CAT 3

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hanges are present. It has become less common with the increased use of plasma for potassium measurement, rather than serum. Plasma is the supernatant collected from heparinized whole blood, whereas serum is the supernatant remaining after centrifugation of a clotted whole blood sample. Serum K+ is normally 0.3 mmol/L above the plasma K+, but may be higher if K+ is released from the clot formed in the tube. If pseudohyperkalemia is suspected, the plasma potassium should be measured instead of the serum potassium. Pseudohyperkalemia can also occur due to potassium release from muscle cells following prolonged constriction with a tourniquet or limb exercise while a tourniquet is in place.

Redistribution of potassium

Redistribution of potassium from the intracellular to the extracellular space can occur in severe acidosis due to nonorganic acid metabolic acidosis, hyperosmolar states, tissue breakdown, and hyperkalemic periodic paralysis. Organic acids such as lactic acid and ketoacids are less likely to cause hyperkalemia than non-organic acids. These organic acids have greater transmembrane mobility, allowing movement into cells with H+, rather than movement of K+ out of cells in exchange for H+. Hyperkalemia in diabetic ketoacidosis usually results from insulin deficiency and hyperosmolality, rather than acidosis. Hyperglycemia increases extracellular osmolality, drawing water from cells down the osmotic gradient. Potassium follows the water movement (solvent drag), and hyperkalemia results.

Tissue breakdown may liberate large amounts of intracellular potassium, resulting in rapid, life-threatening increases in extracellular potassium. Rhabdomyolysis, tissue necrosis, tumor lysis with chemotherapy, and large hematomas are common causes. In rhabdomyolysis, hypokalemia may precede hyperkalemia, and contribute to muscle breakdown by causing vasoconstriction and decreased blood flow to the involved muscle.

Hyperkalemic periodic paralysis is an autosomal dominant disorder involving the muscle cell sodium channel. During these episodes, potassium moves from the intracellular to extracellular space, accompanied by movement of sodium and water into the cell. The hyperkalemia is accompanied by transient weakness or paralysis.

Decreased potassium excretion

Potassium excretion in the distal nephron depends upon adequate urine flow, aldosterone, and activity of the basolateral Na+/K+-ATPase. The reabsorption of luminal Na+ through aldosterone-sensitive epithelial sodium channels (ENaCs) creates an electrochemical gradient for K+ excretion in the urine. Hyperkalemia can occur in aldosterone-resistant or deficient states by attenuating the electrochemical gradient for K+ secretion. Acquired mineralocorticoid resistance from diabetes mellitus, obstructive uropathy, chronic tubulointerstitial disease, sickle cell anemia, lupus nephritis, and medications, as well as decreased mineralocorticoid production (including medication induced), are commonly associated with type IV renal tubular acidosis (RTA). Type IV RTA is characterized by hyperkalemia, normal anion gap hyperchloremic acidosis, with serum HCO3 values ranging between 16 and 22 mmol/L, and decreased urinary NH4

+ production, causing a positive urine anion gap [Urine (Na+) + (K+) – (Cl−)]. In acute and chronic tubular injury, a

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decreased responsiveness to aldosterone can contribute to hyperkalemia. For acute kidney injury associated with prerenal azotemia or hypovolemic states, decreased urinary flow to the distal tubule and a reduction in sodium-potassium exchange can contribute to hyperkalemia.

Excessive potassium intake

Excessive intake of K+ rarely causes hyperkalemia in the setting of normal renal function. Renal secretion of potassium is typically adequate at glomerular filtration rates (GFR) above 20 to 30 mL/min/1.73 m2. Patients with end-stage renal disease (ESRD) on hemodialysis usually tolerate a daily K+ intake of 2000 mg (51 mEq). Upregulated gut potassium excretion and shifts in transcellular K+ prevent hyperkalemia between dialysis sessions. The loss of these mechanisms may result in the rapid development of hyperkalemia, especially with large exogenous loads of potassium, such as massive blood transfusions. Irradiation of blood and increased age of the blood increase the amount of free potassium that is released during the blood transfusion. Seven-day-old blood has approximately 23 mmol/L of K+, while 42-day-old blood has approximately 50 mmol/L of K+.

PRACTICE POINT

In the setting of acute kidney injury, hyperkalemia associated with rapid transcellular potassium shifts from the intracellular to extracellular compartment can be seen with rhabdomyolysis, tissue necrosis, tumor lysis, and large hematomas. Hyperkalemia in this setting may progress rapidly to cause life-threatening arrhythmias. Emergent nephrology consultation for possible dialysis is required.

SIGNS AND SYMPTOMS

Clinical effects of hyperkalemia relate to altered membrane excitability due to changes in the transcellular potassium gradient. Severe hyperkalemia leads to cardiac arrhythmias and conduction abnormalities. It may also cause weakness of the lower extremities, progressing superiorly to cause flaccid paralysis and respiratory failure. This presentation may mimic Guillain-Barré syndrome, but is easily differentiated by the response to potassium correction. Hyperkalemia may also contribute to metabolic acidosis by interfering with renal ammonium excretion.

EVALUATION OF HYPERKALEMIA IN THE HOSPITALIZED PATIENT

In the hospital setting, the initial evaluation of hyperkalemia includes monitoring for life- threatening arrhythmias, checking for pseudohyperkalemia, eliminating exogenous sources of potassium, evaluating renal function, and evaluating for rapid transcellular shifts of potassium (Figure 241-1).

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Figure 241-1 Diagnostic assessment of hyperkalemia. (ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DKA, diabetic ketoacidosis; ECG, electrocardiogram; GFR, glomerular filtration rate; HHS, hyperosmolar hyperglycemic state; NSAIDs, nonsteroidal anti-inflammatory drugs.)

ECG changes

Even mildly elevated K+ levels may be associated with ECG changes, especially in the setting of rapid rises in plasma K+ values. If ECG changes from hyperkalemia are found or if the plasma K+ value is ≥ 7.0, continuous telemetry is indicated and should continue until the plasma K+ value is ≤ 5.8 and there are no hyperkalemic ECG changes. Frequent chemistry checks are indicated for plasma K+ greater than 5.8 or for hyperkalemia associated with ECG changes, severe hyperglycemia, or any clinical condition which predisposes the patient to rapid changes in plasma K+.

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Plasma potassium levels do not correlate with specific ECG changes. A symmetric increase in T wave height may be seen initially. Hyperkalemia-induced peaked T waves may be difficult to distinguish from the hyperacute T waves of myocardial injury. As potassium levels rise further, flattening of the P waves, prolongation of the PR interval, and prolonged QRS duration occur. Eventually, atrial standstill and a sine wave ECG pattern may be seen (Figure 241-2).

Figure 241-2 ECG changes associated with hyperkalemia and hypokalemia. (Reproduced, with permission, from Flomenbaum N, Goldfrank LR, Hoffman R, et al. eds. Goldfrank’s Toxicologic Emergencies, 8th ed. New York, NY: McGraw-Hill; 2006. Fig. 5-11.)

Urine potassium, transtubular potassium gradient, and urine potassium/creatinine

A 24-hour urine K+ measurement can help differentiate between renal and nonrenal causes of hyperkalemia. With hyperkalemia, urinary excretion of K+ should exceed 40 mmol/d.

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Alternatively, the transtubular potassium gradient (TTKG), a measurement of potassium secretion by the distal nephron corrected for urine osmolality, has been used:

TTKG = (KU/KS) × (SOsm/UOsm)

KU and KS are the concentrations of K + in the urine and serum, and SOsm and UOsm are

the osmolalities of the serum and urine, respectively. Plasma potassium and osmolality can be used instead of serum values to estimate TTKG with minimal effect on clinical interpretation. The accuracy of the TTKG has been called into question by recent studies of urea and potassium handling in the renal tubule. Previous studies using TTKG have suggested that patients with normal renal function and normal potassium intake have a TTKG of 8 to 9. In hyperkalemia, a low TTKG (< 5-7) suggests an inappropriately low secretion of potassium. A high TTKG with hyperkalemia suggests normal aldosterone action and an extrarenal cause of hyperkalemia, except in cases of volume depletion where aldosterone secretion is enhanced with a TTKG > 7, but total renal potassium excretion is limited by low urine flow.

When the TTKG is inappropriately low in the setting of hyperkalemia, an increase in the TTKG to >10 hours after the administration of 0.05 mg of fludrocortisone suggests hypoaldosteronism. If fludrocortisone has no effect on the TTKG, drug-induced or intrinsic renal resistance to aldosterone are likely.

If further studies cast doubt on the usefulness of TTKG, the urine potassium/creatinine ratio will likely be used more frequently when a 24-hour urine potassium is not available. It has been suggested that a patient with hyperkalemia and a normal renal response should have a spot urine ratio of >200 mmol K+/g creatinine (=22.6 mmol K+/mmol creatinine). For a typical patient with a daily creatinine excretion of over 1 g/d, this is significantly more than the 24-hour urinary K+ excretion of >40 mmol used by some clinicians as a cutoff for adequate renal potassium clearance in the setting of hyperkalemia. This further underscores the point that it is difficult to define an exact cutoff for expected renal potassium excretion or urine K+/Cr in the face of hyperkalemia without additional investigation.

TREATMENT OF HYPERKALEMIA

Treatments exist for hyperkalemia which cause net excretion or removal of potassium, such as gastrointestinal resins and laxatives or hemodialysis. As these therapies may not act immediately or may involve logistical difficulties, they are often used in conjunction with short-acting temporizing measures, such as cardiac membrane stabilization with calcium, and agents such as insulin that cause transcellular potassium shifts (Table 241- 2).

TABLE 241-2 Treatment of Hyperkalemia

Mechanism Treatment Dose Onset Duration Comments Cardiac membrane stabilization

Calcium Calcium gluconate 10 mL of 10% solution infused over 2-3 min.

1-3 min 30-60 min

Do not mix with bicarbonate; extreme caution if on digoxin; calcium chloride is an alternative, but poses a risk of tissue

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necrosis, and requires a central line

Redistribution Insulin 10 units regular insulin IV. If BG < 250 mg/dL, give 50 mL of 50% dextrose.

10-20 min 4-6 h peak 30- 60 min

Most reliable treatment to induce redistribution

Redistribution Beta-2 agonist

Albuterol 10- 20 mg nebulized.

30 min 2-4 h peak 90 min

Dose is significantly higher than dose for respiratory treatments; use with caution in patients at risk for side effects such as tachycardia and myocardial ischemia

Removal Kayexalate 30-60 g oral in 20% sorbitol or 60 grams in 250 mL water by retention enema.

1-2 h Variable Risk of colonic necrosis if used in postoperative patients; do not use sorbitol formulation when administering via enema

Removal Hemodialysis — Immediate Same as dialysis duration

Intermittent or continuous

Cardiac membrane stabilization

Intravenous calcium stabilizes the cardiac membrane by inhibiting membrane depolarization. It is the most important initial treatment for severe hyperkalemia. Two forms of calcium are commonly available: calcium gluconate and calcium chloride. Calcium gluconate is preferred because it can be administered through a peripheral intravenous line, whereas calcium chloride requires a central venous line to prevent tissue necrosis. Tissue necrosis can occur if calcium chloride leaks from the venous access into the surrounding tissue. A 10 mL ampule of calcium gluconate contains 90 mg (2.3 mmol) of elemental calcium, and a 10 mL ampule of calcium chloride contains 272 mg (7.0 mmol) of elemental calcium.

The initial dose of calcium gluconate is 10 mL of 10% solution infused over 2 to 3 minutes. An equivalent amount of elemental calcium is contained in 3.3 mL of 10% calcium chloride. The onset of action is 1 to 3 minutes, and duration of action is 30 to 60 minutes. Calcium cannot be mixed with bicarbonate solutions, because precipitation of CaCO3 occurs.

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3 Administration of intravenous calcium to patients taking digoxin requires extreme

caution, as calcium has been shown to potentiate the effects of digoxin toxicity in animal models, especially at very rapid infusion rates. The risk of calcium administration in this setting can be reduced by infusing the calcium gluconate over 20 to 30 minutes. Another option is to administer digoxin immune fab to neutralize the effect of the digoxin.

PRACTICE POINT

In the setting of digoxin toxicity, mild hyperkalemia (serum K+ > 5.0 mmol/L) has been linked to significant mortality, and digoxin immune fab may be indicated.

Potassium redistribution

Insulin is the most reliable means of inducing transcellular potassium shifts. The usual dose is 10 units of regular insulin intravenously, followed immediately by 50 mL of 50% dextrose (25 g of dextrose). For a blood glucose > 250, insulin can be administered alone with close glucose monitoring. The effect begins in 10 to 20 minutes, peaks at 30 to 60 minutes, and lasts 4 to 6 hours. Potassium levels typically drop by 0.5 to 1.2 mmol/L. An infusion of 10 units of regular insulin can also be administered over 1 hour in 10% dextrose.

Beta-2 agonists have an additive effect with insulin in transiently reducing plasma potassium by redistribution. High doses of nebulized albuterol are used, typically 10 to 20 mg of nebulized albuterol in 4 mL of normal saline over 10 minutes. Plasma potassium levels usually fall by 0.5 to 1 mmol/L. The effect begins in 30 minutes, peaks at 90 minutes, and lasts 2 to 4 hours. Intravenous albuterol has also been used, but it is not available in the United States. As some patients, including those with renal failure, have a reduced response to albuterol, it should not be the only agent used. Caution should be exercised for individuals at risk for side effects such as cardiac ischemia from the resulting increase in heart rate.

Sodium bicarbonate (NaHCO3) does not reliably lead to the redistribution of potassium, and it should not be considered as first-line therapy for hyperkalemia. This is especially true in high anion gap acidosis, where hyperkalemia is usually not a direct consequence of the presence of organic acids. If intravenous or oral NaHCO3 is used to treat metabolic acidosis caused by nonorganic anions, which is usually associated with a normal anion gap, plasma potassium may fall, but it is not preferred treatment even in this setting. Oral NaHCO3 is useful for chronic treatment of type IV renal tubular acidosis.

Potassium removal

Sodium polystyrene sulfonate (Kayexalate) exchanges Na+ for K+ in the gastrointestinal tract. When taken orally, sorbitol has been typically added to the resin to speed passage through the gastrointestinal tract. However, an FDA warning has been issued about the risk of colonic necrosis when kayexalate is used with sorbitol, and thus the powdered form of kayexalate not premixed with sorbitol is preferred. If Kayexalate with sorbitol is the only form available, diluting with water is appropriate. Each gram of resin binds 0.5 to 1.2 mmol of K+. Oral doses of 15 to 60 g are typical. Sodium polystyrene sulfonate can also be administered rectally as a retention enema, at a dose of 30 to 60 g in 250 mL of water

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every 6 hours. The solution should be introduced by gravity, flushed with an additional 50 to 100 mL of nonsodium containing fluid, retained 30 to 60 minutes or longer, and cleansed with 250 to 1000 mL of nonsodium containing solution at body temperature. Sorbitol should not be used rectally due to risk of colonic necrosis. Oral or rectal Kayexalate should not be used in postoperative patients for the same reason.

Favorable data have been published for two novel potassium reduction agents. Sodium zirconium cyclosilicate (ZS-9) is a highly selective potassium trap, whereas patiromer is a nonabsorbed polymer which exchanges calcium for potassium, primarily in the distal colon. Patiromer is FDA approved, ZS-9 is under FDA review, and further studies are needed to evaluate their suitability for acute potassium reduction. Initial studies have focused on their use for more chronic potassium reduction, which may allow broader use of potassium-sparing medications.

Dialysis is required for treatment of refractory hyperkalemia. Intermittent hemodialysis removes potassium most rapidly. Continuous renal replacement therapy is an option for patients who have ongoing causes of severe hyperkalemia, such as tissue necrosis or rhabdomyolysis. Peritoneal dialysis provides gradual removal of potassium. Although peritoneal dialysis is rarely used in developed countries when the other modalities are available, peritoneal dialysis is an established therapy for acute kidney injury. Since electricity is not required for its use and access is placed in the peritoneal cavity rather than in large veins, it is an option for hyperkalemia treatment in a variety of situations such as difficulty with placing vascular access for hemodialysis, disasters associated with overwhelming caseloads, or power failure

Diuretics are unreliable for the acute treatment of hyperkalemia in the setting of compromised renal function. In patients with adequate renal function, the combination of a loop and thiazide diuretic is more effective for potassium removal than either alone. Of the loop diuretics, torsemide and bumetanide have higher bioavailability than furosemide.

Potassium intake reduction

The typical daily potassium intake for a patient with end-stage renal disease is 2000 mg (51 mmol) of potassium per day, but patients with acute kidney injury may require even more stringent potassium restriction.

HYPOKALEMIA ETIOLOGY

Hypokalemia (K+ < 3.5 mmol/L) can result from redistribution, increased potassium excretion from renal and nonrenal sources, or decreased potassium intake. Medications, especially loop and thiazide diuretics, frequently cause hypokalemia. Hypokalemia is common with tubular toxins such as amphotericin B and cisplatin. High doses of penicillin or semisynthetic penicillins such as ticarcillin and carbenicillin occasionally cause renal potassium wasting in the distal nephron due to a transient anion effect. Inhalation of toluene (glue sniffing) may cause distal renal tubular acidosis with associated hypokalemia.

Pseudohypokalemia

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Falsely low serum or plasma potassium values may occur in conditions such as acute leukemia due to time-dependent uptake of potassium by the increased abnormal white cell mass. Rapid analysis of the sample, or storing the sample at 4°C prior to analysis, can prevent the potassium uptake and confirm the diagnosis of pseudohypokalemia.

Redistribution

Insulin directly stimulates potassium entry into cells by increasing the activity of the Na+/K+-ATPase pump. This mechanism is independent of stimulation of cellular glucose entry. Beta-2-adrenergic activators stimulate Na+/K+-ATPase mediated cellular potassium uptake by a slightly different cellular mechanism. Thus, insulin and beta-2-adrenergic activation may act synergistically to cause hypokalemia. Aldosterone stimulates direct cellular uptake and redistribution due to increased Na+/K+-ATPase activity. It also acts in the distal renal tubule to enhance potassium excretion.

Thyrotoxic periodic paralysis causes severe hypokalemia by redistribution, in conjunction with extremity and limb girdle weakness, hypophosphatemia, and hypomagnesemia. It is more common in patients of Asian and Hispanic origin. Attacks often occur during rest after vigorous physical activity, and can also be precipitated by carbohydrate-rich meals. Other rare genetic forms of hypokalemic periodic paralysis also exist.

Nonrenal potassium losses

Common nonrenal causes of hypokalemia include intestinal loss of potassium from diarrhea, celiac disease, ileostomy, and chronic laxative abuse. Potassium loss from vomiting and nasogastric suctioning can result in hypokalemia, although renal potassium losses from aldosterone activation may be more important in this setting. Potassium losses through the skin are usually low, except in the setting of extreme physical exertion. Severe burns may lead to hypokalemia by multiple mechanisms.

Renal potassium loss

Aldosterone-producing adenomas (Conn syndrome) cause hypertension and hypokalemia by stimulation of aldosterone receptors in the distal renal tubule. Cortisol also activates the aldosterone receptor. Normally, cortisol is converted to cortisone by 11-beta- hydroxysteroid dehydrogenase-2 (11βHSD-2) before it can reach the aldosterone receptor. Very high cortisol levels, as seen in Cushing syndrome, overwhelm the ability of 11βHSD-2 to degrade cortisol to cortisone, and the nondegraded cortisol activates the aldosterone receptor in the distal tubule and precipitates hypokalemia. Similarly, glycyrrhizinic acid, a component of black licorice that is sometimes added to chewing tobacco, inhibits 11βHSD-2, preventing cortisol degradation and causing hypertension and hypokalemia. With vomiting and nasogastric suctioning, potassium wasting in the urine occurs through aldosterone secretion in the setting of volume depletion, as noted above.

Hypokalemia can be associated with an RTA, due to disease of either the proximal (type II RTA) or distal (type I RTA) renal tubules. Either can result from autoimmune, genetic, endocrine, medication-induced, toxin-induced, or idiopathic causes. Rare causes of hypokalemia associated with metabolic alkalosis involve defects in the thick ascending limb of Henle transport proteins (Bartter syndrome), mutations in the thiazide-sensitive

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Na+/Cl− cotransporter in the distal convoluted tubule (Gitelman syndrome), or increased activation of the epithelial sodium channel (ENaC) in the distal tubule (Liddle syndrome).

Decreased potassium intake

Decreased potassium intake is rarely a cause of hypokalemia, except in severe malnutrition. For patients with normal renal function who consume the recommended 4700 mg (120 mmol) of potassium per day, 90% (108 mmol) is excreted in the urine. When intake is sharply reduced, urinary potassium loss decreases to < 15 to 20 mmol/d in order to conserve potassium.

SIGNS AND SYMPTOMS

Individuals with serum potassium levels between 3.0 and 3.5 mEq/L are often asymptomatic. However, there is a risk of cardiac arrhythmias for individuals with predisposing conditions such as coronary artery disease. At serum potassium levels between 2.5 and 3.0 mEq/L, patients report generalized weakness and constipation. When serum potassium levels drop below 2.5 mEq/L, there is an increased risk of muscle necrosis and rhabdomyolysis. At serum potassium levels less than 2.0 mEq/L, ascending paralysis and respiratory failure can occur.

EVALUATION OF HYPOKALEMIA

An algorithm for the diagnosis of hypokalemia is presented in Figure 241-3. Pseudohypokalemia and transcellular shifts should be excluded. Magnesium levels should be measured early in the workup of hypokalemia. Many disorders, such as diarrhea and excess diuresis, deplete both potassium and magnesium. Moreover, hypomagnesemia may lead to renal potassium wasting via potassium channels in the distal tubule, and make hypokalemia more refractory to treatment.

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Figure 241-3 Diagnostic assessment of hypokalemia. (DKA, diabetic ketoacidosis; RTA, renal tubular acidosis.)

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The next step is determining whether hypokalemia arose from a renal or nonrenal source. An obvious cause may be apparent, such as profuse diarrhea or escalating doses of a loop or thiazide diuretic. When the cause of hypokalemia is unclear, a 24-hour urine potassium measurement may differentiate between renal and nonrenal losses. In the setting of hypokalemia, urinary K+ losses should fall to less than 15 to 20 mmol/d. Potassium excretion above this level suggests a renal contribution to hypokalemia.

When a 24-hour urine K+ is not available, a spot urine ratio of 22 mmol K+/g creatinine (=2.5 mmol K+/mmol creatinine) marks the cutoff between hypokalemia secondary to intracellular shifts (if < 22 mmol K+/g Cr) and renal loss (if >22 mmol K+/g creatinine).

The TTKG (see above) has been used to help establish the cause of hypokalemia, but the use of TTKG has been cast into doubt by recent studies of urea and K+ handling in the renal tubule. An inappropriately high TTKG (> 4) in hypokalemia has been interpreted as suggesting an increased distal potassium secretion and renal potassium loss. A low TTKG can occur with nonrenal potassium wasting, with urinary potassium losses from osmotic diuresis, with hypokalemia secondary to diuretics which were discontinued at the time of TTKG measurement, or with hypokalemia associated with K+ shifts.

Patients with renal potassium wasting should be further classified by acid-base status. Patients with acidosis may have RTA, diabetic ketoacidosis, or tubular dysfunction from drugs such as amphotericin B or acetazolamide. Patients with alkalosis and hypertension may have mineralocorticoid excess or Liddle syndrome. Hypokalemia with alkalosis and normal or low blood pressure may be caused by vomiting, diuretics, and Bartter or Gitelman syndrome. The spot urine chloride is a useful diagnostic tool in evaluating the etiology of hypokalemia in the setting of metabolic alkalosis, with a spot low urine chloride (< 10 mmol/L) suggesting volume depletion and a chloride-responsive state.

ECG changes

ECG changes in hypokalemia are shown in Figure 241-2. U waves appear following the T waves, and become progressively more prominent in comparison to the T waves as potassium levels decrease. Ultimately, the U wave merges with the T wave, and the QT interval appears prolonged.

TREATMENT OF HYPOKALEMIA

Potassium repletion is the cornerstone of therapy for hypokalemia. As extracellular potassium comprises a fraction of the total body potassium store, relatively large amounts of potassium are required to correct the total body potassium deficit. A plasma K+ 1 mmol/L below normal corresponds to a total body potassium deficit of approximately 200 to 400 mmol, and a drop in plasma K+ to 2 mmol/L below normal requires 400 to 800 mmol for repletion. Typically, daily repletion is significantly less than the total body deficit as the time required for redistribution is prolonged. Underlying disorders such as metabolic alkalosis that are causing or perpetuating hypokalemia must also be addressed. Continuous telemetry and frequent electrolyte checks should be performed in severe hypokalemia, or in conditions in which the serum potassium may decline rapidly, such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).

Oral repletion

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If there is no immediate threat to life, oral potassium can be used to treat hypokalemia. Generally, potassium chloride (KCl) is indicated for hypokalemia associated with diuretic use or volume depletion. A typical initial dose in a patient with normal renal function is 40 to 100 mmol (40-100 mEq) per day, in two to three divided doses. Liquid, wax matrix, and microencapsulated forms exist. Compliance is poor with the liquid form due to the strong taste. Although the wax matrix form is easier to swallow, it has been associated with erosions of the gastrointestinal tract. The microencapsulated formulation is associated with the fewest complications.

Other potassium preparations are available for different indications. Oral potassium phosphate is found in many foods, and is indicated for combined potassium and phosphorus depletion. Terminology may be misleading. For example, Neutra-Phos actually has more potassium than K-Phos. Potassium bicarbonate is useful for the treatment of both metabolic acidosis and hypokalemia, while potassium citrate may prevent renal stones.

Intravenous repletion

KCl is preferred for intravenous repletion. Potassium phosphate may be used for dual phosphorus and potassium depletion. Potassium can be infused through a peripheral intravenous line at a maximum rate of 10 mmol/h. Higher rates require a central venous line and continuous ECG monitoring. Infusion rates of 20 to 40 mmol/h are reserved for cases of life-threatening hypokalemia requiring emergent correction. One liter bags of IV fluids typically have a maximum of 60 mEq of K+ added in order to avoid infusing an excess amount of K+.

Intravenous potassium is a common cause of iatrogenic hyperkalemia. A typical intravenous dose with normal renal function is 20 to 40 mmol (20-40 mEq). Although 20 mmol of intravenous KCl might increase plasma K+ by 0.25 mmol/L, transcellular shifts make it difficult to predict the effect of therapy. Renal potassium clearance generally decreases significantly at a GFR below 20 to 30 mL/min/1.73 m2, and requires reduction in potassium dosing and additional monitoring.

Hypokalemia in DKA and HHS

The use of insulin in DKA and HHS drives potassium into the intracellular space, and also decreases the hyperglycemia-induced osmolar driving force for movement of potassium from the intracellular to the extracellular space. Rapid and sometimes life-threatening potassium shifts may result. In 2009, the American Diabetes Association recommended that insulin should not be started until the serum potassium is known. If the serum potassium is < 3.3 mmol/L, insulin therapy is held until the potassium is repleted to 3.3 mmol/L or above. If the serum potassium is ≥ 3.3 mmol/L, insulin therapy can be initiated. For serum potassium ≥ 3.3 and < 5.2 mmol/L, potassium supplementation as 20 to 30 mEq K+ in each liter of IV fluid is given during insulin therapy. The goal is to achieve serum potassium values between 4 to 5 mmol/L. Potassium supplementation is initially held for serum potassium values > 5.2 mmol/L, but is often subsequently required, as total body stores of potassium are usually depleted and insulin plus intravenous fluid therapy eventually unmasks the total body potassium deficit.

PRACTICE POINT

Extreme caution and frequent monitoring are required in the treatment of hyperkalemia in diabetic ketoacidosis and hyperosmolar hyperglycemic state. Generally, these patients have a total body potassium deficit. Administration of insulin drives potassium intracellularly through direct stimulation of Na+/K+-ATPase, while both insulin and intravenous fluids reduce the glucose-induced hyperosmolality that drives solvent drag. These two interventions can lead to a rapid decrease in plasma potassium.

PRACTICE POINT

Potassium should not be mixed with glucose-containing solutions, because the glucose will stimulate insulin secretion and drive potassium from the extracellular to the intracellular space.

Thyrotoxic hypokalemic periodic paralysis

Oral propranolol (3 mg/kg) is first-line treatment for thyrotoxic periodic paralysis because it rapidly reverses hypokalemia, hypophosphatemia, and hypomagnesemia, and is not associated with rebound hyperkalemia. Propranolol 1 mg IV pushed slowly every 10 minutes, up to a total of 3 mg IV, is an alternative regimen. Aggressive potassium repletion for this disorder has been associated with a 25% or greater incidence of hyperkalemia, so if oral or IV potassium is given, subsequent close serial monitoring of plasma potassium is warranted. Treatment to establish a euthyroid state is the long term priority to prevent future attacks.

MAGNESIUM BALANCE

A typical American diet contains 300 to 400 mg/d of elemental magnesium. Approximately 30% to 40% of dietary magnesium is absorbed in the gut. Additionally, 40 mg/d of magnesium is secreted in the small intestine, of which 20 mg/d is reabsorbed in the colon and rectum. Approximately 100 mg appears in the urine each day, which is 5% of the filtered load. Specific cutoffs for hypomagnesemia and hypermagnesemia are difficult to establish because of the poor correlation between extracellular concentration and total body stores. Plasma magnesium levels of 1.7 to 2.3 mg/dL (0.70-0.95 mmol/L) are considered normal, but a normal serum level may be present despite total body magnesium depletion.

PRACTICE POINT

Magnesium unit conversion 41.2 mmol of elemental magnesium is equivalent to 1 g of magnesium (24.3 mg = 1 mmol). Since the charge of the magnesium cation is 2+, 1 mmol = 2 mEq. For a common preparation used for IV magnesium repletion, 1 g of magnesium sulfate (MgSO47H2O) contains 8.1 mEq (98.6 mg) of elemental magnesium.

HYPOMAGNESEMIA ETIOLOGY OF HYPOMAGNESEMIA

Hypomagnesemia results from low dietary intake, gastrointestinal losses, and renal losses. Poor intake of magnesium is common in alcoholics and hospitalized patients receiving inadequate magnesium supplementation in parenteral nutrition or intravenous fluids. The causes of impaired gastrointestinal absorption include diarrhea, inflammatory bowel disease, laxative abuse, proton pump inhibitors, and small bowel resection.

Osmotic and loop diuretics provoke urinary losses of magnesium. Acutely, thiazide diuretics increase magnesium absorption in the distal convoluted tubule, but long-term use can reduce magnesium reabsorption and cause hypomagnesemia. Urinary magnesium wasting is also seen in alcoholics. Many nephrotoxic drugs, such as amphotericin B, aminoglycosides, cisplatin, foscarnet, and cyclosporine, interfere with magnesium reabsorption in the thick ascending limb or distal convoluted tubule and cause magnesium wasting. Rare familial disorders, such as Gitelman syndrome, are also associated with urinary magnesium losses.

Miscellaneous causes of hypomagnesemia include acute pancreatitis, in which magnesium and calcium are saponified in necrotic fat, hungry bone syndrome, where magnesium, calcium, and phosphate are absorbed by bone after parathyroidectomy for hyperparathyroidism, and diabetic ketoacidosis, where magnesium levels fall due to osmotic diuresis and insulin-related transmembrane shifts.

HYPOMAGNESEMIA AND ASSOCIATED ELECTROLYTE ABNORMALITIES

Hypokalemia

Hypomagnesemia and hypokalemia often coexist due to similar common underlying etiologies, such as excess gastrointestinal losses and diuretics. Hypokalemia is often difficult to treat without magnesium repletion.

Hypercalcemia

Elevated ionized serum calcium levels induce renal Mg2+ wasting. Hypomagnesemia is common in hypercalcemia of malignancy. However, in hypercalcemia secondary to hyperparathyroidism, magnesium deficiency is rare due to the parathyroid hormone (PTH)- induced stimulation of renal Mg2+ reabsorption.

Hypocalcemia

Hypomagnesemia may cause hypocalcemia due to inhibition of PTH secretion and by induction of skeletal resistance to PTH. Hypocalcemia may be present in up to half of patients with hypomagnesemia.

CLINICAL MANIFESTATIONS

Mild hypomagnesemia may be asymptomatic. Severe hypomagnesemia leads to neuromuscular, neurologic, and cardiovascular symptoms. Neuromuscular abnormalities include hyperreflexia, carpopedal spasm, delirium, seizures, tetany, and paralysis. Chvostek and Trousseau signs may be present. ECG manifestations include torsades de pointes, premature ventricular contractions, ventricular tachycardias, and ventricular

fibrillation. There is also an increased risk of digitalis cardiac toxicity. As serum magnesium levels do not always correlate with total body magnesium stores, normomagnesemic magnesium depletion may be considered in patients with unexplained hypocalcemia and hypokalemia and clinical risk factors for magnesium deficiency.

EVALUATION OF HYPOMAGNESEMIA

Urine studies

Urine studies are useful to evaluate renal vs nonrenal causes of hypomagnesemia. The fractional excretion of magnesium (FeMg) is given by:

The 0.7 in the denominator is a correction factor for the 30% of plasma magnesium bound to plasma proteins. A FeMg of > 3% in a patient with normal GFR indicates renal magnesium loss. A 24-hour magnesium collection can also be obtained and is normally 3 to 5 mmol (75-125 mg)/24 hours. In the presence of hypomagnesemia, normal kidneys should be able to reduce the 24-hour urinary excretion of magnesium even further, to 1 mmol or less.

TREATMENT OF HYPOMAGNESEMIA

Oral repletion

The most popular formulation for oral replacement is magnesium oxide (242 mg = 20 mEq Mg2+ per 400 mg tablet), with a typical dose of 400 mg two to three times per day. Magnesium chloride, magnesium gluconate, magnesium lactate, and magnesium L- aspartate are other options. Diarrhea is a common side effect. It may be reduced with the use of a sustained release formulation, such as magnesium chloride (64 mg per 535 mg tablet). The potassium-sparing diuretics triamterene and amiloride, which block ENaC in the distal renal tubule, can assist in treatment of hypomagnesemia refractory to oral supplementation.

PRACTICE POINT

Refractory hypokalemia and hypocalcemia occur with severe Mg2+ deficiency, and Mg2+ repletion is necessary for correction.

Intravenous repletion

Symptomatic or severe hypomagnesemia should be treated with intravenous magnesium. For active seizures or cardiac arrhythmias, an initial dose of 8 to 16 mEq of Mg2+ (1-2 g of MgSO47H2O) is administered over 2 minutes. For nonemergency repletion, 64 mEq of Mg

(8 g of MgSO47H2O) can be given over the first 24 hours, followed by 32 mEq of Mg 2+ daily

for six additional days. Since magnesium is renally cleared, the dose should be reduced by 25% to 50% and the plasma magnesium level monitored after each dose for GFR < 20 to 30 mL/min/1.73 m2.

HYPERMAGNESEMIA ETIOLOGY

Hypermagnesemia usually results from iatrogenic causes, such as magnesium treatment for preeclampsia or eclampsia, or inadvertent administration of excessive doses of magnesium-containing supplements, laxatives, Epsom salts, enemas, or antacids. The risk of hypermagnesemia is particularly high for patients with severely impaired renal function.

CLINICAL MANIFESTATIONS

Clinical manifestations are unusual with plasma magnesium levels < 4.5 to 5 mg/dL. Above this range, nausea, vomiting, cutaneous flushing, hyporeflexia, and mild hypotension can be seen. For plasma magnesium levels > 7 to 10 mg/dL, there may be loss of tendon reflexes, muscle weakness, and hypotension. Respiratory muscle paralysis occurs when magnesium levels exceed 12 to 15 mg/dL. ECG changes with plasma magnesium values > 5 mg/dL include prolonged PR interval, an increased QRS interval, prolonged QT interval, and bradycardia. Complete heart block is seen for plasma Mg2+ > 10 to 15 mg/dL, and cardiac arrest for levels > 15 mg/dL.

TREATMENT

In mild cases, stopping magnesium administration may be sufficient. Dialysis can be performed for extreme cases. Intravenous calcium (100-200 mg of elemental calcium given over 5-10 minutes) can be used to temporarily antagonize the effects of magnesium until dialysis can be performed. Details regarding intravenous calcium administration can be found in the section on treatment of hyperkalemia. Intravenous volume infusion may be helpful in promoting magnesium excretion in patients who are not volume overloaded and who have adequate renal function.

DISCHARGE CHECKLIST

For patients with potassium disorders at risk for cardiac arrhythmias, is the potassium level within the normal range prior to discharge? For patients with potassium disorders at low risk of cardiac arrhythmias, is the potassium level between 3 and 5.6? Are clinical symptoms or ECG changes associated with potassium disorders absent? If the patient is discharged with mild hypokalemia or mild hyperkalemia, is there a clinical plan to achieve a normal plasma potassium (3.5- 5) which can be re-evaluated at follow-up? Have patients with hypokalemia been counselled regarding potential dietary sources of potassium? (These include dark leafy greens, avocadoes, peaches, prunes, raisins, potatoes, squash, beans, and fish, as well as the commonly cited bananas and orange juice.) Has follow-up testing been arranged for potassium, magnesium, and creatinine, if appropriate?