although the amount of potassium filtered by the glomerulus approaches 700 mEq (700 mmol) per day, only approximately 10% to 20% is actually excreted in the urine.10 However, this amount can vary based on dietary intake, serum potassium concentration, and aldosterone activity. For example, more potassium is renally excreted in conditions that result in high aldosterone activity (e.g., dehydration) when the body is attempting to conserve sodium or when there is an increase in dietary potassium intake.
Hormones such as insulin, catecholamines, and aldosterone dramatically affect potassium homeostasis. Insulin is the most important hormonal mediator of potassium balance because it stimulates the cellular Na+-K+-ATPase pump to increase transport of potassium into liver, muscle, and adipose tissue.7 There is a complex negative feedback loop in which insulin secretion tightly regulates serum potassium concentrations: an increase of only a few tenths of a milliequivalent (mmol) of potassium stimulates pancreatic insulin secretion in an attempt to prevent hyperkalemia from developing.1 If hyperkalemia does occur, glucagon is released from the liver to protect against insulin-induced hypoglycemia. Conversely, hypokalemia inhibits insulin secretion, a finding that explains why some patients receiving diuretics develop hyperglycemia.
An elevation in circulating catecholamines such as epinephrine usually results in the intracellular movement of potassium by two mechanisms.10 They stimulate the β-receptor, which directly activates the Na+K+-AT Pase pump. Second, they stimulate glycogenolysis, which raises blood glucose concentrations, thereby increasing insulin secretion. This dual mechanism is often used therapeutically in patients with hyperkalemia to normalize serum potassium concentrations.
Aldosterone, a mineralocorticoid that is secreted from the adrenal glands in response to high serum potassium concentrations, promotes urinary potassium excretion. Aldosterone works in the distal tubule and collecting duct to promote the reabsorption of sodium and water in exchange for potassium. Aldosterone may also have extrarenal activity by stimulating cellular Na+-K+-ATPase pump activity.10
Changes in acid-base status significantly affect the serum potassium concentration. For example, the infusion of metabolic inorganic acids, such as hydrochloric acid, results in an increase in serum potassium. The body compensates for excessive hydrogen ions by moving them from the serum into the cell in exchange for intracellular potassium, to maintain electroneutrality. The processes by which this occurs are highly complex, and involve cellular H+-K+-ATPase pumps and both Na+-HCO3– and K+-HCO3– cotransporters.11 The efflux of potassium into the serum can result in hyperkalemia. A commonly quoted approximation of the pH effect is that for every 0.1 unit decrease in pH, there is a corresponding increase in serum potassium of 0.6 to 0.8 mEq/L (0.6 to 0.8 mmol/L) (with a wide range of 0.2 to 1.7).6 This is often referred to as false hyperkalemia because there is not a true excess of total-body potassium. Metabolic acidosis associated with lactic acidosis and ketoacidosis does not result in hyperkalemia, because both cations and anions enter the cell, thus maintaining electroneutrality.1 Respiratory acidosis also does not significantly affect the serum potassium concentration.
Conversely, metabolic alkalosis has been associated with hypokalemia. As a result of a net loss of hydrogen ion from the serum, intracellular hydrogen ions enter the serum to increase the acidity of the blood. To maintain electroneutrality, extracellular potassium ions are shifted intracellularly. This creates a relative deficiency of potassium in the serum. Serum potassium decreases approximately 0.6 mEq/L (0.6 mmol/L) for each 0.1 unit increase in blood pH. This is frequently termed false hypokalemia because there is not a true deficiency in total-body potassium.
Finally, hyperosmolality can result in enhanced movement of potassium from the cell into the extracellular fluid. This occurs most likely because of the associated cell shrinkage and water loss, which increases the intracellular-to-extracellular potassium gradient.4 This is seen most commonly in conditions such as diabetic ketoacidosis. Conversely, hypoosmolality does not seem to affect potassium distribution.
Hypokalemia (defined as a serum potassium concentration <3.5 mEq/L [<3.5 mmol/L]) is a commonly encountered electrolyte abnormality in clinical practice. Hypokalemia can be categorized as mild (serum potassium 3.1 to 3.5 mEq/L [3.1 to 3.5 mmol/L]), moderate (serum potassium 2.5 to 3 mEq/L [2.5 to 3 mmol/L]), or severe (<2.5 mEq/L [<2.5 mmol/L]).12 When hypokalemia is detected, a diagnostic workup that evaluates the patient’s comorbid disease states and concomitant medications should be initiated. Hypokalemia is virtually nonexistent in healthy adults. This is due in part to the relatively high potassium content in the typical Western diet as well as the body’s effective potassium-sparing mechanisms, which tightly regulate the serum potassium concentration. However it has been estimated that as many as 50% of patients who receive thiazide or loop diuretics have serum potassium concentrations less than 3.5 mEq/L (3.5 mmol/L).13
While hypokalemia may be thought of as merely a laboratory abnormality, there are serious potential consequences associated with persistent hypokalemia. Recent data suggest that hypokalemia increases mortality in patients with chronic heart failure and in those with CKD, a population typically thought to be more sensitive to the effects of hyperkalemia.14 In fact, even mild hypokalemia in patients with CKD appears to confer a greater risk of dying compared with those with mild to moderate hyperkalemia.15
Etiology and Pathophysiology
Hypokalemia results when there is a total-body potassium deficit, or when serum potassium is shifted into the intracellular compartment. Total-body deficits occur in the setting of poor dietary intake of potassium, or when there are excessive renal and GI losses of potassium. Maintaining a consistent dietary intake of potassium is important because the body has no effective method for storing potassium. At steady state, potassium excretion matches potassium intake; approximately 90% of ingested potassium is renally excreted, whereas 10% is excreted in feces.10 This underscores the importance of eating a well-balanced diet. Elderly patients with chronic diseases and those undergoing surgery are at increased risk for developing hypokalemia because of insufficient intake or losses resulting from surgery.
Many drugs can cause hypokalemia by a variety of mechanisms including intracellular potassium shifting and increased renal or stool losses (Table 36-1). The most common cause of drug-induced hypokalemia is loop and thiazide diuretic administration as these agents inhibit renal sodium reabsorption, which results in increased sodium delivery to the distal tubule. Consequently, hypokalemia develops because the distal tubule selectively reabsorbs sodium, and excretes potassium down its concentration gradient. Second, because diuretics result in volume contraction, aldosterone is secreted that further promotes the renal excretion of potassium. If concomitant potassium supplements are not provided to patients receiving loop and thiazide diuretics, mild to moderate hypokalemia is inevitable.
TABLE 36-1 Mechanism of Drug-Induced Hypokalemia
The second most common etiology of hypokalemia is excessive loss of potassium-rich GI fluid as a result of diarrhea and/or vomiting. The typical potassium loss in feces is approximately 10 mEq (10 mmol) per day.8 In diarrheal states, this amount increases proportionally with the volume of stool output. Vomiting also accounts for substantial potassium losses, which have been estimated to be as high as 30 to 50 mEq (30 to 50 mmol) per liter of vomitus.13Metabolic alkalosis can also occur in cases of severe diarrhea and vomiting as a result of loss of these bicarbonate-rich fluids. This causes an intracellular shifting of potassium, which lowers the serum concentration of potassium even further. Prolonged diarrhea and vomiting can significantly affect children and elderly patients because their kidneys are unable to effectively maintain adequate fluid status.
Hypomagnesemia, which is present in more than 50% of cases of clinically significant hypokalemia, contributes to the development of hypokalemia because it reduces the intracellular potassium concentration and promotes renal potassium wasting.16 While the precise mechanism of the accelerated renal loss is unknown, many believe that the intracellular potassium concentration may decrease because hypomagnesemia impairs the function of the Na+-K+-ATPase pump thereby promoting K+ wasting. Alternatively, the combination of increased sodium delivery to the distal tubule, elevated aldosterone concentrations, and hypomagnesemia may cause the renal outer medullary potassium channels to excrete potassium.16 What is clear is that hypokalemia and hypomagnesemia often coexist as a result of drugs (diuretic administration) or disease states (diarrhea). When concomitant hypokalemia and hypomagnesemia occur, the magnesium deficiency should be corrected first, otherwise full repletion of the potassium deficit is difficult.
CLINICAL PRESENTATION Hypokalemia
• The signs and symptoms of hypokalemia are usually nonspecific and highly variable between patients
• Symptoms are highly dependent on the degree of hypokalemia and its rapidity of onset
• Mild hypokalemia is often asymptomatic
• Moderate hypokalemia is associated with cramping, weakness, malaise, and myalgias
• Cardiovascular: In severe hypokalemia, ECG changes often include ST-segment depression or flattening, T-wave inversion, and U-wave elevation. Clinical arrhythmias include heart block, atrial flutter, paroxysmal atrial tachycardia, ventricular fibrillation, and digitalis-induced arrhythmias
• Musculoskeletal: Cramping and impaired muscle contraction
• Serum potassium concentration below 3.5 mEq/L (3.5 mmol/L) is diagnostic. Hypomagnesemia (serum magnesium concentration below 1.7 mg/dL [1.4 mEq/L; 0.70 mmol/L]) can also be present
The goals of hypokalemia management are to prevent and/or treat serious life-threatening complications, normalize the serum potassium concentration, identify and correct the underlying cause of hypokalemia, and finally prevent overcorrection of the serum potassium concentration.
General Approach to Therapy
The general approach to therapy depends on the degree and rapidity with which hypokalemia developed and the presence of symptoms. Serum potassium concentrations between 3.5 and 4 mEq/L (3.5 and 4 mmol/L) are a sign of early potassium depletion. No pharmacologic therapy is recommended at this point; however, these patients should be encouraged to increase their dietary intake of potassium-rich foods. When the serum potassium concentration is between 3 and 3.5 mEq/L (3 and 3.5 mmol/L), the patient’s concomitant conditions and therapies will largely determine whether pharmacologic therapy should be initiated. Oral potassium supplementation should be initiated in patients with underlying cardiac conditions that predispose them to cardiac arrhythmias. This includes patients receiving concomitant digoxin therapy. Patients with serum potassium concentrations below 3 mEq/L (3 mmol/L) should always be treated to achieve values between 4 and 4.5 mEq/L (4 and 4.5 mmol/L). In asymptomatic patients, oral therapy is the preferred route of administration. IV potassium can be necessary in symptomatic patients with severe depletion, or in patients who are intolerant to oral supplementation. In patients with concomitant moderate to severe hypomagnesemia, the magnesium deficit should be corrected before potassium supplementation.10,12
The best and most abundant source of potassium supplementation comes from dietary sources, in particular, fresh fruits and vegetables, fruit juices, and meats. Table 36-2 lists foods that are excellent sources of potassium. Salt substitutes that contain potassium chloride are another effective, inexpensive source of potassium. Increased dietary intake of foods with high potassium content, however, is not recommended long term because it can add unwanted calories to the patient’s diet. Moreover, dietary potassium is almost entirely coupled with phosphate, rather than chloride, so it is not as effective in correcting potassium loss associated with hypochloremic conditions such as vomiting, nasogastric suctioning, and diuretic therapy.
TABLE 36-2 Foods that are High in Potassium
Formal guidelines for potassium supplementation were last published by the National Council on Potassium in Clinical Practice in 2000 (Table 36-3).17 These guidelines provided a comprehensive framework for potassium administration as a prophylactic and therapeutic replacement in many distinct patient populations. When deciding how to design the optimal regimen, one must consider: (a) the patient’s normal baseline potassium concentration; (b) underlying medical conditions that can affect potassium balance; (c) concomitant medications that can affect potassium balance; (d) the patient’s dietary and salt intake; and (e) the patient’s ability to comply with the therapeutic regimen.17
TABLE 36-3 General Consensus Guidelines for Potassium Replacement
A general rule for potassium replacement is that for every 1 mEq/L (1 mmol/L) decrease of potassium below 3.5 mEq/L (3.5 mmol/L), there is a corresponding total-body potassium deficit of 100 to 400 mEq (100 to 400 mmol). Because of the wide variance in projected deficits, each patient’s therapy must be individualized and adjustments made on the basis of the patient’s signs, symptoms, and frequent measurements of serum potassium. In patients receiving chronic loop or thiazide diuretic therapy, 40 to 100 mEq (40 to 100 mmol) of oral potassium supplementation can correct mild to moderate potassium deficits. Doses up to 120 mEq (120 mmol) can be required in more severe deficiencies. When providing oral potassium supplementation, the total daily dose should be divided into three to four doses to minimize the development of GI side effects. Patients receiving diuretics can become chronically hypokalemic and can benefit from combination potassium-sparing diuretic therapy.
Whenever possible, potassium supplementation should be administered by mouth. Three salts are available for oral potassium supplementation: chloride, phosphate, and bicarbonate. Potassium phosphate should be used when patients are both hypokalemic and hypophosphatemic; potassium bicarbonate is most commonly used when potassium depletion occurs in the setting of metabolic acidosis. Potassium chloride, however, is the primary salt form used because it is the most effective treatment for the most common causes of potassium depletion (i.e., diuretic-induced and diarrhea-induced) as these conditions are associated with potassium and chloride losses.
Potassium chloride can be administered in either tablet or liquid formulations (Table 36-4). The liquid forms are generally less expensive; however, patient compliance can be low because of their strong, unpleasant taste. Two sustained-release solid dosage forms are currently available in the United States: a wax-matrix formulation, and a microencapsulated formulation. The microencapsulated tablet is generally preferred because it disintegrates better in the stomach and is associated with less GI irritation. IV potassium use should be limited to: (a) severe cases of hypokalemia (serum concentration <2.5 mEq/L [<2.5 mmol/L]); (b) patients exhibiting signs and symptoms of hypokalemia such as electrocardiogram (ECG) changes or muscle spasms; or (c) patients unable to tolerate oral therapy. IV supplementation is more dangerous than oral therapy because it is more likely to result in hyperkalemia, phlebitis, and pain at the site of infusion.
TABLE 36-4 Differentiation of Available Potassium Supplements
The vehicle in which IV potassium is administered is important. Whenever possible, potassium should be prepared in saline-containing solutions (e.g., 0.9% or 0.45% sodium chloride [NaCl]). Dextrose-containing solutions stimulate insulin secretion, which can cause intracellular shifting of potassium, worsening the patient’s hypokalemia, and should be avoided whenever possible. Generally, 10 to 20 mEq (10 to 20 mmol) of potassium is diluted in 100 mL 0.9% NaCl for IV administration. These concentrations are safe when administered through a peripheral vein over 1 hour. When infusion rates exceed 10 mEq/h (10 mmol/h) ECG monitoring should be performed to detect cardiac changes. The serum potassium concentration should be evaluated following the infusion of each 30 to 40 mEq (30 to 40 mmol) to direct further potassium replacement requirements. Multiple doses of potassium can be repeated as needed until the serum potassium concentration normalizes. To allow adequate time for the potassium to equilibrate between the intra- and extracellular spaces, the clinician should wait at least 30 minutes from the end of each infusion before obtaining a serum concentration. Care should be taken to avoid sampling from the same line in which the potassium was infused, as this can result in a spuriously high potassium concentration.
In cases of severe potassium depletion, patients can require as much as 300 to 400 mEq/day (300 to 400 mmol/day). In this instance, it is common practice to dilute 40 to 60 mEq (40 to 60 mmol) in 1,000 mL 0.45% NaCl and infuse at a rate not exceeding 40 mEq/h (40 mmol/h). This should be performed in an intensive care unit under continuous ECG monitoring. Because of the high potassium concentration, and the risk for burning pain and peripheral venous sclerosis, the infusion should be through a central venous catheter into a large vein (e.g., superior vena cava) but care must be taken not to place the tip of the catheter into the right atrium.18 Directly delivering high potassium concentrations into the heart can result in cardiac arrhythmias. Given the volume required to infuse this dose of potassium, this infusion strategy might be impractical in certain clinical situations (e.g., patients requiring fluid restriction). A reasonable approach is to split the potassium dose between the oral and IV routes. For example, if a symptomatic patient requires 120 mEq (120 mmol) of potassium, the clinician can give 60 mEq (60 mmol) as the immediate-release potassium liquid, and the other 60 mEq (60 mmol) can be given through the IV route (20 mEq/100 mL/h [20 mmol/100 mL/h] in three doses). When giving large potassium doses, serum monitoring should be performed following the administration of half the dose to guide the clinician as to the need for additional potassium. This can also help avoid the development of hyperkalemia.
In the rare circumstances when cardiac arrest from hypokalemia is imminent, IV bolus dosing of potassium 10 mEq (10 mmol) over 5 minutes can be initiated and repeated once, if necessary.18
Potassium-sparing diuretics are an alternative to chronic exogenous potassium supplementation, especially when patients are concomitantly receiving drugs that are known to deplete potassium (e.g., diuretics or amphotericin B). Spironolactone inhibits the effect of aldosterone in the distal convoluted tubule, thereby decreasing potassium elimination in the urine. Spironolactone is especially effective as a potassium-sparing agent in patients with primary or secondary hyperaldosteronism. Amiloride and triamterene act by an aldosterone-independent mechanism; however, the precise mechanism of their potassium sparing is unknown.
Spironolactone is available as 25-, 50-, and 100-mg tablets. The usual starting dose is 25 to 50 mg daily, and can be titrated to a maximum dose of 400 mg/day. The potassium-retaining effects generally take approximately 48 hours to occur. Important side effects include hyperkalemia, gynecomastia, breast tenderness, and impotence in men. Triamterene is available as 50- and 100-mg capsules. The usual starting dose is 50 mg twice daily, which can be titrated to 100 mg twice daily. Triamterene 50 mg is available as a combination product with hydrochlorothiazide 25 mg and is commonly used for the treatment of hypertension. Common side effects include hyperkalemia, sodium depletion, and metabolic acidosis. Amiloride is available as a 5-mg tablet. The usual starting dose is 5 mg daily; however, 10 mg can be given in those with severe hypokalemia. This is also available as a combination product with hydrochlorothiazide 50 mg. The most common side effects are hyperkalemia and metabolic acidosis.
Concomitant use of potassium supplementation with potassium-sparing diuretics is not necessary. There is a significant risk of hyperkalemia during combination therapy, especially in patients with underlying renal insufficiency or diabetes mellitus.
Evaluation of Therapeutic Outcomes
Serum potassium concentrations should be monitored regularly while the patient is receiving potassium supplementation. For patients receiving prophylactic potassium supplementation during diuretic therapy, the serum potassium and magnesium concentrations, as well as renal function should be monitored every 1 to 2 months in stable patients. In hospitalized patients receiving oral therapy for mild hypokalemia, the potassium concentration should be monitored every 2 to 3 days. Generally, the potassium concentration begins to increase within 72 hours. If it does not increase by at least 1 mEq/L (1 mmol/L) within 96 hours, the clinician should suspect concomitant magnesium depletion. Patients receiving IV potassium supplementation require close ECG monitoring if the infusion rate is greater than 20 mEq/h (20 mmol/h): doses greater than this should be administered only in the presence of continuous ECG monitoring. Additionally, the patient should have potassium concentrations obtained halfway through, and 30 minutes following completion of the total potassium dose to guide further potassium dosing. Finally, the patient should be assessed for adverse effects such as pain at the infusion site or phlebitis.
Clinical Bottom Line
Hypokalemia is a frequent medical condition caused by both biological processes as well as drug therapy. While mild hypokalemia is frequently asymptomatic, severe hypokalemia can cause fatal cardiac dysrhythmias, particularly in patients receiving concomitant medications such as digoxin. Patients receiving drugs that cause potassium wasting, e.g., thiazide or loop diuretics, should be closely followed for the development of hypokalemia and appropriate potassium supplementation should be started when necessary. Generally oral potassium is sufficient for mild hypokalemia; IV potassium is reserved for severe deficiency, and its use should be monitored closely.
Hyperkalemia, defined as a serum potassium concentration greater than 5 mEq/L (5 mmol/L), can be further classified according to its severity: mild hyperkalemia (5.1 to 5.9 mEq/L [5.1 to 5.9 mmol/L]), moderate hyperkalemia (6 to 7 mEq/L [6 to 7 mmol/L]), and severe hyperkalemia (above 7 mEq/L [7 mmol/L]).17
Hyperkalemia is much less common than hypokalemia. In fact, if all patients with acute and chronic kidney disease were excluded, the true prevalence of hyperkalemia would be insignificant. The incidence of hyperkalemia in hospitalized patients is highly variable, and reports have ranged from 1.4% to 10%.17 Most cases of hyperkalemia are the result of overcorrection of hypokalemia with IV potassium supplements. Severe hyperkalemia occurs more commonly in elderly patients with renal insufficiency who receive chronic oral potassium supplementation.
Etiology and Pathophysiology
Hyperkalemia develops when potassium intake exceeds excretion (true hyperkalemia) (i.e., elevated total-body stores), or when the transcellular distribution of potassium is disturbed (i.e., normal total-body stores). The four primary causes of hyperkalemia—(a) increased potassium intake, (b) decreased potassium excretion, (c) tubular unresponsiveness to aldosterone, and (d) redistribution of potassium into the extracellular space—are discussed below.
Hyperkalemia Associated with Increased Potassium Intake
Hyperkalemia in this setting is almost always associated with renal insufficiency. Patients with stage 4 or 5 CKD and dialysis patients who are noncompliant with dietary potassium restrictions often present with life-threatening hyperkalemia. Many of these patients do not realize that fresh fruits and vegetables contain large amounts of potassium. Anecdotally, in many dialysis centers the incidence of hyperkalemia peaks during the summer months, when fresh garden produce is available. Another common dietary source associated with the development of hyperkalemia is potassium chloride salt substitutes. Many dialysis patients are instructed to use salt substitutes to avoid excessive sodium intake in an attempt to control volume overload. These patients unwittingly become hyperkalemic because these products contain approximately 10 to 15 mEq (10 to 15 mmol) potassium per gram, or 200 mEq (200 mmol) per tablespoon. Finally, many over-the-counter herbal and alternative medicine products may contain significant concentrations of potassium. It is essential for patients with CKD to receive education regarding dietary sources of potassium as well as information on the potassium content of herbal products because the ingestion of these can lead to hyperkalemia.
Hyperkalemia Associated with Decreased Renal Potassium Excretion
Normally functioning kidneys excrete 80% of the daily potassium intake. Therefore, when the kidney is unable to excrete potassium appropriately, as in acute kidney injury (AKI) and stage 4 to 5 CKD, potassium is retained and often results in hyperkalemia. Finally, many drugs can inhibit the kidney’s ability to excrete potassium by inhibiting aldosterone and thus contribute to an increase in serum potassium concentrations.
Severe hyperkalemia is more common in AKI than in CKD because patients are often hypercatabolic and can have underlying disorders, such as rhabdomyolysis or tumor lysis syndrome, which result in release of potassium from injured or lysed cells.19 Severe hyperkalemia is rare in stable CKD patients, perhaps because of enhanced GI and renal potassium excretion.20 Data suggest that hyperkalemia directly stimulates renal K+ excretion through an effect that is independent of, and additive to, that of aldosterone.20 Although the overall incidence of hyperkalemia is higher in patients with CKD when compared with patients without CKD, due to these adaptive mechanisms and their decreased susceptibility to cardiac effects of chronic hyperkalemia, it has been associated with a lower mortality rate.21 Renal excretion of potassium is also inhibited by various endocrinologic disorders, including adrenal insufficiency, Addison’s disease, and selective hypoaldosteronism. All of these disorders involve a decreased production of aldosterone, which results in the retention of potassium.
Several drugs have profound effects on the kidney’s ability to regulate potassium. Five drug classes in particular have specific effects on the kidney: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), direct renin inhibitors, potassium-sparing diuretics, and prostaglandin inhibitors such as nonsteroidal antiinflammatory drugs (NSAIDs). Although hyperkalemia with these drugs is typically dose dependent, the rates of hyperkalemia have been reported to range from 5% to 10% in most clinical trials. Other commonly used drugs that can cause hyperkalemia are digoxin, cyclosporine, tacrolimus, trimethoprim-sulfamethoxazole, heparin, and pentamidine.
Tubular Unresponsiveness to Aldosterone
Certain medical conditions, such as sickle cell anemia, systemic lupus erythematosus, and amyloidosis, can produce a defect in tubular potassium secretion, possibly as the result of an alteration in the aldosterone-binding site.
Redistribution of Potassium into the Extracellular Space
The efflux of potassium from within the cell into the extracellular fluid, which is associated with no change in total-body potassium stores, is to be expected in the presence of metabolic acidosis, diabetes mellitus, chronic renal failure, or lactic acidosis. β-Blockers can also result in a transcellular potassium shift.
The serum potassium concentration can also be falsely elevated in some conditions, and not reflect the actual in vivo potassium concentration, that is, pseudohyperkalemia. Pseudohyperkalemia occurs most commonly in the setting of extravascular hemolysis of red blood cells. When a blood specimen is not processed promptly and cellular destruction occurs, intracellular potassium is released into the serum. It can also occur in conditions of thrombocytosis or leukocytosis. If severe hyperkalemia is found in a patient who is asymptomatic with an otherwise normal laboratory report, the hyperkalemia is most likely pseudohyperkalemia, and a repeat blood sample should be evaluated. Truly elevated potassium concentrations are normally associated with other laboratory abnormalities, such as low carbon dioxide (acidosis) or elevated blood urea nitrogen and creatinine concentrations (indicating renal insufficiency).
CLINICAL PRESENTATION Hyperkalemia
• Related to the effects of excessive potassium on neuromuscular, cardiac, and smooth muscle cell function
• Frequently asymptomatic
• The patient might complain of heart palpitations or skipped heartbeats
• ECG changes (see Fig. 36-1 for description)
• Serum potassium concentration above 5.5 mEq/L (5.5 mmol/L)
FIGURE 36-1 The earliest electrocardiographic manifestation of hyperkalemia is an increase in the rate of ventricular repolarization, which results in a peaking of the T wave at serum potassium concentrations of ~5.5 to 6 mEq/L (~5.5 to 6 mmol/L) (B), relative to the normal ECG presentation (A). Further increases in the serum potassium concentration above 6 mEq/L (6 mmol/L) result in conduction delays through the His-Purkinje system, the atrial myocardium, and the ventricular myocardium. The ECG manifestations of these conduction delays and the sequence in which they occur are a widening of the PR interval (C), delay through the His-Purkinje system, a loss of the P wave (D), delay through the atrial myocardium, a widening of the QRS complex (E), and delay through the ventricular myocardium. Finally, there is a merging of the QRS complex with the T wave (F), which results in a sine-wave appearance.
The goals of therapy for the treatment of hyperkalemia are to antagonize adverse cardiac effects, reverse signs and symptoms that are present, and return the serum and total-body stores of potassium to normal. The design of the treatment approach is determined by the severity of hyperkalemia, the rapidity of its development, and the patient’s clinical condition. Although ECG changes are directly proportional to the plasma potassium concentration and its rate of increase, they may not be present in all patients. In contrast, ventricular fibrillation may be the first cardiac manifestation of hyperkalemia in some patients.22 Asymptomatic patients with mild hyperkalemia usually require no specific therapy other than dietary education to control intake, and monitoring of serum potassium daily if an inpatient or weekly if an outpatient to assure resolution. Severe hyperkalemia (above 7 mEq/L [7 mmol/L]) or moderate hyperkalemia (6 to 6.9 mEq/L [6 to 6.9 mmol/L]), when associated with clinical symptoms or ECG changes, requires immediate treatment. Initial treatment of severe and moderate symptomatic hyperkalemia is focused on antagonism of the cardiac membrane actions of hyperkalemia (e.g., with calcium). Secondarily, one should attempt to decrease extracellular potassium concentration by promoting its intracellular movement (e.g., with glucose, insulin, β2-receptor agonists, or sodium bicarbonate) or enhance its removal from the body by hemodialysis, the oral administration of cation-exchange resins, and/or the use of loop diuretics. In any case, the underlying cause of hyperkalemia should be identified and reversed, and exogenous potassium must be withheld.
General Approach to Treatment
A general treatment approach for patients with hyperkalemia is outlined in Figure 36-2. In patients who have acute ECG changes, IV calcium should be administered to prevent or treat any cardiac manifestations of hyperkalemia. At the same time, the serum potassium concentration should be rapidly decreased to below 5 mEq/L (5 mmol/L) within minutes by administering drugs that cause an intracellular shift, followed by those that increase the elimination of potassium from the body.22 If the patient is asymptomatic, rapid correction may not be necessary, and will likely depend on the clinical context associated with the rise in serum potassium concentration. If one anticipates the need to reduce total-body potassium stores, an ion exchange resin (e.g., sodium polystyrene sulfonate [SPS]) that results in removal of potassium from the body over several hours to days may be initiated shortly after the emergent care has been instituted. SPS use is contraindicated in patients with bowel dysfunction.
FIGURE 36-2 Treatment approach for hyperkalemia. (Serum potassium of 5.5 mEq/L is equivalent to 5.5 mmol/L.)
A recent study suggested that hemodialysis patients who ingested foods supplemented with glycyrrhetinic acid, the active ingredient in licorice, were better able to maintain plasma potassium concentrations within the normal range compared with hemodialysis patients given placebo.23,24 Glycyrrhetinic acid inhibits the enzyme 11β-hydroxy-steroid dehydrogenase II, thereby increasing cortisol availability in the colon. The net result is enhanced potassium elimination in the feces. Other nonpharmacologic therapies, specifically available for dialysis-dependent patients with end-stage renal disease (ESRD), are the institution of intermittent dialysis or hemofiltration therapy.
Various drug therapies have been used to lower the serum potassium concentration. The optimal regimen for a given patient is dependent on the rapidity and degree of lowering that is necessary. Table 36-5provides an overview of the available therapies, and their respective onset and duration of action one can expect.
TABLE 36-5 Therapeutic Alternatives for the Management of Hyperkalemia
While specific treatment recommendations vary, it is generally accepted that asymptomatic patients with potassium concentrations below 6 mEq/L (6 mmol/L) can be treated conservatively. In patients with normal renal function, or those with stage 3 or 4 CKD, this typically involves the administration of furosemide to promote urinary potassium excretion. When given IV at a dosage of 40 to 80 mg, urine flow usually increases within minutes and persists for approximately 4 to 6 hours. Close monitoring of the patient’s volume status and other electrolyte concentrations is required while the patient is receiving furosemide or other loop diuretic therapy. Of note, the effectiveness of diuretics in treating hyperkalemia has not been studied in a randomized, controlled fashion.
SPS (Kayexalate®) is a cation-exchange resin that can be administered orally or rectally by enema. SPS is available in powder form or prepackaged as a 33% sorbitol suspension. The oral route is more effective than the enema and is better tolerated by the patient. As the resin passes through the intestines, each gram of SPS exchanges 1 mEq (1 mmol) of sodium for 1 mEq (1 mmol) of potassium ions, which are in a relatively higher concentration in the large intestine. The onset of action of SPS is within 1 hour, and it can be repeated every 4 hours as needed. The sorbitol component of the suspension promotes the excretion of the cationically modified potassium exchange resin by inducing diarrhea. The usual oral SPS dose is 15 to 60 g in the 33% sorbitol suspension.
There have been several reports of colonic necrosis with the use of SPS.25,26 In 2009, the U.S. FDA mandated a boxed warning for SPS due to reports of colonic necrosis and other serious GI toxicities.27 The GI toxicities were believed to be associated with the 70% sorbitol; however, there are also reports of GI toxicity with the 33% sorbitol solution. A common finding in these reports was that toxicity occurred most commonly in patients who recently underwent GI surgery or had a current or previous history of bowel dysfunction. This FDA warning was updated in 2011. A recent commentary provided some needed perspective on the role of SPS in treating hyperkalemia.28 While the authors echoed the FDA warning, they found little risk to using the SPS 33% sorbitol suspension or SPS powder mixed in water for oral administration. They also noted that necrosis was most commonly found when SPS was administered as a retention enema in patients who had recent GI surgery, or bowel dysfunction. These authors recommended that the retention enema route of administration be abandoned given the risk of side effects and the fact that the enema route appears to be less effective compared with oral administration.
In symptomatic patients, or in those with severe hyperkalemia, emergency care is indicated. Initial therapy in this setting is the administration of IV calcium chloride or gluconate 1 g to protect the heart from life-threatening arrhythmias.22 Calcium antagonizes the cardiac membrane effect of hyperkalemia by reducing the electrical threshold potential for cardiac myocytes and reverses ECG changes within minutes. IV calcium should not be given to patients receiving digoxin as it can lead to digoxin toxicity. Its duration of action is 30 to 60 minutes, and it can be repeated as needed based on ECG findings. IV calcium can be given as either the chloride or gluconate salt; each is available as a 10% solution by weight. Calcium chloride provides approximately three times more calcium than equal volumes of the gluconate salt; however, it can cause tissue necrosis if extravasation occurs. For this reason, calcium gluconate is more commonly administered, with the standard dose being 10-mL IV bolus over 5 to 10 minutes.
Rapid correction of hyperkalemia may necessitate the administration of drugs that result in an intracellular shift of potassium, such as insulin and dextrose, sodium bicarbonate, and a β2-adrenergic receptor agonist (e.g., albuterol or terbutaline). The treatment of choice depends on the underlying medical disorders accompanying hyperkalemia. For example, in patients with concomitant metabolic acidosis, a sodium bicarbonate bolus or infusion of 50 to 100 mEq (50 to 100 mmol) is the preferred therapy (see Chap. 37 for additional information). Sodium bicarbonate helps us to correct the metabolic acidosis by raising the extracellular pH, in addition to causing a rapid intracellular potassium shift. It should be noted that sodium bicarbonate is much less effective when hyperkalemia is not related to metabolic acidosis.1 Sodium bicarbonate is also less effective in patients with ESRD, in whom a decrease in serum potassium may not be seen for as long as 4 hours. Sodium bicarbonate can also lead to sodium and volume overload in patients with stage 4 or 5 CKD. Administration of a fast-acting (e.g., Insulin Lispro) or regular insulin (5 to 10 units IV and dextrose (10% or 50%) is an effective method of reducing potassium. Insulin increases the activity of the Na+-K+-ATPase pump, thereby intracellularly shifting potassium. Glucose should be given with insulin unless the serum glucose is above 250 mg/dL (13.9 mmol/L) because hypoglycemia can develop as a result of the effects of the insulin therapy. An IV bolus of 10 units of regular insulin and 25 g of dextrose usually lowers the serum potassium concentration by 0.6 mEq/L (0.6 mmol/L) in dialysis-dependent patients.22 β2-Adrenergic agonists have a dual mechanism for lowering serum potassium. First, they stimulate the Na+-K+-ATPase pump to promote intracellular potassium uptake. Second, they stimulate pancreatic β-receptors to increase insulin secretion. Albuterol can be administered via IV (0.5 mg given over 15 minutes) or via nebulizer (10 to 20 mg nebulized over 10 minutes); however, it should be noted that injectable albuterol is not available in the United States. In ESRD patients, decreases in plasma potassium concentration of 0.6 mEq/L (0.6 mmol/L) and 1 mEq/L (1 mmol/L) can be anticipated after inhalation of 10 and 20 mg of albuterol, respectively. Of note, the doses of inhaled albuterol used for hyperkalemia are at least four times higher than those typically used for bronchospasm. There are important limitations with albuterol therapy, most notably variable bioavailability via the inhaled route (leading to potential over- or under-dosing and unpredictability of response) and second, cardiac side effects such as tachycardia, which are undesirable in patients who already have an abnormal ECG. Furthermore, as many as 40% of patients may be resistant to the hypokalemic effects of albuterol and patients already receiving a nonselective β2-receptor antagonist may not respond. Therefore, albuterol should not be used alone for the urgent treatment of hyperkalemia in CKD patients.22 The use of subcutaneous terbutaline has also been shown to be effective in a small group of dialysis patients with hyperkalemia.29
A Cochrane Review evaluated the emergency treatment of hyperkalemia.30 Many of the reviewed studies were small, and not all intervention groups had sufficient data for meta-analysis to be performed. However, given these limitations, inhaled and nebulized β-agonists, and IV insulin-and-glucose were all deemed effective. The combination of nebulized β-agonists with IV insulin and glucose appeared to be more effective than either agent alone. The meta-analysis results were equivocal for IV bicarbonate, and notably, SPS was not effective by 4 hours.
A major problem with drawing conclusions from this meta-analysis is the heterogeneity of the study population. Most of the data were from nonrandomized, noncontrolled observational studies and case reports. Doses of the drugs were not standardized and follow-up was often lacking. Therefore, the clinician should exercise caution when extrapolating these findings to his or her clinical practice. This underscores the need for clinicians to be able to interpret the limitations of the published literature. Nonetheless, the Cochrane database review corroborates the approach detailed in Figure 36-2.
SPS is commonly prescribed to both inpatients and outpatients for the management of hyperkalemia. Recent data, however, question its clinical effectiveness. Also, emerging data suggest its use may be associated with GI necrosis, especially in patients who recently underwent GI surgery or have current bowel injury.
Evaluation of Therapeutic Outcomes
The evaluation of therapeutic outcomes differs based on the severity of hyperkalemia. For example, mild or moderate asymptomatic hyperkalemia is observed much more frequently compared with symptomatic, severe hyperkalemia. Many drugs such as ACEIs, ARBs, direct renin inhibitors, and spironolactone result in asymptomatic hyperkalemia. In patients with normal renal function, once these drugs are initiated and the dose titrated, clinicians should check the potassium concentration at least monthly. For those patients with renal dysfunction, monitoring should be more frequent, such as biweekly until the dose is stabilized. In the case where the patient has been on a stable dose for a long period of time and hyperkalemia develops, the clinician should attempt to downward titrate the dose or switch to another medication without hyperkalemia as a side effect (e.g., calcium channel blocker).
In patients who have acute symptomatic hyperkalemia (e.g., ECG changes), frequent potassium concentration and ECG monitoring is warranted. The patient should receive continuous ECG telemetry monitoring until the serum potassium concentration decreases below 5 mEq/L (5 mmol/L), and the ECG abnormalities resolve. Similarly, while the patient is receiving emergent therapy, serial serum potassium concentrations should be obtained hourly until the potassium concentration decreases below 5 mEq/L (5 mmol/L). For patients who receive insulin and dextrose therapy for hyperkalemia, blood glucose monitoring should be performed hourly or more frequently if patients demonstrate signs and symptoms of hypoglycemia. For patients who receive large doses of sodium bicarbonate therapy for hyperkalemia, an arterial blood gas or serum chemistry profile should be obtained to assess their acid-base status. Furthermore, the patient should be evaluated for signs of fluid overload secondary to the high sodium load. Patients receiving albuterol or terbutaline therapy should be questioned regularly regarding the development of palpitations and tachycardia. The patient’s medication records should be reviewed to assure the patient is not receiving drug therapy that increases the serum potassium concentration. Furthermore, the patient should be questioned regarding the occurrence of diarrheal stool output.
Clinical Bottom Line
Hyperkalemia commonly occurs in patients with reduced kidney function or other metabolic disturbances. It can rapidly evolve into a medical emergency; therefore, prompt identification and appropriate pharmacotherapy is needed. In patients with mild hyperkalemia, potassium binding resins or loop diuretics may be useful, and should be used as first-line therapy. In severe hyperkalemia with ECG changes, IV calcium should be given to protect against cardiac dysrhythmias. Additionally rapid-acting therapies such as IV insulin and dextrose are indicated to move potassium intracellularly.
DISORDERS OF MAGNESIUM HOMEOSTASIS
Magnesium plays a central role in cellular function and is an important cofactor in more than 300 biochemical reactions in the body, especially those systems that are dependent on adenosine triphosphate. Mitochondrial function, protein synthesis, cell membrane function, parathyroid hormone (PTH) secretion, and glucose metabolism are just a few important functions affected by magnesium.31 It is the fourth most abundant extracellular cation and the second most abundant intracellular cation, after potassium. Disorders of magnesium homeostasis are commonly encountered in clinical situations and most frequently are manifested as alterations in cardiovascular and neuromuscular function. Life-threatening conditions such as paralysis and cardiac arrhythmias can occur, making the proper recognition and treatment of these problems of paramount importance. Altered magnesium balance also plays a key role in chronic disease states such as diabetes mellitus, CKD, osteoporosis, development of kidney stones, as well as heart and vascular disease.32
Magnesium is principally distributed in bone (67%) and muscle (20%). Because of its predominantly intracellular distribution, measurement of magnesium in the extracellular compartment may not accurately reflect the total-body magnesium content. The majority of magnesium in the extracellular fluid is in the ionized form as only 20% is bound to serum proteins. The normal range for serum magnesium is 1.4 to 1.8 mEq/L [1.7 to 2.3 mg/dL or 0.70 to 0.95 mmol/L].
The recommended daily dietary magnesium intake for adults is approximately 420 mg/day and 320 mg/day for men and women, respectively. The maintenance of magnesium homeostasis depends on the balance between intake and output. Thirty percent to 40% of ingested magnesium is absorbed in the small bowel. The absorption of magnesium decreases as the dietary intake increases. Reductions in absorption have also been noted in the elderly and those with CKD. A small amount is present in intestinal secretions and reabsorbed in the sigmoid colon. The kidneys play a major role in maintaining magnesium balance. Approximately 95% of the filtered magnesium is reabsorbed, thus in most patients less than 5% is excreted in the urine.32 Renal magnesium handling is unique in that approximately 20% of the filtered magnesium is reabsorbed in the proximal tubule; the majority of reabsorption occurs in the thick ascending limb of the loop of Henle. This explains why loop diuretics often cause profound urinary magnesium wasting. Unlike most other important electrolytes, there is no hormonal regulation of the distribution of magnesium between bone and circulating or intracellular magnesium pools. Because of this, both hypomagnesemia and hypermagnesemia commonly occur.
Hypomagnesemia is a common problem in both ambulatory and hospitalized patients. Although the exact prevalence is difficult to estimate, it has been reported that up to 65% of intensive care unit patients are magnesium deficient. Although serum magnesium concentrations are not a reliable index of total-body magnesium content, they remain the primary diagnostic tool to evaluate body stores.
Etiology and Pathophysiology
Hypomagnesemia is usually associated with disorders of the intestinal tract or kidney.33 Drugs or conditions that interfere with intestinal absorption or increase renal excretion of magnesium can result in hypomagnesemia (Table 36-6). Decreased intestinal absorption as a result of small bowel disease is the most common cause of hypomagnesemia worldwide. These disorders include regional enteritis; radiation enteritis; ulcerative colitis; acute and chronic diarrhea; pancreatic insufficiency and other malabsorptive syndromes; small-bowel bypass surgery; and chronic laxative abuse. Hypomagnesemia is commonly associated with alcoholism. The etiology is often multifactorial, including reduced intake, pancreatic insufficiency, chronic vomiting and diarrhea, and urinary magnesium wasting. In addition, patients who are hospitalized for acute alcohol withdrawal often receive IV glucose and can experience even greater reductions in their serum magnesium concentration.
TABLE 36-6 Causes of Hypomagnesemia
Prolonged parenteral fluid administration without magnesium
Malabsorption syndromes (e.g., tropical sprue, celiac disease, radiation enteritis, or intestinal lymphectasia)
Short-bowel syndrome (e.g., small-bowel resection or ileal bypass)
Prolonged nasogastric suction
Excessive laxative use
Intestinal and biliary fistulas
Prolonged diarrhea (ulcerative colitis, Crohn’s disease, or cancer of the colon)
Primary tubular disorders
Primary renal magnesium wasting
Renal tubular acidosis
Diuretic phase of acute tubular necrosis
Postrenal transplant dieresis
Drug-induced renal losses
Hormone-induced renal losses
“Hungry bone syndrome” after parathyroidectomy
Glucose, amino acid, or insulin administration
Massive blood transfusion (citrate)
Pancreatitis with lipidemia (magnesium soap)
Excessive sweating and lactation
Hypercalcemia and hypercalciuria
Extracellular fluid volume expansion
Primary renal magnesium wasting can be caused by a defect in renal tubular magnesium reabsorption, or inhibition of sodium reabsorption in those segments in which magnesium transport follows passively. The former condition is associated with hypercalciuria, nephrolithiasis, and progressive renal disease, while the latter is associated with Gitelman’s and Bartter’s syndromes.33 Much more common than these is renal magnesium wasting secondary to thiazide and loop diuretics. Other commonly used drugs that can cause renal magnesium wasting include aminoglycosides, amphotericin B, cyclosporine, digoxin, tacrolimus, cisplatin, pentamidine, and foscarnet.
The treatment goals in the management of hypomagnesemia are (a) resolution of the signs and symptoms, (b) restoration of normal magnesium concentrations, (c) correction of concomitant electrolyte abnormalities, and (d) identification and correction of the underlying cause of magnesium depletion.
General Approach to Treatment
Nearly all of the data regarding magnesium replacement therapy have been derived from relatively old data in acutely ill, hospitalized patients. Magnesium supplementation can be given by the oral, intramuscular (IM), or IV route. The severity of the magnesium depletion and the presence of severe signs and symptoms should dictate the route of administration. Because IM administration is painful, it should be reserved for those patients with severe hypomagnesemia and limited venous access. IV bolus administration is associated with flushing, sweating, and a sensation of warmth; thus bolus administration should be avoided if possible. Additionally, because calcium forms a complex with the sulfate moiety, which is then excreted, large amounts of IV magnesium sulfate should be administered with caution to hypocalcemic patients, as it can further exacerbate calcium deficiency.32 There have been no clinical trials assessing the optimal regimen for magnesium replacement; however, it is widely accepted that 8 to 12 g of magnesium sulfate be administered in the first 24 hours followed by 4 to 6 g per day for 3 to 5 days to adequately replete body stores.34 Even if severe magnesium depletion is present, approximately 50% of the administered dose is excreted in the urine. Consequently, magnesium replacement should be performed over 3 to 5 days, and continued supplementation should be provided for patients unable to eat and for those patients with continued magnesium wasting. Table 36-7 lists the commonly used magnesium oral supplements and their respective elemental magnesium content.
TABLE 36-7 Common Magnesium Products and Their Elemental Magnesium Content
There are currently no nonpharmacologic options for the management of hypomagnesaemia.
It is currently controversial whether all asymptomatic patients require magnesium supplementation. However, should treatment be warranted, those patients with serum magnesium concentrations greater than 1 mEq/L (1.2 mg/dL [0.5 mmol/L]) can be treated with oral supplements. Oral supplementation is preferred because magnesium uptake is a slow process that may require prolonged administration. Several magnesium products are available, including magnesium-containing antacids or laxatives, comprised of a variety of magnesium salts in tablet or capsule formulations. Many of the oral products contain very little magnesium, which necessitates three or four doses per day. As expected, diarrhea is the most common dose-limiting side effect of oral therapy, which can greatly reduce patient compliance. Therefore, sustained release magnesium products are preferred as they not only improve patient compliance, but also reduce the occurrence of GI side effects.
CLINICAL PRESENTATION Hyperkalemia
• The dominant organ systems affected by hypomagnesemia are the neuromuscular and cardiovascular systems
• Neuromuscular symptoms such as tetany, twitching, and generalized convulsions are common
• Cardiac symptoms include heart palpitations
• Neuromuscular: Presence of Chvostek’s sign, Trousseau’s sign, tremor, and tetany
• Cardiovascular: Cardiac arrhythmias (ventricular fibrillation, torsade de pointes, or digoxin-induced arrhythmias), sudden cardiac death, and hypertension can be present. ECG abnormalities include widened QRS complex and peaked T waves with mild hypomagnesemia; and prolonged PR interval, progressive widening of QRS complex, and flattened T waves with moderate to severe hypomagnesemia
• Serum magnesium concentration less than 1.4 mEq/L (1.7 mg/dL [0.70 mmol/L]). Serum potassium and calcium concentrations can also be low
In cases of severe magnesium depletion (serum concentrations <1 mEq/L [<1.2 mg/dL; <0.5 mmol/L]), or if signs and symptoms are present regardless of the serum concentration, IV magnesium should be administered. A dose of 4 to 6 grams should be administered over 12 to 24 hours and repeated as necessary in order to maintain magnesium concentrations above 1 mEq/L (1.2 mEq [0.5 mmol/L]). Doses of 2 to 4 grams infused over 1 hour are frequently used clinically; however, these result in transient benefit because of the extensive renal excretion. Therapy should be continued until the signs and symptoms have completely resolved. In patients with renal insufficiency, the dose should be reduced by 25% to 50%.
Evaluation of Therapeutic Outcomes
In patients with acute, asymptomatic mild to moderate hypomagnesemia receiving therapy, serum magnesium concentrations should be obtained at least daily during their hospitalization. Patients receiving oral magnesium therapy should be questioned regarding GI tolerance and the occurrence of diarrhea. Patients being treated for symptomatic severe hypomagnesemia should have their serum magnesium concentration monitored hourly until the serum concentration reaches 1.5 mEq/L (1.8 mg/dL [0.75 mmol/L]) and the symptoms resolve. At that point, the serum magnesium concentration can be monitored every 6 to 12 hours for the next 24 hours while receiving magnesium supplementation. Once the magnesium concentration is stable in the normal range, a concentration can be obtained daily. It should be reiterated that it typically takes 3 to 5 days to fully replete total-body magnesium stores. Patients receiving oral magnesium-containing antacids or supplements should be asked regularly about the occurrence of diarrhea.
Clinical Bottom Line
Hypomagnesemia is generally associated with kidney or GI tract disorders. In cases of mild, chronic magnesium loss, oral magnesium preparations can be used; however, the dose-limiting side effect is diarrhea. For more severe cases of hypomagnesemia, IV magnesium sulfate can be safely administered. Repeated doses may be needed as IV magnesium is rapidly eliminated in urine. In such cases, close monitoring of serum magnesium concentrations is needed.
Hypermagnesemia (serum magnesium >2 mEq/L [>2.4 mg/dL; >1 mmol/L]) is a rare occurrence that is generally seen in patients with stage 4 or 5 CKD when magnesium intake exceeds the excretory capacity of the kidneys. Elderly patients are prone to hypermagnesemia because of their reduced glomerular filtration rate (GFR) and because of their tendency to consume magnesium-containing antacids and vitamins.
Etiology and Pathophysiology
Because absolute magnesium excretion decreases as GFR declines, serum magnesium concentrations tend to increase in patients with moderate to severe CKD. Indeed, magnesium concentrations steadily increase as the GFR decreases below 30 mL/min/1.73 m2 (0.29 mL/s/m2). As long as the patient maintains a normal diet, the serum magnesium concentration typically stabilizes at approximately 2.5 mEq/L (3 mg/dL [1.25 mmol/L]). If patients with stage 4 or 5 CKD are taking concomitant magnesium-containing antacids, the serum concentration can approach 6 mEq/L (7.3 mg/dL [3 mmol/L]), a value associated with signs and symptoms of toxicity. Critically ill patients with multiorgan system failure receiving enteral or parenteral nutrition are also prone to develop hypermagnesemia. Finally, the parenteral treatment of eclampsia with magnesium sulfate can lead to hypermagnesemia. Table 36-8 lists other causes of hypermagnesemia.
TABLE 36-8 Causes of Hypermagnesemia
The signs and symptoms of hypermagnesemia reflect magnesium’s action on the neuromuscular and cardiovascular systems.34,35 The main symptoms include lethargy, confusion, dysrhythmias, and muscle weakness. Symptoms are rare when the serum concentration is below 4 mEq/L (4.9 mg/dL [2 mmol/L]) (Fig. 36-3).
FIGURE 36-3 Clinical findings associated with hypermagnesemia. (Serum magnesium levels in mmol/L can be determined by multiplying the serum magnesium value expressed in mEq/L by 0.5.)
The goals of therapy are to (a) reverse the neuromuscular and cardiovascular manifestations of hypermagnesemia, (b) decrease the magnesium concentration toward normal values, and (c) identify and treat the underlying cause of hypermagnesemia.
There are currently no nonpharmacologic options for the management of hypermagnesemia.
There are three primary means of treating hypermagnesemia: (a) reduce magnesium intake, (b) enhance elimination of magnesium, and (c) antagonize the physiologic effects of magnesium. The optimal treatment regimen for the management of hypermagnesemia depends on the severity of the patient’s signs and symptoms and the degree of serum concentration elevation. IV elemental calcium doses of 100 to 200 mg directly antagonize the neuromuscular and cardiovascular effects of hypermagnesemia. Oral calcium is not effective because of its relatively poor bioavailability and slow onset of action. The clinical effect of calcium is immediate, but the effect is transient; hence, repeated IV doses of 100 to 200 mg of elemental calcium (e.g., 2 g of calcium gluconate) might need to be administered hourly until the signs or symptoms abate and the magnesium concentration is normalized. Supportive care with cardiac pacing, vasopressors, and mechanical ventilation can be necessary in life-threatening situations. In patients with normal renal function, or those with stage 1, 2, or 3 CKD, forced diuresis with 0.45% NaCl and loop diuretics can promote magnesium elimination. An initial IV bolus of furosemide 40 mg or a similar equivalent can be used. Subsequent dosing can be determined based on the patient’s clinical response. Patients with CKD can require long-term loop diuretic therapy to maintain adequate fluid and electrolyte balance. In dialysis patients, their hemodialysis prescription should be changed to employ magnesium-free dialysate.
Evaluation of Therapeutic Outcomes
Patients who are receiving IV calcium salts for the treatment of severe, symptomatic hypermagnesemia should have their serum magnesium concentration evaluated hourly until symptoms abate and the magnesium concentration decreases below 4 mg/dL (3.3 mEq/L [1.64 mmol/L]). Furthermore, the patient should be continuously monitored to detect ECG changes. In CKD patients who can produce urine, forced diuresis with saline and furosemide should reduce the serum magnesium concentration within 6 to 12 hours. Close monitoring of the urine output and physical examination for signs of volume overload are important. Emergency hemodialysis will usually correct the hypermagnesemia within 4 hours and is a reasonable option for those who are currently receiving hemodialysis. To prevent further episodes of hypermagnesemia, the patient should receive dietary education regarding foods and beverages that contain large quantities of magnesium (Table 36-9).
TABLE 36-9 Magnesium Content of Selected Foods
Clinical Bottom Line
Hypermagnesemia is generally associated with advanced CKD. Severe cases of hypermagnesium can result in neurologic symptoms or cardiac dysrhythmias. Should these symptoms occur, IV calcium can counteract these effects. Forced diuresis with saline and loop diuretics is useful in lowering magnesium in patients with mild to moderate renal dysfunction; hemodialysis should be reserved for ESRD patients.
As discussed throughout the chapter, there are numerous patient considerations that must be taken into account when designing appropriate pharmacotherapy for potassium and magnesium disorders. At this time, there are no genetic, genomic, or pharmacokinetic factors that are used to personalize pharmacotherapy for the treatment of these electrolyte disorders.
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