Chapter 4. Disorders of Potassium Balance: Hypokalemia & Hyperkalemia

General Considerations

Potassium is the principal cation of the intracellular fluid (ICF) where its concentration is between 120 and 150 mEq/L. The extracellular fluid (ECF) and plasma potassium concentration [K] is much lower—in the 3.5–5.0 mEq/L range. The very large transcellular gradient is maintained by active K transport via the Na-K-ATPase pumps present in all cell membranes and the ionic permeability characteristics of these membranes. The resulting greater than 40-fold transmembrane [K] gradient is the principal determinant of the transcellular resting potential gradient, about −90 mV with the cell interior negative (Figure 4–1). Normal cell function requires maintenance of the ECF [K] within a relatively narrow range. This is particularly important for excitable cells such as myocytes and neurons. The pathophysiologic effects of dyskalemia on these cells result in most of the clinical manifestations.

Individual potassium intakes vary widely—a typical Western diet provides between 50 and 100 mEq K per day. Under steady-state conditions, an equal amount is excreted, mainly in urine (about 90%), and to a lesser extent in stool (5–10%) and sweat (1–10%). Normally, homeostatic mechanisms maintain plasma [K] precisely between 3.5 and 5.0 mEq/L. Rapid regulation of potassium concentration is needed to prevent potentially fatal hyperkalemia after every meal and is largely due to transcellular K shifts. The normal postprandial rise in insulin concentration moves both K and glucose into the intracellular compartment, where 98% of total body K (˜3000 mEq) is located. Postprandial insulin release is primarily related to increased plasma glucose concentrations but hyperkalemia also directly stimulates pancreatic β-cells to release insulin. Insulin deficiency and/or resistance increase plasma [K]. Epinephrine and norepinephrine also rapidly regulate transcellular K balance and become especially important during and following vigorous exercise. Hyperadrenergic states such as alcohol withdrawal and hyperthyroidism, β-sympathomimetics such as the tocolytic terbutaline, and theophylline poisoning often generate hypokalemia due to translocation of K from the ECF into cells.

Metabolic alkalosis stimulates cellular K uptake whereas some forms of hyperchloremic and other inorganic (mineral) acidoses enhance movement of K out of cells. However, the common organic metabolic acidoses (lactic and ketoacidosis) do not directly cause any K shift. Respiratory acid–base abnormalities generally have small effects. Although it had been assumed that the alkalemia produced by respiratory alkalosis would move K into cells, the opposite has been found, ie, a small increase in plasma [K] due to associated α-adrenergic stimulation. Respiratory acidosis increases plasma [K] slightly. Hyperosmotic conditions that shift fluid out of cells are an important cause of K translocation to the ECF. Finally, hypokalemia per se moves K from the intracellular to the extracellular space.

Potassium Metabolism

Potassium absorption in the small intestine is not specifically controlled. Although colonic epithelial cells can increase K secretion in response to chronic hyperkalemia (patients with chronic kidney disease), the net effect on K balance is minor. Although the [K] in stool water may be high, the quantity of water in formed stool is small—thus absent diarrhea, total stool K excretion is low and most ingested K is absorbed.

Potassium excretion is principally into the urine and the main regulator of body K balance is the kidney. Potassium is freely filtered (600–800 mEq/day) and then largely reabsorbed in the proximal tubule and thick ascending loop of Henle. The K load delivered to the cortical collecting duct (CCD) is about 10–15% of filtered K and the intraluminal [K] of fluid entering this segment is low. It is here that major regulation of K excretion occurs. Sodium (Na) reabsorption and K and H secretion in the CCD is dependent on the amount of Na delivered to this segment, the “absorbability” of the anion, and the activity of the mineralocorticoid aldosterone. In the CCD, Na is absorbed through epithelial Na channels (ENaC) present on the luminal surface of the predominant (principal) cells in this segment. The absorption of large amounts of Na, especially when delivered with an anion not easily absorbed (Cl, HCO3, and others), generates a negative charge within the lumen and enhances the secretion of K and H (Figure 4–2). Aldosterone regulates the rate of Na absorption through these channels at multiple levels. It affects the rate of energy (ATP) generation, the activity of Na-K-ATPase pumps, and the number and “open state” of the ENaC channels themselves.

In normal individuals, an inverse relationship exists between aldosterone activity and CCD Na delivery. A high salt intake will expand ECF volume, inhibit renin and aldosterone levels, and increase distal delivery and excretion of Na. High distal Na delivery counterbalances low aldosterone activity and the net effect is normal CCD K and H secretion and excretion. Conversely, a low salt intake contracts the ECF, stimulates renin and aldosterone levels, and markedly reduces distal CCD Na delivery and excretion. In this case, low CCD Na delivery is linked to high aldosterone activity and again normal K and H secretion and excretion is maintained. This reciprocal interplay between aldosterone activity and distal Na delivery is physiologic and acts to simultaneously maintain both volume and electrolyte homeostasis.

Pathophysiologic conditions exist when high CCD Na delivery combines with high aldosterone activity or low CCD Na delivery coexists with low aldosterone activity. In the first circumstance, the magnitude of CCD Na absorption increases markedly and results in excessive K and H secretion, thereby generating hypokalemia and metabolic alkalosis. Conversely, the second scenario causes a major reduction in CCD Na reabsorption and very low rates of K and H secretion leading to hyperkalemia and metabolic acidosis. Increased CCD Na delivery together with high aldosterone levels occurs in patients with primary hyperaldosteronism and as a result of thiazide and/or loop diuretics. Reduced CCD Na delivery together with low aldosterone activity occurs in some forms of hyporeninemic hypoaldosteronism and when aldosterone antagonists are given to patients with disorders with reduced “effective” intra-arterial volume such as hepatic cirrhosis or congestive heart failure.

Clinical Findings

Nerve, cardiac conduction, and muscle cells are especially sensitive to changes in transcellular voltage and therefore are most affected by hypokalemia or hyperkalemia. Figure 4–3 shows how either condition can cause muscle weakness.

Hypokalemia increases the resting potential across the myocyte membrane, ie, the cell becomes more negative and less sensitive to excitation. Severe hypokalemia thus leads to a hyperpolarization block and flaccid paralysis. It may also cause rhabdomyolysis and paralytic ileus. Renal manifestations include metabolic alkalosis, nephrogenic diabetes insipidus, and formation of renal cysts. Chronic hypokalemia has been implicated in the development of hypertension.

Hyperkalemia reduces the resting potential, ie, the cell becomes less negative. Following depolarization, the cell is unable to adequately repolarize and becomes unexcitable. Severe hyperkalemia causes a depolarization block and flaccid paralysis. Clinical manifestations include fatigue, myalgia, and muscle weakness (especially lower extremity), hyporeflexia, paresthesias, muscle cramps, electrocardiogram (ECG) changes, and cardiac arrhythmia (Figure 4–4). Muscle weakness may progress to ascending paralysis, hypoventilation, and respiratory failure.

The clinical manifestations of an abnormal plasma [K] vary greatly and depend on (1) its magnitude, (2) acuity of onset, (3) the relative contributions of K shift versus change in total body K, and (4) coexisting abnormalities that either potentiate or blunt the [K] effects, including underlying heart disease, drugs (digoxin, antiarrhythmic agents), hypocalcemia or hypercalcemia, cardiac pacing devices, and others.

The resting membrane potential is determined by the ratio of intracellular and extracellular [K] (Ki/Ke). An acute K shift into or from the intracellular space alters intracellular [K] only minimally since it is quantitatively so large; about 3000 mEq or 98% of total body K is within cells. However, the effect on the extracellular concentration can be dramatic because the total quantity of K outside of cells is only about 60 mEq. Therefore, acute K shifts will markedly affect the Ki/Ke ratio and can cause profound cellular hyperpolarization or depolarization with muscular, neurologic, and cardiac symptoms (Figure 4–5). In contrast, states of chronic K depletion reduce both intracellular and extracellular K levels and have a much smaller effect on Ki/Ke with fewer and less severe clinical manifestations. Furthermore, K shifts produce much more rapid changes in plasma [K] and thus the effects are often more dramatic than with states of total body K depletion or excess. This has important clinical implications: A dialysis patient with a chronically elevated [K] who presents with a [K] of 6.5 mEq/L and minimal ECG effects may not require urgent intervention. However, a diabetic patient with chronic kidney disease who develops acute hyperglycemia and a rapid [K] rise to 6.5 mEq/L may manifest major ECG changes, which mandate quick action.

Comorbid illness such as coronary heart disease will amplify the clinical importance of dyskalemia by increasing the risk of serious arrhythmia. Hyperkalemic effects on cardiac conduction are well documented and are the principal reason it constitutes a medical emergency (Figure 4–4). The cardiac risks of hypokalemia are less well established. Although increased risk of ectopy is established for patients with acute myocardial infarction and those treated with digoxin and other antiarrhythmic agents, its importance for most other patients remains unclear.

Calcium has important effects on myocyte depolarization. Hypocalcemia reduces the depolarization threshold potential and renders the cardiac myocyte more excitable. Conversely, hypercalcemia reduces membrane excitability by increasing the depolarization threshold (Figure 4–3). This calciumrelated shift of the depolarization threshold reverses the cardiac toxicity of hyperkalemia. Coexisting hyperkalemia and hypocalcemia is a particularly pernicious combination and is common in patients with severe kidney failure.

Essentials of Diagnosis

• Serum [K] below 3.5 mEq/L.
• Most commonly caused by use of thiazide or loop diuretics, vomiting/nasogastric suction, and diarrhea (or laxatives).
• Reduction of total body K stores.
• Excretion less than 20–30 mEq K per day.
• Osmotic diuresis.

Diagnosis & Complications

A serum [K] below 3.5 mEq/L defines hypokalemia, and Table 4–1 lists some of the causes and clinical conditions associated with this disorder. The most common causes of hypokalemia are the use of thiazide or loop diuretics, vomiting/nasogastric suction, and diarrhea (or laxatives). These etiologies are usually readily apparent unless the patient is covertly using drugs or vomiting. A more elaborate evaluation is necessary when these frequent causes are excluded. It is then important to determine whether hypokalemia is primarily due to an intracellular shift of K or to excessive K renal or gastrointestinal losses (sometimes combined with reduced intake).

Hypokalemia due to transcellular K shifts may generate impressive clinical presentations. Examples include several forms of hypokalemic periodic paralysis, the administration of β2-agonists to treat obstructive lung disease or premature labor, theophylline poisoning, and conditions that enhance β-agonist activity such as hyperthyroidism and hypothermia. Insulin also drives K into cells and promotes hypokalemia. Barium poisoning and chloroquine overdose block K exit from cells and cause K accumulation within the ICF and profound hypokalemia. Another cause of K accumulation within cells is a rapid expansion of cell mass that occurs during refeeding after prolonged starvation, with rapidly growing tumors, and when patients with severe pernicious anemia are treated with vitamin B12 .

Patients with hypokalemic periodic paralysis often have a dramatic clinical presentation. At least two distinct subtypes of this syndrome have been characterized: A rare familial form (usually due to an autosomal dominant mutation affecting a calcium channel) and a more common hyperthyroid-associated form. Hyperthyroid periodic paralysis is especially prevalent among young men of Asian (or less often Hispanic) ancestry. They typically present with profound acute muscle paralysis affecting mainly proximal limb muscle groups with sparing of ocular and respiratory muscles. Deep tendon reflexes are generally absent. Paralysis often develops after a period of exercise (which increases β-agonist activity) or following ingestion of carbohydrates (which increases insulin). Clinical signs and symptoms of thyrotoxicosis may be subtle. A prior history of recurrent episodes of weaknesses is common. Plasma [K] is usually below 2 mEq/L, and both hypophosphatemia and mild hypomagnesemia may be seen. Acute treatment with exogenous K salts is appropriate, but rebound hyperkalemia often develops since total body K is normal. Treatment with β-blockers such as propranolol is helpful and correction of the hyperthyroid state is usually curative. The pathophysiology of this disorder is thought to include the effect of thyroid hormone on the Na-K-ATPase, an exaggerated insulin response, the hypera drenergic state of hyperthyroidism, genetic and racial predisposition, and probably inherited mutations of muscle ion transport that remain subclinical until magnified by the hyperthyroid state.

A reduction of total body K stores may be due to gastrointestinal loss, renal loss, or both. The 24-hour urine potassium excretion helps define the etiology. A patient with hypokalemia should excrete less than 20–30 mEq K per day. If this is found, renal losses are generally excluded and either gastrointestinal losses or a transcellular shift should be considered. Higher excretion rates indicate renal K wasting. However, one caveat is that some renal K losses occur intermittently, with intervening periods of appropriate K conservation. For example, diuretics cause excess renal K losses but urine K excretion falls to an appropriately low range when the diuretic effect wears off. Similarly, vomiting or nasogastric suction causes excess renal K loss during the active phase, but K excretion becomes very low in the “equilibrium phase.”

If a 24-hour urine collection cannot be accomplished, an alternative useful measurement is the transtubular [K] gradient, or TTKG. This calculation attempts to correct the urinary [K] for the increase generated by distal water reabsorption after the tubular fluid has exited the CCD. In theory, the TTKG approximates the [K] gradient in the cortical collecting tubule, and is calculated as

A TTKG below 2–3 indicates appropriate renal K conservation in a patient with hypokalemia. However, the TTKG becomes uninterpretable if urine osmolality is less than plasma osmolality or if distal nephron sodium delivery is very low, ie, urine sodium below 20 mEq/L.

Assessment of a patient's volume status and blood pressure provides additional diagnostic clues. Patients with hypokalemia, volume expansion, and hypertension may have primary or exogenous hypermineralocorticoidism. An increased plasma aldosterone level (normal 5–20 ng/dL) and a simultaneous suppressed plasma renin activity (PRA; normal 1–3 ng/mL per hour) indicate autonomous aldosterone secretion. Some advocate calculating an aldosterone/PRA ratio. A ratio greater than 30 and an elevated aldosterone level (above 20 ng/dL) also suggest primary hyperaldosteronism. Autonomous hyperaldosteronism may be due to a unilateral aldosterone-secreting adenoma (Conn syndrome), bilateral adrenal hyperplasia, or rarely, adrenal cancer. Radiologic evaluation often allows determination of the specific syndrome, but adrenal vein sampling is necessary in some cases. Another cause of primary hyperaldosteronism is glucocorticoid-remediable aldosteronism. This rare disorder is due to an autosomal dominant mutation, which leads to sustained synthesis and secretion of aldosterone by ACTH stimulation. Glucocorticoids suppress ACTH and reverse the clinical and biochemical abnormalities of this disorder.

Pseudohyperaldosteronism is characterized by the biochemical and clinical features of an autonomous mineralocorticoid excess state but with suppressed aldosterone levels. It may be due to secretion of a nonaldosterone mineralocorticoid. Examples include adrenal tumors secreting the mineralocorticoid deoxycorticosterone (DOC), some forms of congenital adrenal hyperplasia (17- and 11-hydroxylase deficiency), and conditions that cause glucocorticoids to develop potent mineralocorticoid properties. Glucocorticoids can normally activate the mineralocorticoid receptor. However, the enzyme 11 β-hydroxysteroid dehydrogenase type 2 is present in high concentrations at most sites where mineralocorticoid receptors exist, and inactivates the glucocorticoids. In the absence of this enzyme, physiologic levels of glucocorticoids will produce a mineralocorticoid excess state. The enzyme is congenitally absent or defective in patients with the “apparent mineralocorticoid excess (AME)” syndrome who exhibit a hyperaldosterone-like disorder of hypokalemia, metabolic alkalosis, volume expansion, and hypertension. 11 β-Hydroxysteroid dehydrogenase type 2 is also antagonized by substances such as glycyrrhetinic acid, the active ingredient in true licorice, several decongestants available in Europe, and some brands of chewing tobacco (eg, RedMan). Their excessive use results in the same clinical presentation. Also, this enzyme may be overwhelmed by the markedly elevated cortisol levels in some patients with Cushing syndrome, in particular the form due to ectopic ACTH secretion.

Liddle syndrome also has features of a mineralocorticoid excess state but all known mineralocorticoids are reduced. The disorder is caused by an autosomal dominant mutation, which causes the ENaC in the collecting duct to remain in a persistently open state in the absence of mineralocorticoid stimulation. Clinical and biochemical findings mimic a nonaldosterone mineralocorticoid excess state—volume expansion, hypertension, hypokalemia, metabolic alkalosis, and suppressed levels of renin and aldosterone.

Secondary hyperaldosteronism is a condition characterized by elevated aldosterone levels due to high renin. It occurs in patients with renal artery stenosis, but also in patients with severe hypertension whose major renal arteries are anatomically normal—blood flow in smaller vessels is likely impaired. Rarely, tumors may autonomously secrete renin and thereby cause a state of hyperaldosteronism, hypertension, and hypokalemia. These forms of secondary hyperaldosteronism are all associated with volume expansion and hypertension.

Secondary hyperaldosteronism may also be associated with (and due to) reduced ECF volume and hypotension. This is observed with most diuretics and several renal tubular disorders. Combining high distal renal tubule Na delivery with high aldosterone activity leads to renal K wasting, hypokalemia, and variable degrees of metabolic alkalosis. This is a common effect of loop or thiazide diuretics (acetazolamide will produce hypokalemia and metabolic acidosis due to the excretion of sodium bicarbonate). Combining a loop and thiazide diuretic generates an especially powerful kaliuretic response and the combination should be used judiciously.

Two classes of autosomal recessive genetic disorders mimic the effects of thiazide or loop diuretics. Gitelman syndrome is due to a defect of the thiazide-sensitive NaCl transporter in the early distal renal tubule. Bartter syndrome is caused by one of several generic mutations that impair the function of the Na-K-2Cl transporter in the thick ascending limb of Henle that is inhibited by loop diuretics. Both are characterized by similar clinical and biochemical abnormalities: Volume contraction, hypotension, high levels of urinary prostaglandins, renal K and NaCl wasting, and high renin and aldosterone levels. Distinguishing characteristics are reduced urine calcium excretion and severe hypomagnesemia in Gitelman syndrome patients, but hypercalciuria in those with Bartter syndrome. It is almost impossible to discern these patients from those using diuretics surreptitiously unless urine is assayed for these substances and/or specific genetic mutations are identified. While Bartter syndrome is typically a pediatric disease diagnosed early in life, the phenotype of Gitelman syndrome is often subclinical and is not diagnosed until adulthood.

In the intensive care unit, osmotic diuresis is a relatively common cause of hypokalemia and hypernatremia. It is usually due to hyperglycemia or urea in patients with highly catabolic conditions (acute illness, high-dose steroids) who are also receiving parenteral nutrition or tube feeding. Sodium delivered to the distal tubule together with the glucose or urea is reabsorbed in exchange for K and H. Infusion of mannitol can also generate this syndrome. Several nephrotoxic drugs inappropriately increase distal tubule Na delivery, generating K wasting. Some also cause magnesiuria and hypomagnesemia, which itself promotes kaliuresis. Examples include aminoglycoside antibiotics, amphotericin B, cisplatin, and foscarnet. Patients with acute myeloid or lymphoblastic leukemia may develop proximal or distal tubule dysfunction. Hypokalemia as well as metabolic acidosis, hyponatremia, hypocalcemia, hypophosphatemia, and hypomagnesemia may result.

Na delivered to the distal nephron with a poorly reabsorbed nonchloride anion can accelerate K and H secretion. This is magnified by development of ECF contraction with high levels of renin and aldosterone (Figure 4–2). The disorder occurs in patients treated with high-dose Na-penicillin, during development and treatment of diabetic ketoacidosis (Na-β-hydroxybutyrate), with inhalation of toluene/glue (Na-hippurate), and during vomiting or nasogastric suction (when NaHCO3 spills into the distal tubule and urine). By a similar mechanism, hypokalemia develops when patients with proximal renal tubular acidosis (RTA type 2) are aggressively treated with exogenous bicarbonate salts. Patients with classic distal tubular acidosis (RTA type 1) also have accelerated distal tubule Na-K exchange and hypokalemia. However, in contradistinction to proximal RTA, renal K excretion and hypokalemia improve with NaHCO3 therapy, in part because ECF volume expands.

The colon secretes K and absorbs chloride in exchange for HCO3. When urine comes in contact with the bowel wall, chloride is removed while K and HCO3 are secreted. This results in hypokalemia and a hyperchloremic metabolic acidosis. Clinical situations in which this occurs include ureteral implants into the sigmoid colon and interposition of colon segments between the kidney and bladder.

Treatment

The best treatment for hypokalemia is prevention. The combination of a loop and thiazide diuretic is particularly kaliuretic and should be used infrequently. Incorporating an aldosterone antagonist (spironolactone or eplerenone) or a distal tubule Na channel blocker (amiloride or triamterene) in the diuretic regimen is helpful. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) also reduce K losses generated by diuretics, in part by reducing aldosterone levels.

Potassium replacement is necessary when K has been lost and total K stores are reduced. Occasionally, exogenous K is used to treat the acute clinical manifestations generated by severe K shifts into cells. However, such replacement must be done cautiously since total body K stores are normal and rebound hyperkalemia occurs. This has been described following treatment of hypokalemic periodic paralysis, and after cessation of intravenous tocolytic therapy with terbutaline for preterm labor.

Whenever possible, K should be replenished via the oral route. Potassium-rich foods (dried fruit, nuts, bananas, oranges, tomatoes, spinach, potatoes, and meat) are often less effective for replacement because their K content is relatively low compared to total calories and because food K is largely composed of organic salts (see below). K salts are required to replenish major deficits. In general, a plasma [K] between 3 and 3.5 mEq/L represents a K deficit of 200–400 mEq, while a plasma [K] between 2.0 and 3.0 mEq/L requires 400–800 mEq.

Potassium replacement salts are divided into two broad classes: Potassium chloride (KCl) and potassium bicarbonate (KHCO3). Organic K salts can be metabolized, mole for mole, to KHCO3 and are therefore included in the second group. KCl is the most appropriate and effective replacement for K deficits associated with metabolic alkalosis. Conversely, alkalinizing K salts (KHCO3, K-citrate, K-acetate, K-gluconate) are best for hypokalemia associated with metabolic acidosis, such as RTA, or chronic diarrhea. Alkalizing K salts are more palatable and better tolerated than oral KCl. However, organic K salts should not be used to treat hypokalemia associated with metabolic alkalosis. In this setting, alkalinizing K salts are poorly retained and less effectively reverse the K deficit and metabolic alkalosis. Table 4–2 lists the various forms of oral potassium salts.

When the oral route cannot be used, or total K deficits are severe, intravenous replacement becomes necessary. A parenteral fluid KCl concentration of 20–40 mEq/L is generally well tolerated. KCl concentrations of 60 mEq/L and greater are painful and may induce peripheral vein necrosis. When intravenous administration of a large volume of fluid is contraindicated, K concentrations of up to 200 mEq/L (20 mEq in 100 mL of isotonic saline) may be given via a central vein, but the administration rate should not exceed 10–20 mEq per hour. Central venous administration of very concentrated K solutions requires a rate-controlling pump. The choice of intravenous fluid must also be considered, because dextrose will increase insulin and shift K into cells, thereby potentially worsening hypokalemia!

Essentials of Diagnosis

• Serum [K] above 5.0 mEq/L.
• Acute or chronic renal failure is the most common cause.
• Transcellular shift of K from the intracellular to the extracellular space.
• Inhibition of the endocrine sequence.

Diagnosis & Complications

The causes of hyperkalemia, defined as a serum [K] above 5.0 mEq/L, are listed in Table 4–3. Acute or chronic renal failure is by far the most common cause or major contributor to hyperkalemia. When the kidney and the renin–angiotensin–aldosterone axis function normally, the plasma [K] is maintained in the normal range despite wide extremes in intake. Therefore, persistent or chronic hyperkalemia almost always indicates impaired renal excretion, either due to intrinsic pathology or inadequate endocrine signaling. However, rapid K shifts from cells to the ECF can generate acute hyperkalemia, despite normal renal and endocrine function. Such “shift” hyperkalemia is exacerbated by coexistent renal dysfunction and/or hormonal derangements.

Pseudohyperkalemia is an artifact related to the collection and/or preparation of the specimen or an artifact of the K measurement procedure itself. It is generally a diagnosis of exclusion and should not delay prompt intervention. Potential causes include repeated fist clenching during phlebotomy, hemolysis due to traumatic venipuncture, particularly with small gauge needles, delayed processing of the specimen (especially when placed on ice), K release from white blood cells in severe leukocytosis (usually >100 × 103/μL) or from platelets with extreme thrombocytosis (usually >1000 × 103/μL), and prolonged tourniquet application in some individuals. Some patients inherit a propensity to leak K from red blood cells ex vivo due to a membrane defect. Measurement of plasma rather than serum [K] may eliminate some of these artifacts.

A transcellular shift of K from the intracellular to the extracellular space is a common cause of acute hyperkalemia. It is often due to direct damage or destruction of cell membranes. Examples include tumor lysis related to chemotherapy, acute intravascular hemolysis due to infection, transfusion reaction or severe hemolytic anemia, hemolysis developing within a large hematoma, extensive burns, rhabdomyolysis, and intestinal ischemia/necrosis.

Excessive K efflux may also develop across intact cell membranes as a result of certain drugs, metabolic disorders, and inherited diseases. Drugs that block β-agonist activity favor K efflux from cells. The muscle relaxant succinylcholine consistently promotes cellular K efflux and many cases of profound hyperkalemia have been reported, especially in patients with an underlying neuromuscular or renal disorder. A pharmacologic dose of digitals inhibits Na-K-ATPase in cardiac myocytes, but toxic levels inhibit these pumps in systemic muscle cells and may thereby generate extreme hyperkalemia. Potassium translocation also occurs with insulin deficiency or resistance, certain hyperosmolar conditions such as hyperglycemia, and some forms of inorganic (usually hyperchloremic) metabolic acidoses. It was previously assumed that acidemia, especially with metabolic acidosis, caused protons to move into cells with reciprocal K efflux. However, organic metabolic acidoses, such as ketoacidosis and lactic acidosis, do not generate K shifts. Although hyperkalemia may develop in these patients, it is usually the result of a pathophysiologic process and not the academia per se. Hyperkalemia does occur frequently with lactic acidosis, but is principally due to tissue ischemia/necrosis and concomitant renal insufficiency. Hyperkalemia is also a common finding in diabetic ketoacidosis due to the combination of insulin deficiency, hyperosmolarity (hyperglycemia), and decreased renal perfusion, rather than the academia per se. In contrast, the infusion of some inorganic acids, such as HCl, will directly shift K out of cells. “Shift” hyperkalemia also develops when HCl precursors are infused, such as the chloride salts of arginine or lysine. Genetic defects of cell membrane ion transporters, usually epithelial Na channels, cause the syndrome of hyperkalemic periodic paralysis.

Most nonphysiologic states of hypoaldosteronism (ie, not secondary to ECF expansion) generate chronic hyperkalemia because of reduced distal tubule (CCD) K secretion. This is exacerbated by concomitant renal insufficiency or markedly reduced distal tubule Na delivery. Pathologic hypoaldosteronism may be the consequence of a direct block of hormonal synthesis (a congenital or acquired enzyme defect or adrenal damage) or secondary to dysregulation of the signals mediating aldosterone synthesis and release. The most important physiologic regulator of systemic aldosterone is angiotensin II activity, and the most common form of pathologic hypoaldosteronism is due to reduced renin activity and hence angiotensin II levels. This “hyporeninemic hypoaldosteronism” often develops in patients with long standing diabetes mellitus as a result of progressive interstitial renal disease with atrophy and/or destruction of the renin-secreting cells in the juxtaglomerular apparatus. Other interstitial renal diseases, such as those associated with sickle cell disease, analgesic nephropathy, and chronic urinary outlet obstruction (especially in elderly men), may produce a state of hyporeninemic hypoaldosteronism as well. Elderly patients often have an underlying element of hyporeninemic hypoaldosteronism and are prone to develop hyperkalemia. In addition, their renal function is typically underappreciated because of low body mass.

Hypoaldosteronism slows the rate of distal tubule proton secretion. In addition, hyperkalemia inhibits renal ammonia synthesis and reduces NH4Cl excretion. These defects combine to generate a syndrome of hyperkalemic, hyperchloremic metabolic acidosis called renal tubular acidosis type 4. Correction of the hyperkalemia often increases urine ammonia excretion and reverses the metabolic acidosis.

Inhibition of the endocrine sequence at any step will promote hyperkalemia: Renin → angiotensin I → angiotensin II → aldosterone → activation of distal tubule Na reabsorption and K (and H) secretion. Clinically important causes include the following:

1. Suppressed renin secretion by β-blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclosporine, and tacrolimus.

2. Impaired angiotensin II generation by ACEI.

3. Blockade of type I angiotensin II receptor by ARB.

4. Inhibition of the enzymatic sequence responsible for aldosterone synthesis by drugs such as heparin or ketoconazole.

5. Destruction of the adrenal gland as a result of autoimmune disease or infection.

6. Competitive antagonism of mineralocorticoid receptors by spironolactone or eplerenone.

7. Blockade of the cortical collecting duct epithelial sodium channels by triamterene, amiloride, trimethoprim, or pentamidine.

8. Blunted renal epithelial response to aldosterone as a result of a series of inherited disorders (the congenital pseudohypoaldosteronism syndromes)

Many other factors contribute to the hyperkalemia, which commonly develops in patients with diabetes mellitus. Autonomic sympathetic neuropathy reduces renin levels and blunts β activity, thus promoting K efflux. The multiple medications often prescribed include ACEI, ARBs, aldosterone antagonists, and NSAIDs (see below). These patients may also ingest excess K in the form of salt substitutes and their global kidney function is typically impaired. With suboptimal diabetic control, the combined effects of insulin deficiency and hyperglycemia may increase plasma [K] acutely and dramatically.

The contribution of reduced renal K excretion to the development of hyperkalemia is usually readily apparent. If not, a quantitative urine collection to measure daily K excretion is helpful. Chronic hyperkalemia will stimulate renal K excretion and the 24-hour urine should contain more than 80 mEq. If a quantitative urine collection cannot be obtained, the TTKG (described in the hypokalemia section) should be greater than 10, provided urine osmolality is above 300 mOsm/L and urinary Na excretion is above 20 mEq/L.

Treatment

It is better to prevent hyperkalemia than to treat it. A careful review of patient medications, diet, and in particular over-the-counter drugs (NSAIDs) is mandatory. Hidden sources of K, such as herbal medicines, sports drinks, and salt substitutes, must be sought. The recent demonstration that aldosterone antagonists provide a survival benefit to patients with congestive heart failure (who are usually also taking ACEI and/or ARB drugs plus β-blockers) has generated a major increase in the prevalence of hyperkalemia among these patients.

When hyperkalemia is acute and severe, emergency intervention is necessary. Treatment options for acute and severe hyperkalemia include the following:

• 1. Direct reversal of cardiotoxic effects with intravenous calcium.
• 2. Translocating K into cells:
  • a. Insulin infusion—with glucose if appropriate.
  • b. β2-Adrenergic agonists such as albuterol.
  • c. NaHCO3 infusion.
• 3. Increasing K excretion:
  • a. Via the kidney by ECF volume expansion and kaliuretic diuretics.
  • b. Via the gastrointestinal tract by inducing diarrhea and K-binding resins.
  • c. Via dialysis for patients with severe acute or chronic renal failure.

If [K] is greater than 6.4 and peaked T waves are an isolated ECG abnormality, calcium should probably be infused. It is clearly indicated when a hyperkalemic patient manifests more ominous ECG abnormalities (Figure 4–3). Calcium directly antagonizes the cardiac membrane-depolarizing effects of hyperkalemia (Figure 4–4). The indication for calcium in the absence of electrocardiographic changes is unclear; however, such infusions are relatively safe in the absence of overt hypercalcemia, marked hyperphosphatemia, or digitalis toxicity. One ampule (10 mL) of 10% calcium gluconate contains 4.6 mEq of elemental calcium and is given as a slow intravenous push over 2–5 minutes. Alternatively, one ampule (10 mL) of calcium chloride 10%, containing about three times as much elemental calcium (13.6 mEq), is acceptable, but should be given more slowly and cautiously. Extravasation of either salt can produce tissue necrosis (calcium chloride is more irritating then calcium gluconate). The beneficial effect on the ECG is usually seen immediately. The dose of calcium may be repeated if ECG abnormalities persist or recur. Lidocaine is contraindicated because it can precipitate ventricular fibrillation and asystole. Importantly, calcium infusions do not directly affect the plasma [K] per se and their beneficial effects are short lived (about 1–2 hours). Therefore, this treatment must be promptly followed by other regimens that ultimately reduce plasma [K] by translocation into cells or excretion.

The three agents that drive extracellular potassium into cells are listed above. Insulin stimulates Na-K-ATPase (and the Na-H exchanger—Figure 4–1) and reliably reduces [K] by 0.5–1 mEq/L within 10–20 minutes in most patients. For a maximum K lowering effect, supraphysiologic levels of insulin are required, typically 10 units of regular insulin intravenous push. Subcutaneous or intramuscular injections and “low-dose” intravenous infusions should not be utilized because they do not produce adequate plasma insulin levels. Intravenous glucose is also administered if the patient is not already hyperglycemic. A reasonable approach is to administer one ampule (50 mL) of 50% glucose, followed by an intravenous infusion of 10% glucose at about 75 mL/hour. Hyperglycemia must be avoided because this will shift K out of cells. Infusion of glucose alone to stimulate endogenous insulin secretion in nondiabetic patients is less effective because it generates lower peak insulin levels.

The β2-agonist albuterol also stimulates Na-K-ATPase and moves K into cells. This effect is additive to that of insulin and occurs within 30–60 minutes. The parenteral form of albuterol is not available in the United States, and the drug is given via the respiratory tract by nebulizer at a dose of 10–20 mg in 4 mL of saline. This relatively high dose is well tolerated by most patients, but contraindicated for patients with acute cardiac ischemia or severe myocardial disease. However, it is less reliable than insulin because significant numbers of patients are resistant to its K-lowering effect and therefore it should never be used alone.

Hypertonic NaHCO3 , 1–3 ampules (44 mEq/50 mL each) by intravenous infusion over 30–45 minutes, has been used in the treatment of hyperkalemia for many years. Overall, its potassium-lowering effect is weak and of slow onset. Hypertonic NaHCO3 lowers [K] via multiple mechanisms including expansion of the ECF with dilution of [K]. Hypertonic NaHCO3 does expand the ECF and should be avoided in volume overloaded patients and those with congestive heart failure.

Hyperkalemia associated with increased total K stores requires K to be removed. If kidney function is adequate, loop and thiazide diuretics (and especially in combination) markedly increase urinary K excretion. Thiazide diuretics are particularly helpful in the treatment of hyporeninemic hypoaldosteronism. Thiazides become less effective when kidney function declines, whereas high-dose loop diuretics may remain useful until renal function reaches “end stage.” Occasionally, patients with hypoaldosteronism are volume contracted and the exogenous mineralocorticoid fludrocortisone is useful.

Stool potassium excretion is enhanced by administering laxatives to generate electrolyte-rich diarrhea and by binding gastrointestinal luminal K to nonabsorbable resins, such as sodium polystyrene sulfonate (Kayexalate). The resin powder is generally premixed with sorbitol (15 g suspended in 60 mL of 70% sorbitol), which speeds its transit through the gut and in itself increases fecal K loss. The usual oral dose is 30 g. The resin powder can also be ingested with other laxatives. The acute K-lowering effect of this treatment is minor and resin K binders may be more effective for chronic therapy. These resins can also be administered via enema, though this route may be less effective. A rare complication of the sodium polystyrene sulfonate in sorbitol suspension is bowel necrosis. This may be due to the hypertonic sorbitol rather than the resin itself and is more common with rectal administration.

Acute hemodialysis, generally reserved for patients with acute or chronic severe kidney failure, rapidly lowers plasma [K] and can reduce total body K stores by about 25–50 mEq per hour.