K is the most abundant intracellular cation, but only about 2% of total body K is extracellular. Because most intracellular K is contained within muscle cells, total body K is roughly proportional to lean body mass. An average 70-kg adult has about 3500 mEq of K.

K is a major determinant of intracellular osmolality. The ratio between ICF and ECF K concentrations strongly influences cell membrane polarization, which in turn influences important cell processes, such as the conduction of nerve impulses and muscle (including myocardial) cell contraction. Thus, relatively small alterations in plasma K concentration can have major clinical manifestations.

In the absence of factors that shift K in or out of cells (see Fluid and Electrolyte Metabolism: Intracellular shift), the plasma K level correlates closely with total body K content. Assuming a constant plasma pH, a decrease in plasma K concentration from 4 to 3 mEq/L indicates a total K deficit of 100 to 200 mEq. A fall in plasma K to < 3 mEq/L indicates a total K deficit of about 200 to 400 mEq.

Insulin moves K into cells; high levels of insulin thus lower plasma K concentration. Low insulin levels, as in diabetic ketoacidosis, cause K to move out of cells, thus raising plasma K, sometimes even in the presence of total body K deficiency. β-Adrenergic agonists, especially selective β₂-agonists, move K into cells, whereas β-blockade and α-agonists probably move K out of cells. Acute metabolic acidosis causes K to move out of cells, whereas acute metabolic alkalosis causes K to move into cells. However, changes in plasma HCO₃ concentration may be more important than changes in pH; acidosis caused by accumulation of mineral acids (nonanion gap, hyperchloremic acidosis) is more likely to elevate plasma K. In contrast, metabolic acidosis due to accumulation of organic acids (increased anion gap acidosis) does not cause hyperkalemia. Thus, the hyperkalemia common in diabetic ketoacidosis results more from insulin deficiency than from acidosis. Acute respiratory acidosis and alkalosis affect plasma K concentration less than metabolic acidosis and alkalosis. Nonetheless, plasma K concentration should be interpreted in the context of the plasma pH (and HCO₃ concentration).

Dietary K intake normally varies between 40 and 150 mEq/day. In the steady state, fecal losses are usually close to 10% of intake. Urinary excretion contributes to K balance. When K intake increases (> 150 mEq of K is ingested daily), about 50% of the excess K appears in the urine over the next several hours. Most of the remainder is transferred into the intracellular compartment to minimize the rise in plasma K. If elevated K intake continues, renal K excretion rises because of K-stimulated aldosterone secretion; aldosterone promotes K excretion. In addition, K absorption from stool appears to be under some regulation and may fall by 50% in chronic K excess.

When K intake falls, intracellular K again serves as a reserve against wide swings in plasma K concentration. Renal K conservation develops relatively slowly in response to decreases in dietary K and is far less efficient than the kidneys' ability to conserve Na. Thus, K depletion is a frequent clinical problem. Urinary K excretion of 10 mEq/day represents near-maximal renal K conservation and implies significant K depletion.

Acute acidosis impairs K excretion, whereas chronic acidosis and acute alkalosis can promote K excretion. Increased delivery of Na to the distal nephron, as occurs with high Na intake or loop diuretic therapy, promotes K excretion.

Pseudohypokalemia, or falsely low serum K, occasionally occurs in patients with chronic myelocytic leukemia with a WBC count > 10⁵/μL if the specimen remains at room temperature before being processed because of uptake of plasma K by abnormal leukocytes in the sample. It is prevented by prompt separation of plasma or serum in blood samples.

Pseudohyperkalemia, or falsely elevated serum K, is more common, typically occurring from hemolysis and release of intracellular K. To prevent this, phlebotomy personnel should not rapidly aspirate blood through a narrow-gauge needle or excessively agitate blood samples. Pseudohyperkalemia can also result from platelet count > 10⁶/μL due to release of K from platelets during clotting. In cases of pseudohyperkalemia, the plasma K (unclotted blood), as opposed to serum K, is normal.

Hypokalemia

Hypokalemia is serum K concentration < 3.5 mEq/L caused by a deficit in total body K stores or abnormal movement of K into cells. The most common causes are excess losses from the kidneys or GI tract. Clinical features include muscle weakness and polyuria; cardiac hyperexcitability may occur with severe hypokalemia. Diagnosis is by serum measurement. Treatment is administration of K and addressing the cause.

Etiology and Pathophysiology

Hypokalemia can be caused by decreased intake of K but is usually caused by excessive losses of K in the urine or from the GI tract.

GI tract losses

Abnormal GI K losses occur in chronic diarrhea and include losses due to chronic laxative abuse or bowel diversion. Other causes include clay pica, vomiting, and gastric suction (which removes HCl, causing the kidneys to excrete K). Rarely, villous adenoma of the colon causes massive K loss from the GI tract. GI K losses may be compounded by concomitant renal K losses due to metabolic alkalosis and stimulation of aldosterone due to volume depletion.

Intracellular shift

The transcellular shift of K into cells may also cause hypokalemia. This can occur in glycogenesis during TPN or enteral hyperalimentation or after administration of insulin. Stimulation of the sympathetic nervous system, particularly with β₂-agonists (eg, albuterol, terbutaline) may increase cellular K uptake. Similarly, severe hypokalemia occasionally occurs in thyrotoxic patients from excessive β-sympathetic stimulation (hypokalemic thyrotoxic periodic paralysis). Familial periodic paralysis (see Inherited Muscular Disorders: Familial Periodic Paralysis) is a rare autosomal dominant disease characterized by transient episodes of profound hypokalemia thought to be due to sudden abnormal shifts of K into cells. Episodes frequently involve varying degrees of paralysis. They are typically precipitated by a large carbohydrate meal or strenuous exercise, but variants have been described without these features.

Renal losses

Various disorders can increase renal K excretion. Excretion can increase in adrenal steroid excess due to direct mineralocorticoid effects on K secretion by the distal nephron. Cushing's syndrome, primary hyperaldosteronism, rare renin-secreting tumors, glucocorticoid-remediable aldosteronism (a rare inherited disorder involving abnormal aldosterone metabolism), and congenital adrenal hyperplasia can cause hypokalemia from excess mineralocorticoid formation. Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSDH) prevents the conversion of cortisol, which has some mineralocorticoid activity, to cortisone, which does not. Substances such as glycyrrhizin (found in natural licorice and used in the manufacture of chewing tobacco) inhibit 11β-HSDH, resulting in high circulating levels of cortisol and renal K wasting.

Liddle syndrome (see also Abnormal Renal Transport Syndromes: Liddle Syndrome) is a rare autosomal dominant disorder characterized by severe hypertension and hypokalemia. Liddle syndrome is caused by unrestrained Na reabsorption in the distal nephron due to one of several mutations found in genes encoding for epithelial Na channel subunits. Inappropriately high reabsorption of Na results in both hypertension and renal K wasting.

Bartter and Gitelman's syndromes are uncommon genetic disorders characterized by renal K and Na wasting, excessive production of renin and aldosterone, and normotension. Bartter syndrome (see also Abnormal Renal Transport Syndromes: Bartter Syndrome) is caused by mutations in a loop diuretic–sensitive ion transport mechanism in the loop of Henle. Gitelman's syndrome is caused by loss of function mutations in a thiazide-sensitive ion transport mechanism in the distal nephron.

Renal K wasting can also be caused by numerous congenital and acquired renal tubular diseases, such as the renal tubular acidoses and Fanconi syndrome, an unusual syndrome resulting in renal wasting of K, glucose, phosphate, uric acid, and amino acids.

Drugs

Diuretics are by far the most commonly used drugs that cause hypokalemia. K-wasting diuretics that block Na reabsorption proximal to the distal nephron include thiazides, loop diuretics, and osmotic diuretics. By inducing diarrhea, laxatives, especially when abused, can cause hypokalemia. Surreptitious diuretic and/or laxative abuse is a frequent cause of persistent hypokalemia, particularly among patients preoccupied with weight loss and among health care practitioners with access to prescription drugs.

Other drugs that can cause hypokalemia include amphotericin B, antipseudomonal penicillins (eg, carbenicillin), and high-dose penicillin. Finally, hypokalemia occurs in both acute and chronic theophylline intoxication.

Symptoms and Signs

Mild hypokalemia (plasma K 3 to 3.5 mEq/L) rarely causes symptoms. Plasma K < 3 mEq/L generally produces muscle weakness and may lead to paralysis and respiratory failure. Other muscular dysfunction includes cramping, fasciculations, paralytic ileus, hypoventilation, hypotension, tetany, and rhabdomyolysis. Persistent hypokalemia can impair renal concentrating ability, producing polyuria with secondary polydipsia.

Cardiac effects of hypokalemia are usually minimal until plasma K levels are < 3 mEq/L. Hypokalemia produces sagging of the ST segment, depression of the T wave, and elevation of the U wave. With marked hypokalemia, the T wave becomes progressively smaller and the U wave becomes increasingly larger. Sometimes, a flat or positive T wave merges with a positive U wave, which may be confused with QT prolongation (see Fig. 2: Fluid and Electrolyte Metabolism: ECG patterns in hypokalemia and hyperkalemia.). Hypokalemia may produce premature ventricular and atrial contractions, ventricular and atrial tachyarrhythmias, and 2nd- or 3rd-degree atrioventricular block. Such arrhythmias become more severe with increasingly severe hypokalemia; eventually, ventricular fibrillation may occur. Patients with significant preexisting heart disease and/or those receiving digoxin are at risk of cardiac conduction abnormalities even from mild hypokalemia.

Fig. 2
ECG patterns in hypokalemia and hyperkalemia. (Serum K is in mEq/L.)

Diagnosis

Hypokalemia is diagnosed on the basis of a plasma or serum K level < 3.5 mEq/L. If the cause is not apparent by history (in particular, the drug history), further investigation is warranted. After acidosis and other causes of intracellular K shift have been eliminated, 24-h urinary K is measured. In hypokalemia, K secretion is normally < 15 mEq/L. Extrarenal (GI) K loss or decreased K ingestion is suspected in chronic unexplained hypokalemia when renal K secretion is < 15 mEq/L. Secretion of ≥ 15 mEq/L suggests a renal cause for K loss. Unexplained hypokalemia with increased renal K secretion and hypertension suggests an aldosterone-secreting tumor or Liddle syndrome. Hypokalemia with increased renal K loss and normal BP suggests Bartter syndrome, but hypomagnesemia, surreptitious vomiting, and diuretic abuse are more common and should also be considered.

Treatment and Prevention

Many oral K supplements are available. Because they cause GI irritation and occasional bleeding, they are usually given in divided doses. Liquid KCl given orally elevates levels within 1 to 2 h, but it is poorly tolerated in doses > 25 to 50 mEq due to bitter taste. Wax-impregnated KCl preparations are safe and better tolerated. GI bleeding may be even less common with microencapsulated KCl preparations. Several preparations containing 8 or 10 mEq/capsule are available.

When hypokalemia is severe, is unresponsive to oral therapy, or occurs in hospitalized patients with active disease, K must be replaced parenterally. Because K solutions can irritate peripheral veins, the concentration should not exceed 40 mEq/L. The rate of correction of hypokalemia is limited because of the lag in K movement into cells. Routine infusion rates should not exceed 10 mEq/h. In hypokalemic-induced arrhythmia, IV KCl must be given more rapidly, usually through a central vein or using multiple peripheral veins simultaneously. Infusion of 40 mEq KCl/h can be undertaken but only with continuous cardiac monitoring and hourly plasma K determinations. Glucose solutions are avoided because elevation in the plasma insulin levels could result in transient worsening of hypokalemia.

In K deficit with high plasma K concentration, as in diabetic ketoacidosis, IV K is deferred until the plasma K starts to fall. Even when K deficits are severe, it is rarely necessary to give > 100 to 120 mEq of K in a 24-h period unless K loss continues. When hypokalemia occurs with hypomagnesemia, both the K and Mg deficiencies must be corrected to stop ongoing renal K wasting (see Fluid and Electrolyte Metabolism: Hypomagnesemia).

Routine K replacement is not necessary in most patients receiving diuretics. However, plasma K should be monitored when diuretics are used, particularly in patients with decreased left ventricular function, receiving digoxin, with diabetes, and with asthma who are receiving β₂-agonists. Triamterene 100 mg po once/day or spironolactone 25 mg po qid do not increase K excretion and may be useful in patients who become hypokalemic but must use diuretics. If hypokalemia develops, K supplementation is indicated. When plasma K is < 3 mEq/L, oral KCl supplementation is often necessary. Because a decrease in plasma K of 1 mEq/L correlates with a 200- to 400-mEq deficit in total body K stores, usually 20 to 80 mEq/day in excess of any ongoing K losses should be given over several days to correct K deficits. The need for K supplementation may continue for several weeks during refeeding after prolonged starvation.

Hyperkalemia

Hyperkalemia is serum K concentration > 5.5 mEq/L resulting from excess total body K stores or abnormal movement of K out of cells. The usual cause is impairment of renal excretion; it can also occur in metabolic acidosis as in uncontrolled diabetes. Clinical manifestations are generally neuromuscular, resulting in muscle weakness and cardiac toxicity that, if severe, can degenerate to ventricular fibrillation or asystole. Diagnosis is by measuring serum or plasma K. Treatment involves giving a cation exchange resin and, in emergencies, Ca gluconate, insulin, and dialysis.

Etiology and Pathophysiology

Normal kidneys eventually excrete K loads, so sustained hyperkalemia usually implies diminished renal K excretion. Hyperkalemia also may be caused by transcellular movement of K out of cells in metabolic acidosis; hyperglycemia in the presence of insulin deficiency; moderately heavy exercise, particularly in the presence of β-blockade; digoxin intoxication; acute tumor lysis; acute intravascular hemolysis; or rhabdomyolysis. Much more unusual is hyperkalemic familial periodic paralysis, a rare inherited disorder characterized by episodic hyperkalemia due to sudden movement of K out of cells, usually precipitated by exercise (see Inherited Muscular Disorders: Familial Periodic Paralysis).

Hyperkalemia from total body K excess is particularly common in oliguric states (especially acute renal failure) and with rhabdomyolysis, burns, bleeding into soft tissue or the GI tract, and adrenal insufficiency. In chronic renal failure, hyperkalemia is uncommon until the GFR falls to < 10 to 15 mL/min unless dietary K intake is excessive or another source of excess K load is present, such as oral or parenteral K therapy, GI bleeding, tissue injury, or hemolysis. Other potential causes of hyperkalemia in chronic renal failure are hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis), ACE inhibitors, K-sparing diuretics, fasting (suppression of insulin secretion), β-blockers, and NSAIDs. If sufficient KCl is ingested or given parenterally, severe hyperkalemia may result even with normal renal function. Causes are usually iatrogenic, such as giving K supplements to patients taking ACE inhibitors. Other drugs that may limit renal K output, thereby producing hyperkalemia, include cyclosporine, lithium, heparin, and trimethoprim.

Symptoms and Signs

Although flaccid paralysis occasionally occurs, hyperkalemia is usually asymptomatic until cardiac toxicity develops (see Fig. 2: Fluid and Electrolyte Metabolism: ECG patterns in hypokalemia and hyperkalemia.). Initial ECG changes occur with K > 5.5 mEq/L, characterized by shortening of the QT interval and tall, symmetric, peaked T waves. K > 6.5 mEq/L produces nodal and ventricular arrhythmias, widening of the QRS complex, PR interval prolongation, and disappearance of the P wave. Finally, the QRS complex degenerates into a sine wave pattern, and ventricular fibrillation or asystole ensues.

In the rare disorder hyperkalemic familial periodic paralysis, weakness frequently develops during attacks and can progress to frank paralysis.

Diagnosis

The diagnosis is made by plasma K level > 5.5 mEq/L. Because severe hyperkalemia requires prompt treatment, it should be considered in patients at high risk, such as those with renal failure, advanced heart failure treated with ACE inhibitors and K-sparing diuretics, or symptoms of urinary obstruction, particularly if arrhythmias or other electrocardiographic signs of hyperkalemia are present.

Diagnosis of the cause of hyperkalemia includes review of drugs and measurement of electrolytes, BUN, and creatinine. In cases in which renal failure is present, additional tests, including a renal ultrasound to exclude obstruction, are needed (see Renal Failure: Diagnosis).

Treatment

Mild hyperkalemia

Patients with plasma K < 6 mEq/L and no ECG abnormalities may respond to diminished K intake or stopping K-elevating drugs. The addition of a loop diuretic enhances renal K excretion. Na polystyrene sulfonate in sorbitol can be given (15 to 30 g in 30 to 70 mL of 70% sorbitol po q 4 to 6 h). It acts as a cation exchange resin and removes K through the GI mucosa. Sorbitol is administered with the resin to ensure passage through the GI tract. Patients unable to take drugs orally because of ileus or other reasons may be given similar doses by enema. About 1 mEq of K is removed per gram of resin given. Resin therapy is slow and often fails to lower plasma K significantly in hypercatabolic states. Because Na is exchanged for K when Na polystyrene sulfonate is used, Na overload may occur, particularly in oliguric patients with preexisting volume overload.

Moderate to severe hyperkalemia

Plasma K > 6 mEq/L, especially with electrocardiographic changes, requires aggressive therapy to shift K into cells. The first 2 of the following measures are performed immediately:

1. Administration of 10 to 20 mL 10% Ca gluconate (or 5 to 10 mL 22% Ca gluceptate) IV over 5 to 10 min. Ca antagonizes the effect of hyperkalemia on cardiac muscle excitability. Caution should be used when giving Ca to patients taking digoxin because of the risk of precipitating hypokalemia-related arrhythmias. If the ECG has deteriorated to a sine wave or asystole, Ca gluconate may be given more rapidly (5 to 10 mL IV over 2 min). CaCl can also be used but can be irritating and should be given through a central venous catheter. The effect occurs within minutes but lasts only 20 to 30 min. Ca infusion is a temporizing measure while awaiting the effects of other treatments and may need to be repeated.
2. Administration of regular insulin 5 to 10 units IV followed immediately by or administered simultaneously with rapid infusion of 50 mL 50% glucose. Infusion of 10% D/W should follow at 50 mL/h to prevent hypoglycemia. The effect on plasma K peaks in 1 h and lasts for several hours.
3. A high-dose β-agonist, such as albuterol 10 to 20 mg inhaled over 10 min (5 mg/mL concentration) can safely lower plasma K by 0.5 to 1.5 mEq/L and may be a helpful adjunct. The peak effect occurs in 90 min.
4. Administration of IV NaHCO₃ is controversial. It may lower serum K over several hours. Reduction may result from alkalinization or the hypertonicity due to the concentrated Na in the preparation. The hypertonic Na that it contains may be harmful for dialysis patients who also may have volume overload. If given, the usual dose is 45 mEq (1 ampule of 7.5% NaHCO₃) infused over 5 min and repeated in 30 min. HCO₃ therapy has little effect when used by itself in patients with advanced renal insufficiency unless acidemia is also present.

In addition to the above strategies for lowering K by shifting it into cells, maneuvers to remove K from the body should also be performed early in the treatment of severe or symptomatic hyperkalemia. K can be removed via the GI tract by administration of Na polystyrene sulfonate (see Fluid and Electrolyte Metabolism: Mild hyperkalemia) or by hemodialysis. Hemodialysis should be instituted promptly after emergency measures in patients with renal failure or if emergency treatment is ineffective. Peritoneal dialysis is relatively inefficient at removing K.

Last full review/revision November 2005