Hypokalemia

Practice Essentials

Hypokalemia is generally defined as a serum potassium level of less than 3.5 mEq/L (3.5 mmol/L). Moderate hypokalemia is a serum level of 2.5-3.0 mEq/L, and severe hypokalemia is a level of less than 2.5 mEq/L.^[53] Hypokalemia is a potentially life-threatening imbalance that may be iatrogenically induced.

Hypokalemia may result from inadequate potassium intake, increased potassium excretion, or a shift of potassium from the extracellular to the intracellular space. Increased excretion is the most common mechanism. Poor intake or an intracellular shift by itself is a distinctly uncommon cause, but several causes often are present simultaneously. (See Etiology.)

Gitelman syndrome is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis and low blood pressure. See the image below.

View Image

A model of transport mechanisms in the distal convoluted tubule. Sodium-chloride (NaCl) enters the cell via the apical thiazide-sensitive NCC and leav....

Signs and symptoms

Patients are often asymptomatic, particularly those with mild hypokalemia. Symptoms that are present are often from the underlying cause of the hypokalemia rather than the hypokalemia itself. The symptoms of hypokalemia are nonspecific and predominantly are related to muscular or cardiac function. Complaints may include the following:

• Weakness and fatigue (most common)
• Muscle cramps and pain (severe cases)
• Worsening diabetes control or polyuria
• Palpitations
• Psychological symptoms (eg, psychosis, delirium, hallucinations, depression)

Physical findings are often within the reference range. Abnormal findings may reflect the underlying disorder. Severe hypokalemia may manifest as bradycardia with cardiovascular collapse. Cardiac arrhythmias and acute respiratory failure from muscle paralysis are life-threatening complications that require immediate diagnosis.

See Presentation for more detail.

Diagnosis

In most cases, the cause of hypokalemia is apparent from the history and physical examination. First-line studies include measurement of urine potassium, a serum magnesium assay, and an electrocardiogram (ECG). Measurement of urine potassium is of vital importance because it establishes the pathophysiologic mechanism and, thus, is used in formulating the differential diagnosis. This, in turn, will guide the choice of further tests.

If the urine potassium level is less than 20 mEq/L, consider the following:

• Diarrhea and use of laxatives
• Diet or total parenteral nutrition (TPN) contents
• The use of insulin, excessive bicarbonate supplements, and episodic weakness

If the urine potassium level is higher than 40 mEq/L, consider diuretics. If diuretic use has been excluded, measure arterial blood gases (ABG) and determine the acid-base balance. Alkalosis suggests one of the following:

• Vomiting
• Bartter syndrome
• Gitelman syndrome
• Mineralocorticoid excess

Depending on history, physical examination findings, clinical impressions, and urine potassium results, the following tests may be appropriate, but they should not be first-line tests unless the clinical index of suspicion for the disorder is high:

• Drug screen in urine and/or serum for diuretics, amphetamines, and other sympathomimetic stimulants
• Serum renin, aldosterone, and cortisol
• 24-hour urine aldosterone, cortisol, sodium, and potassium
• Pituitary imaging to evaluate for Cushing syndrome
• Adrenal imaging to evaluate for adenoma
• Evaluation for renal artery stenosis
• Enzyme assays for 17-beta hydroxylase deficiency
• Thyroid function studies in patients with tachycardia, especially Asians^[1]
• Serum anion gap (eg, to detect toluene toxicity)

See Workup for more detail.

Management

The treatment of hypokalemia has 4 facets, as follows:

• Reduction of potassium losses
• Replenishment of potassium stores
• Evaluation for potential toxicities
• Determination of the cause to prevent future episodes, if possible

Decreasing potassium losses

• Discontinue diuretics/laxatives
• Use potassium-sparing diuretics if diuretic therapy is required (eg, severe heart failure)
• Treat diarrhea or vomiting
• Administer H2 blockers to patients receiving nasogastric suction
• Control hyperglycemia if glycosuria is present

Replenishment

• For every 1 mEq/L decrease in serum potassium, the potassium deficit is approximately 200-400 mEq; however, this calculation could either overestimate or underestimate the true potassium deficit
• Patients with a potassium level of 2.5-3.5 mEq/L may need only oral potassium replacement
• If the potassium level is less than 2.5 mEq/L, intravenous (IV) potassium should be given, with close followup, continuous ECG monitoring, and serial potassium levels
• The serum potassium level is difficult to replenish if the serum magnesium level is also low

Surgical care

Surgical intervention is required only with certain etiologies, such as the following:

• Renal artery stenosis
• Adrenal adenoma
• Intestinal obstruction producing massive vomiting
• Villous adenoma

See Treatment and Medication for more detail.

• References

Pathophysiology

Potassium, the most abundant intracellular cation, is essential for the life of an organism. Potassium homeostasis is integral to normal cellular function, particularly of nerve and muscle cells, and is tightly regulated by specific ion-exchange pumps, primarily by cellular, membrane-bound, sodium-potassium adenosine triphosphatase (ATPase) pumps.^[2]

Potassium is obtained through the diet. Gastrointestinal absorption of potassium is complete, resulting in daily excess intake of approximately 1 mEq/kg/day (60-100 mEq). Of this excess, 90% is excreted through the kidneys, and 10% is excreted through the gut.

Potassium homeostasis is maintained predominantly through the regulation of renal excretion; the adrenal gland and pancreas also play significant roles. The most important site of regulation is the renal collecting duct, where aldosterone receptors are present.

Potassium excretion is increased by the following factors:

• Aldosterone
• High sodium delivery to the collecting duct (eg, diuretics)
• High urine flow (eg, osmotic diuresis)
• High serum potassium levels
• Delivery of negatively charged ions to the collecting duct (eg, bicarbonate)

Potassium excretion is decreased by the following factors:

• Absolute aldosterone deficiency or resistance to aldosterone effects
• Low sodium delivery to the collecting duct
• Low urine flow
• Low serum potassium levels
• Renal failure

An acute increase in osmolality causes potassium to exit from cells. An acute cell/tissue breakdown releases potassium into extracellular space.

Renal factors in potassium homeostasis

Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion likewise is increased. In the absence of potassium intake, however, obligatory renal losses are 10-15 mEq/day. Thus, chronic losses occur in the absence of any ingested potassium.

The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min.

Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases. The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load.

Potassium distribution

Potassium is predominantly an intracellular cation; therefore, serum potassium levels can be a very poor indicator of total body stores. Because potassium moves easily across cell membranes, serum potassium levels reflect movement of potassium between intracellular and extracellular fluid compartments, as well as total body potassium homeostasis.

Several factors regulate the distribution of potassium between the intracellular and extracellular space, as follows:

• Glycoregulatory hormones: (1) Insulin enhances potassium entry into cells, and (2) glucagon impairs potassium entry into cells
• Adrenergic stimuli: (1) Beta-adrenergic stimuli enhance potassium entry into cells, and (2) alpha-adrenergic stimuli impair potassium entry into cells
• pH: (1) Alkalosis enhances potassium entry into cells, and (2) acidosis impairs potassium entry into cells

Physiologic mechanisms for sensing extracellular potassium concentration are not well understood. Adrenal glomerulosa cells and pancreatic beta cells may play a role in potassium sensing, resulting in alterations in aldosterone and insulin secretion.^{[3, 4]} As the adrenal and pancreatic hormonal systems play important roles in potassium homeostasis, this would not be surprising; however, the molecular mechanisms by which these potassium channels signal changes in hormone secretion and activity have still not been determined.

Muscle contains the bulk of body potassium, and the notion that muscle could play a prominent role in the regulation of serum potassium concentration through alterations in sodium pump activity has been promoted for a number of years. Potassium ingestion stimulates the secretion of insulin, which increases the activity of the sodium pump in muscle cells, resulting in an increased uptake of potassium.

Studies in a model of potassium deprivation demonstrate that acutely, skeletal muscle develops resistance to insulin-stimulated potassium uptake even in the absence of changes in muscle cell sodium pump expression. However, prolonged potassium deprivation leads to a decrease in muscle cell sodium-pump expression, resulting in decreased muscle uptake of potassium.^{[5, 6, 7]}

Thus, there appears to be a well-developed system for sensing potassium by the pancreas and adrenal glands. High potassium states stimulate cellular uptake via insulin-mediated stimulation of sodium-pump activity in muscle and stimulate potassium secretion by the kidney via aldosterone-mediated enhancement of distal renal expression of secretory potassium channels (ROMK).

Low potassium states result in insulin resistance, impairing potassium uptake into muscle cells, and cause decreased aldosterone release, lessening renal potassium excretion. This system results in rapid adjustments in immediate potassium disposal and helps to provide long-term potassium homeostasis.

Pathogenic mechanisms

Hypokalemia can occur via the following pathogenetic mechanisms:

• Deficient intake
• Increased excretion
• A shift from the extracellular to the intracellular space

Although poor intake or an intracellular shift by itself is a distinctly uncommon cause, several causes often are present simultaneously.

Increased excretion

The most common mechanisms leading to increased renal potassium losses include the following:

• Enhanced sodium delivery to the collecting duct, as with diuretics
• Mineralocorticoid excess, as with primary or secondary hyperaldosteronism
• Increased urine flow, as with an osmotic diuresis

Gastrointestinal losses, from diarrhea, vomiting, or nasogastric suctioning, also are common causes of hypokalemia. Vomiting leads to hypokalemia via a complex pathogenesis. Gastric fluid itself contains little potassium, approximately 10 mEq/L. However, vomiting produces volume depletion and metabolic alkalosis, which are accompanied by increased renal potassium excretion.

Volume depletion leads to secondary hyperaldosteronism, which in turn leads to enhanced cortical collecting tubule secretion of potassium in response to enhanced sodium reabsorption. Metabolic alkalosis also increases collecting tubule potassium secretion due to the decreased availability of hydrogen ions for secretion in response to sodium reabsorption.

Extracellular/intracellular shift

Hypokalemia caused by a shift from extracellular to intracellular space often accompanies increased excretion, leading to a potentiation of the hypokalemic effect of excessive loss. Intracellular shifts of potassium often are episodic and frequently are self-limited, as, for example, with acute insulin therapy for hyperglycemia.

Additional considerations

Regardless of the cause, hypokalemia produces similar signs and symptoms. Because potassium is overwhelmingly an intracellular cation and a variety of factors can regulate the actual serum potassium concentration, an individual can incur very substantial potassium losses without exhibiting frank hypokalemia. For example, diabetic ketoacidosis results in a significant potassium deficit; however, serum potassium in a patient presenting with diabetic ketoacidosis is rarely low and frequently is frankly elevated.

Conversely, hypokalemia does not always reflect a true deficit in total body potassium stores. Acute insulin administration can drive potassium into cells transiently, producing short-lived hypokalemia but not signifying potassium depletion.

Complications

Cardiovascular complications

Hypokalemia has widespread actions in many organ systems that, over time, may result in cardiovascular disease. Cardiovascular complications are clinically the most important harbingers of significant morbidity or mortality from hypokalemia.

Although hypokalemia has been implicated in the development of atrial and ventricular arrhythmias, ventricular arrhythmias have received the most attention. Even moderate hypokalemia may inhibit the sodium-potassium pump in myocardial cells, promoting spontaneous early afterdepolarizations that lead to ventricular tachycardia/fibrillation.^[8]

Increased susceptibility to cardiac arrhythmias is observed with hypokalemia in the following settings:

• Chronic heart failure
• Underlying ischemic heart disease/acute myocardial ischemia
• Aggressive therapy for hyperglycemia, such as with diabetic ketoacidosis
• Digitalis therapy
• Treatment with class III antiarrhythmic drugs (eg, dofetilide)^[8]
• Methadone therapy^[9]
• Conn syndrome^[10]

Low potassium intake has been implicated as a risk factor for the development of hypertension and/or hypertensive end-organ damage. Hypokalemia leads to altered vascular reactivity, likely from the effects of potassium depletion on the expression of adrenergic receptors, angiotensin receptors, and mediators of vascular relaxation. The result is enhanced vasoconstriction and impaired relaxation, which may play a role in the development of diverse clinical sequelae, such as ischemic central nervous system events or rhabdomyolysis.

Treatment of hypertension with diuretics without due attention to potassium homeostasis exacerbates the development of end-organ damage by fueling the metabolic abnormalities. These patients are then at higher risk for lethal hypokalemia under stress conditions such as myocardial infarction, septic shock, or diabetic ketoacidosis.

Muscular complications

Muscle weakness, depression of the deep-tendon reflexes, and even flaccid paralysis can complicate hypokalemia. Rhabdomyolysis can be provoked, especially with vigorous exercise. However, rhabdomyolysis has also been seen as a complication of severe hypokalemia, complicating primary hyperaldosteronism in the absence of exercise.^[11]

Renal complications

Abnormalities of renal function often accompany acute or chronic hypokalemia. These may include nephrogenic diabetes insipidus. They also may include metabolic alkalosis from impaired bicarbonate excretion and enhanced ammoniagenesis, as well as cystic degeneration and interstitial scarring.

Gastrointestinal complications

Hypokalemia decreases gut motility, which can lead to or exacerbate an ileus. Hypokalemia also is a contributory factor in the development of hepatic encephalopathy in the setting of cirrhosis.

Metabolic complications

Hypokalemia has a dual effect on glucose regulation by decreasing insulin release and peripheral insulin sensitivity. Clinical evidence suggests that the hypokalemic effect of thiazide is the causative factor in thiazide-associated diabetes mellitus.^[12]

• References

Etiology

As mentioned, hypokalemia can result from inadequate potassium intake, increased potassium excretion, or a shift of potassium from the extracellular to the intracellular space. Increased excretion is the most common mechanism. Poor intake or an intracellular shift by itself is a distinctly uncommon cause, but several causes often are present simultaneously.

Inadequate potassium intake

Inadequate potassium intake may result from any of the following:

• Eating disorders^[13] : Anorexia, bulimia, starvation, pica, and alcoholism
• Dental problems: Impaired ability to chew or swallow
• Poverty: Inadequate quantity or quality of food (eg, "tea-and-toast" diet of elderly individuals)
• Hospitalization: Potassium-poor TPN

Increased potassium excretion

Increased excretion of potassium, especially coupled with poor intake, is the most common cause of hypokalemia. Increased potassium excretion may result from any of the following:

• Mineralocorticoid excess (endogenous or exogenous)
• Hyperreninism from renal artery stenosis
• Osmotic diuresis: Mannitol and hyperglycemia can cause osmotic diuresis
• Increased gastrointestinal losses
• Drugs
• Genetic disorders

Endogenous sources of excess mineralocorticoid include the following:

• Cushing syndrome
• Primary hyperaldosteronism, most commonly from an adrenal adenoma or bilateral adrenal hyperplasia
• Secondary hyperaldosteronism from volume depletion, congestive heart failure, cirrhosis, or vomiting
• Tumor that is producing adrenocorticotropic hormone
• Genetic disorders

Exogenous causes of mineralocorticoid excess include the following:

• Steroid therapy for immunosuppression
• Glycyrrhizic acid - Inhibits 11-beta hydroxysteroid dehydrogenase; contained in licorice and Chinese herbal preparations
• Renal tubular disorders - Type I and type II renal tubular acidosis
• Hypomagnesemia

Gastrointestinal loss of potassium can result from vomiting, diarrhea, or small intestine drainage. The problem can be particularly prominent in tropical illnesses, such as malaria and leptospirosis.^[14] Severe hypokalemia has also been reported with villous adenomas and VIPomas.^[15]

Drugs that can cause hypokalemia include the following:

• Diuretics (carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics): Increased collecting duct permeability or increased gradient for potassium secretion can result in losses
• Methylxanthines (theophylline, aminophylline, caffeine)
• Verapamil (with overdose)
• Quetiapine (particularly in overdose)
• Ampicillin, carbenicillin, high-dose penicillins
• Bicarbonate
• Antifungal agents (amphotericin B, azoles, echinocandins)^{[16, 17]}
• Gentamicin
• Cisplatin
• Ephedrine (from Ephedra; banned in the United States, but available over the Internet)^[18]
• Beta-agonist intoxication^[19]

Genetic disorders

The following genetic disorders may result in hypokalemia:

• Congenital adrenal hyperplasia (11-beta hydroxylase or 17-alpha hydroxylase deficiency)
• Glucocorticoid-remediable hypertension
• Bartter syndrome
• Gitelman syndrome
• Liddle syndrome
• Gullner syndrome
• Glucocorticoid receptor deficiency
• Hypokalemic period paralysis
• Thyrotoxic periodic paralysis (TTPP)
• Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome)

Bartter syndrome

Bartter syndrome is a group of autosomal recessive disorders characterized by hypokalemic metabolic alkalosis and hypotension.^[20] Sensorineural hearing loss is also a feature of this syndrome. Mutations in 6 different renal tubular proteins in the loop of Henle have been discovered in individuals with clinical Bartter syndrome.^{[21, 22]}

Antenatal Bartter syndrome types 1, 2, 3, and 4A are inherited in an autosomal recessive manner. They result from the following mutations:

• Type 1 is caused by mutation in the Na-K-2Cl cotransporter NKCC2 gene
• Type 2 is caused by a mutation in the adenosine triphosphate (ATP)–sensitive potassium channel ROMK gene
• Type 3 is caused by mutations in the kidney chloride channel B CLCNKB gene^[23]
• Type 4A is caused by mutation in the BSND gene; it can also be associated with hearing loss

Bartter syndrome 4B is caused by mutations in both the CLCNKA and the CLCNKB gene, giving it a unique digenic mode of inheritance.

Autosomal dominant hypocalcemia (ADH) is caused by mutations in the calcium-sensing receptor gene CASR. ADH is characterized by hypocalcemia and hypoparathyroidism; when accompanied by hypokalemia and metabolic alkalosis, it is classified as type 5 Bartter syndrome.^[24] Four activating CASR mutations have been identified in Bartter syndrome type 5.^[25]

The most severe cases of Bartter syndrome manifest antenatally or neonatally as profound volume depletion and hypokalemia. Patients with less severe cases present in childhood or early adulthood with persistent hypokalemic metabolic alkalosis that is resistant to replacement therapy. In general, however, onset of true Bartter syndrome occurs by age 5 years.

Gitelman syndrome

Gitelman syndrome is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis and low blood pressure. It is caused by a defect in the thiazide-sensitive sodium chloride transporter in the distal tubule, which is encoded by the SLC12A3 gene (see the image below).

View Image

A model of transport mechanisms in the distal convoluted tubule. Sodium-chloride (NaCl) enters the cell via the apical thiazide-sensitive NCC and leav....

Compared with Bartter syndrome, Gitelman syndrome generally is milder and presents later; in addition, Gitelman syndrome is complicated by hypomagnesemia, which generally does not occur in Bartter syndrome. Hypocalciuria is also frequently found in Gitelman syndrome, while patients with Bartter syndrome are more likely to have increased urine calcium excretion.

Liddle syndrome

Liddle syndrome is an autosomal recessive disorder characterized by a mutation affecting either the beta or gamma subunit of the epithelial sodium channel in the aldosterone-sensitive portion of the nephron. These subunits are encoded by the SCNN1G and SCNN1B genes and are inherited in an autosomal dominant fashion.

Mutations to these genes lead to unregulated sodium reabsorption, hypokalemic metabolic alkalosis, and severe hypertension. It has been shown that amiloride and triamterene are effective treatments for Liddle syndrome, but spironolactone is not.^[26]

Gullner syndrome

Gullner syndrome, first described in the 1970s after being diagnosed in 2 brothers, was reported to be a “new” form of familial hypokalemia.^[27] Three additional siblings were also found to have elevated renin and decreased potassium levels. The 2 brothers had fatigue and muscle cramps. One responded to a low-sodium diet, and the other required use of a potassium-sparing diuretic. Additional patients were described in 1980 and 1983.^{[28, 29]}

This syndrome was described as being like Bartter syndrome, except that renal histology showed normal juxtaglomerular apparatus and changes to the proximal tubules. Although the locus for the gene associated with Gullner syndrome showed linkage to the HLA-A and HLA-B genes, its identity is still unknown.

Glucocorticoid receptor deficiency syndrome

Glucocorticoid receptor deficiency syndrome is caused by mutations to the NR3C1 gene and has different clinical manifestations in patients who are homozygous than it does in those who are heterozygous. Homozygotes for this condition display mineralocorticoid excess, hypertension, hypokalemia, and metabolic alkalosis.

Heterozygotes may have increased plasma cortisol levels and generally do not have hypokalemia or metabolic alkalosis. However, several reports in the literature have described likely heterozygotes for this condition who have symptoms of either partial adrenal insufficiency or mild virilization in females.^{[30, 31]}

Hypokalemic periodic paralysis

Hypokalemic periodic paralysis types 1 and 2 are caused by mutations in the CACNL1A3 and SCN4A genes, respectively, and are both inherited in an autosomal dominant fashion. Patients with this disorder experience episodes of flaccid, generalized weakness, usually without myotonia. Patients will have hypokalemia during the flaccid attacks. The disorder is treated by administration of potassium and can be precipitated by a large glucose or insulin load, as both forms tend to drive potassium from the extracellular to the intracellular space.

Thyrotoxic periodic paralysis (TTPP)

TTPP is a form of hypokalemic periodic paralysis in which episodes of weakness associated with hypokalemia are seen in individuals with hyperthyroidism. TTPP is most common in Asian males.

The mechanism by which hyperthyroidism produces hypokalemic paralysis is not yet understood, but theories include increased Na-K-ATPase activity, which has been found in patients with both thyrotoxicosis and paralysis. Three single-nucleotide polymorphisms in 3 different regions of the CACNA1S gene have been associated with increased rates of TTPP, compared with normal controls or patients with Graves disease.^[32]

SeSAME syndrome

In addition to seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance, some patients with SeSAME syndrome will have short stature, salt craving with polydipsia, renal potassium and sodium wasting, and polyuria. Hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis are seen.

This syndrome is caused by mutations in the KCNJ10 gene, which encodes an inwardly rectifying potassium channel. It is inherited in an autosomal recessive fashion.^[33]

Shift of potassium from extracellular to intracellular space

A shift of potassium to the intracellular space may result from any of the following:

• Alkalosis (metabolic or respiratory)
• Insulin administration or glucose administration (the latter stimulates insulin release)
• Intensive beta-adrenergic stimulation
• Hypokalemic periodic paralysis
• Thyrotoxic periodic paralysis
• Refeeding: This is observed in prolonged starvation, eating disorders, and alcoholism
• Hypothermia

• References

Epidemiology

The frequency of hypokalemia in the general population is difficult to estimate; however, probably fewer than 1% of people who are not taking medication have a serum potassium level lower than 3.5 mEq/L. Potassium intake varies according to age, sex, ethnic background, and socioeconomic status. Whether these differences in intake produce different degrees of hypokalemia or different sensitivities to hypokalemic insults is not known.

An observational study of patients in a large Swedish healthcare system found that hypokalemia occurred in 49,662 (13.6%) of 364,955 individuals, with 33% recurrence. Female sex, younger age, higher estimate glomerular filtration rate, and baseline use of diuretics were associated with higher hypokalemia risk.^[49]

Up to 21% of hospitalized patients have serum potassium levels lower than 3.5 mEq/L, with 5% of patients exhibiting potassium levels lower than 3 mEq/L. Among elderly patients, 5% demonstrate potassium levels lower than 3 mEq/L.

Of patients taking non–potassium-sparing diuretics, 20-50% develop hypokalemia. African Americans and women are more susceptible. The higher frequency of hypokalemia in the former group may be from lower intake of potassium in African-American men (approximately 25 mEq/day) than in their white counterparts (70-100 mEq/day). Risk of hypokalemia in patients taking diuretics is enhanced by concomitant illness, such as heart failure or nephrotic syndrome.

Other factors associated with a high incidence of hypokalemia include the following:

• Eating disorders (incidence of 4.6-19.7% in an outpatient setting^{[34, 35]} )
• AIDS (23.1% of hospitalized patients)^[36]
• Alcoholism (incidence reportedly as high as 12.6%^[37] in the inpatient setting), likely from a hypomagnesemia-induced decrease in tubular reabsorption of potassium
• Bariatric surgery^[38]

The frequency of hypokalemia increases with age because of increased use of diuretics and potassium-poor diets. However, infants and younger children are more susceptible to viral GI infections; emesis or diarrhea from such infections places them at increased risk for hypokalemia because the depletion of fluid volume and electrolytes from GI loss is relatively higher than that in older children and adults.

Hypokalemia generally is associated with higher morbidity and mortality, especially from cardiac arrhythmias or sudden cardiac death. However, an independent contribution of hypokalemia to increased morbidity/mortality has not been conclusively established. Patients who develop hypokalemia often have multiple medical problems, making the separation and quantitation of the contribution by hypokalemia, per se, difficult.

• References

Patient Education

Instruct patients on the symptoms of hypokalemia or hyperkalemia, as follows:

• Palpitations or notable cardiac arrhythmias
• Muscle weakness
• Increasing difficulty with diabetes control
• Polyuria

Instruct patients on the effects of medications; specifically, which of their drugs will produce serum potassium abnormalities in either direction. For example, tell patients to discontinue diuretics if nausea and vomiting or diarrhea occurs and to call the physician if such gastrointestinal losses persist. Depending on patients' underlying disease or diseases, sudden fluid losses can result in either hypokalemia or hyperkalemia if diuretics, potassium supplements, or antihypertensives are continued.

Diet modification is recommended for those patients who are predisposed to hypokalemia. High sodium intake tends to enhance renal potassium losses. Therefore, instruct patients about the establishment of a low-sodium, high-potassium diet. Bananas, tomatoes, oranges, and peaches are high in potassium.

For patient education information, see Low Potassium (Hypokalemia).

• References

Prognosis

The prognosis for patients with hypokalemia depends entirely on the condition’s underlying cause. For example, a patient with an acute episode of hypokalemia resulting from diarrhea has an excellent prognosis. Hypokalemia due to a congenital disorder such as Bartter syndrome has a poor to nonexistent potential for resolution.

• References

History

The symptoms of hypokalemia are nonspecific and predominantly are related to muscular or cardiac function. Weakness and fatigue are the most common complaints. The muscular weakness that occurs with hypokalemia can manifest in protean ways (eg, dyspnea, constipation or abdominal distention, exercise intolerance). Rarely, muscle weakness progresses to frank paralysis. With severe hypokalemia or total body potassium deficits, muscle cramps and pain can occur with rhabdomyolysis.

Occasionally, a patient may complain of worsening diabetes control or polyuria due to a recent onset of hyperglycemia or nephrogenic diabetes insipidus. Patients also may complain of palpitations. Psychological symptoms may include psychosis, delirium, hallucinations, and depression.^[52]

Patients are often asymptomatic, particularly with mild hypokalemia. Symptoms that are present are often from the underlying cause of the hypokalemia rather than the hypokalemia itself.

When the diagnosis of hypokalemia is discovered, investigate potential pathophysiologic mechanisms.

Poor intake may result from the following:

• Eating disorders
• Dental problems
• Poverty

Increased excretion may be due to the following:

• Medications (eg, diuretics, antiretroviral agents, antibiotics; see Etiology)
• Polyuria
• Vomiting or diarrhea

Shift of potassium into the intracellular space may occur due to the following:

• Recurrent episodes of paralysis
• Use of high doses of insulin
• High-dose beta-agonist therapy (eg, for chronic obstructive pulmonary disease)

Ask whether the patient has had similar episodes in the past. Familial historical data may include surgery for pituitary or adrenal tumors or acute intermittent episodes of paralysis, with or without association with hyperthyroidism.

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Physical Examination

Physical examination findings are often within the reference range. Vital signs generally are normal, except for occasional tachycardia with irregular beats or tachypnea resulting from respiratory muscle weakness. Hypertension may be a clue to primary hyperaldosteronism, renal artery stenosis, licorice ingestion, or the more unusual forms of genetically transmitted hypertensive syndromes, such as congenital adrenal hyperplasia, glucocorticoid-remediable hypertension, or Liddle syndrome.

Relative hypotension should suggest occult laxative use, diuretic use, bulimia, or one of the unusual tubular disorders, such as Bartter syndrome or Gitelman syndrome. Bear in mind that occult diuretic use is far more common than either of those congenital tubular disorders and is, in fact, also called "pseudo-Bartter syndrome."

Muscle weakness and flaccid paralysis may be present. Patients may have depressed or absent deep-tendon reflexes. Hypoactive bowel sounds may suggest hypokalemic gastric hypomotility or ileus.

Severe hypokalemia may manifest as bradycardia with cardiovascular collapse. Cardiac arrhythmias and acute respiratory failure from muscle paralysis are life-threatening complications that require immediate diagnosis.

Tooth erosion may be present in patients with bulimia. This finding has particular significance in patients whose history indicates high risk (eg, obsession with body image or participation in activities such as cheerleading, wrestling, or modeling).

• References

Approach Considerations

Hypokalemia is defined as a condition in which the serum potassium level is less than 3.5 mEq/L (3.5 mmol/L).^[39] By far the most common causes of hypokalemia are potassium losses caused by diuretics or gastrointestinal disorders.

In most cases, the cause of hypokalemia is apparent from the history and physical examination. However, measurement of urine potassium is of vital importance because it establishes the pathophysiologic mechanism behind hypokalemia and, thus, aids in formulating the differential diagnosis. A serum magnesium assay is also important in the differential diagnosis, as well as in therapy, and is therefore performed as a first-line test.

Perform an electrocardiogram (ECG) to determine whether the hypokalemia is affecting cardiac function or to detect digoxin toxicity. The ECG may show atrial or ventricular tachyarrhythmias, decreased amplitude of the P wave, or appearance of a U wave.

Depending on history, physical examination findings, clinical impressions, and urine potassium results, the following tests may be appropriate. They should not be first-line tests, however, unless the clinical index of suspicion for the disorder is high:

• Drug screen in urine and/or serum for diuretics, amphetamines, and other sympathomimetic stimulants
• Serum renin, aldosterone, and cortisol
• 24-hour urine aldosterone, cortisol, sodium, and potassium
• Pituitary imaging to evaluate for Cushing syndrome
• Adrenal imaging to evaluate for adenoma
• Evaluation for renal artery stenosis
• Enzyme assays for 17-beta hydroxylase deficiency
• Thyroid function studies in patients with tachycardia, especially Asians^[1]
• Serum anion gap (eg, to detect toluene toxicity)

Simultaneous serum insulin and C-peptide tests can detect covert insulin use, which may occur in Münchhausen or Münchhausen-by-proxy syndrome. An elevated serum insulin level without an appropriately elevated C-peptide level suggests exogenous insulin administration.

• References

Urine Potassium and Other Electrolytes

Urine potassium

A urine potassium assay establishes the pathophysiologic mechanism of hypokalemia. A spot urine potassium measurement is, for obvious reasons, the easiest and most commonly obtained test. Low urine potassium (< 20 mEq/L) suggests gastrointestinal loss, poor intake, or a shift of extracellular potassium into intracellular space. High urine potassium (>40 mEq/L) suggests renal loss.

If the urine potassium level is less than 20 mEq/L, question the patient regarding the following:

• Diarrhea and use of laxatives
• Diet or total parenteral nutrition (TPN) contents
• The use of insulin, excessive bicarbonate supplements, and episodic weakness

If the urine potassium level is higher than 40 mEq/L, examine the patient's medication list and question the patient regarding the use of diuretics.

Urine potassium in 24 hours

While more cumbersome to obtain, a 24-hour urine measurement of potassium excretion yields more precise data on how much potassium is being lost through renal excretion. Because the kidneys can conserve up to approximately 10-15 mEq of potassium per day, a value of less than 20 mEq on a 24-hour urine specimen suggests appropriate renal conservation of potassium, while values above that indicate some degree of renal wasting. To ensure that a full and accurate 24-hour urine sample has been collected, urine creatinine should be measured simultaneously.

Urine sodium

A spot urine sodium and osmolality test obtained simultaneously with a spot urine potassium test can help to refine the interpretation of the urine potassium level. A low urine sodium level (< 20 mEq/L) with a high urine potassium level suggests the presence of secondary hyperaldosteronism.

Urine sodium:chloride ratio

Wu et al reported that urinary levels of sodium (Na⁺) and chloride (Cl^-) were high and coupled (Na⁺: Cl^- ratio ∼1) in patients with renal tubular disorders and those using diuretics, but urinary Na⁺: Cl^- ratios were skewed or uncoupled in patients with anorexia/bulimia nervosa (5.0 ± 2.2) and in patients abusing laxatives (0.4 ± 0.2).^[50]

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Urine Osmolality

If the urine osmolality is high (>700 mOsm/kg), then the absolute value of the urine potassium concentration can be misleading and can suggest that the kidneys are wasting potassium. For example, suppose the serum potassium level is 3 mEq/L and the urine potassium level is 60 mEq/L. The high urine potassium level would suggest renal potassium loss. However, the final concentration of potassium in the urine is dependent not only on the quantity of potassium secreted in response to sodium reabsorption, but also on the concentration of the urine.

In the above example, if urine osmolality is 300 mOsm/kg (ie, not concentrated relative to serum), then a measured urine potassium of 60 mEq/L indeed suggests renal potassium loss.

However, if the urine osmolality is 1200 mOsm/kg (ie, concentrated 4-fold relative to serum), then the 60-mEq/L potassium concentration would, in the absence of urinary concentration due to water reabsorption, be only 15 mEq/L (ie, very low). The conclusion would then be that the kidneys are not responsible for the low serum potassium.

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Trans-Tubular Potassium Gradient

The TTKG was developed to account for the potentially confounding effect of urine concentration on the interpretation of the urine potassium concentration.^{[41, 42]} In effect, the TTKG represents a back-calculation of what the serum-to–tubular fluid ratio of potassium would be at the level of the cortical collecting tubule, where potassium is secreted before urine concentration has occurred.

This test is performed using the following equation:

TTKG = Urine potassium x serum osmolality/Serum potassium x urine osmolality

A TTKG value of less than 3 suggests that the kidney is not wasting excessive potassium, while a value of greater than 7 suggests a significant renal loss. This test cannot be applied when the urine osmolality is less than the serum osmolality. Potassium excretion at the distal nephron is highly dependent on sodium delivery to that site. Therefore, low urine potassium in the presence of very low urine sodium (< 25 mEq/L) does not allow the clinician to exclude the possibility of a potassium-wasting syndrome.

Measurement of the TTKG was initially considered superior to measurement of urine potassium alone for assessing the contribution of renal excretion to potassium levels. However, it is important to recognize that the TTKG is valid for this purpose only if (1) the urine osmolality is greater than the serum osmolality—that is, the urine is concentrated relative to the serum—and (2) the urine sodium is greater than 20 mEq/L—that is, distal delivery of sodium is adequate for potassium excretion.

Furthermore, recent evidence suggesting that urea recycling may influence potassium secretion has cast some doubt on the utility of the TTKG.^[43] One assumption inherent in the calculation of the TTKG is that the absorption of osmoles distal to the cortical collecting duct is negligible. If further studies suggest that urea transport can influence potassium handling, this test may have to be abandoned.

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Metabolic Profile

Obtain a basic metabolic profile. Measure electrolytes, blood urea nitrogen (BUN), and creatinine. Including the glucose, calcium, and/or phosphorus level is indicated if coexistent electrolyte disturbances are suspected. Consider a digoxin level if the patient is on a digitalis preparation, as hypokalemia can potentiate digitalis-induced arrhythmias.

Serum sodium

A low serum sodium level suggests thiazide diuretic use or marked volume depletion from gastrointestinal losses. A high serum sodium might suggest that nephrogenic diabetes insipidus has occurred secondary to hypokalemia. This could indicate that the hypokalemia is a long-standing problem. A high serum sodium level also may suggest the presence of primary hyperaldosteronism, especially if hypertension also is present.

Serum bicarbonate

A low serum bicarbonate level may suggest renal tubular acidosis, diarrhea, or the use of carbonic anhydrase inhibitors (eg, acetazolamide, topiramate). A high serum bicarbonate level is consistent with either primary or secondary hyperaldosteronism. Causes of secondary hyperaldosteronism could be exogenous prednisone therapy, vomiting, or the use of thiazide or loop diuretics. A high serum bicarbonate level is also consistent with the presence of Bartter, Gitelman, or Liddle syndrome.

Other findings

The glucose level may be elevated; hyperglycemia may suggest that the hypokalemia has been of sufficient severity and duration to impair glucose tolerance.

Creatine kinase may be elevated in the occasional patient whose hypokalemia is of sufficient severity to produce not only muscle weakness but also frank rhabdomyolysis. This most often occurs in the setting of alcoholism, in which total body potassium stores may be quite low because of prolonged periods of poor intake. Severe rhabdomyolysis can lead to renal failure and subsequent severe hyperkalemia.

The magnesium level may be low, because severe hypokalemia often is associated with significant magnesium losses. In such cases, the potassium level cannot be corrected until the hypomagnesemia has been corrected.

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Acid-Base Balance

If diuretic use has been excluded, measure arterial blood gases (ABG) and determine the acid-base balance.

Alkalosis

Alkalosis suggests one of the following:

• Vomiting
• Bartter syndrome
• Gitelman syndrome
• Diuretic abuse
• Mineralocorticoid excess

Acidosis

Acidosis suggests renal tubular acidosis type I or type II (eg, Fanconi syndrome). Other evidence of Fanconi syndrome, such as hypophosphatemia with phosphate wasting, hypouricemia, and renal glycosuria, may alert the clinician to this diagnosis. Renal tubular acidosis may also result from paraproteinemias, amphotericin use, gentamicin use, or glue sniffing (toluene toxicity^[40] ). Patients with toluene toxicity may have a high anion gap with reduced kidney function.

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Electrocardiogram

Perform an ECG to determine whether the hypokalemia is affecting cardiac function or to detect digoxin toxicity. The ECG may show atrial or ventricular tachyarrhythmias, decreased amplitude of the P wave, or appearance of a U wave.

ECG monitoring is imperative for severe hypokalemia (< 2 mEq/L in otherwise healthy individuals or < 3 mEq/L in patients with known or suspected cardiac disease). With a sudden shift of potassium into the cells (eg, with insulin therapy for diabetic ketoacidosis), even individuals with healthy hearts can develop lethal arrhythmias. Continuously monitor patients on digoxin or those with digoxin toxicity.

Although ECG changes may be helpful if present, their absence should not be taken as reassurance of normal cardiac conduction.^[44] The ECG in hypokalemia may appear normal or may have only subtle findings immediately before clinically significant dysrhythmias. ECG findings may include the following:

• Ventricular dysrhythmia
• Prolongation of QT interval^[51]
• ST-segment depression
• T-wave flattening
• Appearance of U waves
• Ventricular arrhythmias (eg, premature ventricular contractions [PVCs], torsade de pointes, ventricular fibrillation)^[45]
• Atrial arrhythmias (eg, premature atrial contractions [PACs], atrial fibrillation)

During therapy, monitor for changes associated with overcorrection and hyperkalemia, including a prolonged QRS, peaked T waves, bradyarrhythmia, sinus node dysfunction, and asystole.

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Approach Considerations

The treatment of hypokalemia has four facets, as follows:

• Reduction of potassium losses
• Replenishment of potassium stores
• Evaluation for potential toxicities
• Determination of the cause to prevent future episodes, if possible

Medications

Usually, oral potassium chloride is administered when potassium levels need to be replenished, as well as, in patients with ongoing potassium loss (eg, those on thiazide diuretics), when it must be maintained. Potassium-sparing diuretics are generally used only in patients with normal renal function who are prone to significant hypokalemia.

Angiotensin-converting enzyme (ACE) inhibitors, which inhibit renal potassium excretion, can ameliorate some of the hypokalemia that thiazide and loop diuretics can cause. However, ACE inhibitors can lead to lethal hyperkalemia in patients with renal insufficiency who are taking potassium supplements or potassium-sparing diuretics.

Surgical care

Generally, hypokalemia is a medical, not a surgical, condition. Surgical intervention is required only with certain etiologies, such as the following:

• Renal artery stenosis
• Adrenal adenoma
• Intestinal obstruction producing massive vomiting
• Villous adenoma

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Decreasing Potassium Losses

Measures to identify and stop ongoing losses of potassium include the following:

• Discontinue diuretics/laxatives
• Use potassium-sparing diuretics if diuretic therapy is required (eg, severe heart failure)
• Treat diarrhea or vomiting
• Administer H2 blockers to patients receiving nasogastric suction
• Control hyperglycemia if glycosuria is present

Because of the risk associated with potassium replacement, alleviation of the cause of hypokalemia may be preferable to treatment, especially if hypokalemia is mild, asymptomatic, or transient and is likely to resolve without treatment. For example, patients with vomiting who are successfully treated with antiemetics may not require potassium replacement.

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Replenishment of Potassium

Replenishment of potassium is the second treatment step. For every 1 mEq/L decrease in serum potassium, the potassium deficit is approximately 200-400 mEq.

Bear in mind, however, that many factors in addition to the total body potassium stores contribute to the serum potassium concentration. Therefore, this calculation could either overestimate or underestimate the true potassium deficit. For example, do not overcorrect potassium in patients with periodic hypokalemic paralysis. This condition is caused by transcellular maldistribution, not by a true deficit.

Patients who have mild or moderate hypokalemia (potassium level of 2.5-3.5 mEq/L) are usually asymptomatic; if these patients have only minor symptoms, they may need only oral potassium replacement therapy. If cardiac arrhythmias or significant symptoms are present, then more aggressive therapy is warranted. This treatment is similar to the treatment of severe hypokalemia.

If the potassium level is less than 2.5 mEq/L, intravenous potassium should be given. Maintain close follow-up care, provide continuous ECG monitoring, and check serial potassium levels.

Higher dosages may increase the risk of cardiac complications. Many institutions have policies that limit the maximum amount of potassium that can be given per hour. Hospital admission or observation in the emergency department is indicated; replacement therapy takes more than a few hours.

The serum potassium level is difficult to replenish if the serum magnesium level is also low. Look to replace both.

Oral potassium is absorbed readily, and relatively large doses can be given safely. Oral administration is limited by patient tolerance because some individuals develop nausea or even gastrointestinal ulceration with enteral potassium formulations.

Intravenous potassium, which is less well tolerated because it can be highly irritating to veins, can be given only in relatively small doses, generally 10 mEq/h. Under close cardiac supervision in emergent circumstances, as much as 40 mEq/h can be administered through a central line. Oral and parenteral potassium can safely be used simultaneously.

Take ongoing potassium losses into consideration by measuring the volume and potassium concentration of body fluid losses. If the patient is severely hypokalemic, avoid glucose-containing parenteral fluids to prevent an insulin-induced shift of potassium into the cells. If the patient is acidotic, correct the potassium first to prevent an alkali-induced shift of potassium into the cells.

Evaluation for potential toxicities

Monitor for toxicity of hypokalemia, which generally is cardiac in nature. Monitor the patient if evidence of cardiac arrhythmias is observed, and institute very aggressive replacement parenterally under monitored conditions.

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Addressing the Cause of Hypokalemia

Determine the underlying cause of the patient’s hypokalemia to treat the condition and prevent further episodes. Again, history and physical examination findings clarify the cause in the vast majority of cases. Look for clues to the etiology (see Presentation and Workup). Inadequate intake as a cause of hypokalemia generally indicates abuse by self or others. Consider psychiatric evaluation for suspected alcoholism or an eating disorder. Consider referral to abuse authorities if neglect (particularly in the case of an elderly person) or abuse is suspected.

Tailor treatment to the individual patient. For example, if diuretics cannot be discontinued because of an underlying disorder such as heart failure, institute potassium-sparing therapies, such as a low-sodium diet, potassium-sparing diuretics, ACE inhibitors, and angiotensin receptor blockers.

The low-sodium diet and potassium-sparing diuretics limit the amount of sodium reabsorbed at the cortical collecting tubule, thus limiting the amount of potassium secreted. ACE inhibitors and angiotensin receptor blockers inhibit the release of aldosterone, thus blocking the kaliuretic effects of that hormone.

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Consultations

The following consultations may be appropriate, depending on clinical findings, for diagnosing and managing underlying conditions in patients with hypokalemia:

• Renal specialist for evaluation of unexplained urine potassium losses suggested to be secondary to a tubular disorder
• Endocrinologist if Cushing syndrome, primary hyperaldosteronism, glucocorticoid-remediable hypertension, or congenital adrenal hyperplasia is suggested
• Psychiatrist or other mental health professional for alcoholism or eating disorders
• Dietitian in cases of hypokalemia due to inadequate dietary intake
• Surgeon for etiologies such as renal artery stenosis, adrenal adenoma, intestinal obstruction producing massive vomiting, and villous adenoma

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Transfer

Transfer generally is not required unless patients experience untreatable cardiac arrhythmias, digoxin toxicity, or paralysis and no facilities are available for monitoring. In general, even severe hypokalemia can be treated successfully in most medical centers.

Patients with severe or symptomatic hypokalemia require transfer to an intensive care unit for intravenous potassium supplementation and continuous ECG monitoring. Patients should be transferred only after any cardiac arrhythmias have been treated and the condition has been stabilized. Depending on the level of hypokalemia, an advanced cardiac life support (ACLS) ambulance should be used to allow continuous cardiac monitoring during transport.

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Diet and Activity

Dietary modification may be necessary for patients with excessive potassium losses (eg, diuretic or laxative use) or patients with hypokalemia who are at increased risk, such as those receiving digoxin. In general, a low-sodium and high-potassium diet is appropriate. Avoidance of specific foods (eg, licorice) may also be necessary for high-risk individuals.

Unless the patient has severe underlying cardiac disease, no activity restrictions are necessary in most cases. Instruct patients to discontinue exercise if muscle pain or cramps develop, because this may herald hypokalemia significant enough to produce rhabdomyolysis. Patients with hypokalemic periodic paralysis may need to modify exercise regimens to avoid periods of strenuous exercise.

Patients at risk for hypokalemia from sweat losses should have adequate potassium and fluid available during activities likely to result in significant sweating and should be given anticipatory guidance regarding symptoms of hypokalemia.

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Inpatient Care

Monitoring potassium levels and treatment

Inpatient care includes monitoring serum potassium levels every 1-3 hours and adjusting supplement doses as necessary. Recall that potassium can shift in and out of cells under several influences. Therefore, several determinations of serum potassium level after presumably adequate replacement are indicated to ensure that serum potassium levels achieve normalcy.

After potassium has been replenished, checking again for several days to determine whether potassium has stabilized or has started falling again is equally important. For example, if an individual presents with nausea, vomiting, and hypokalemia, the physician might understandably attribute the hypokalemia to the nausea and vomiting. However, if after replenishment the patient once again develops hypokalemia without nausea and vomiting, then considering other possible causes of hypokalemia is necessary.

Additionally, if a need for ongoing potassium supplementation is anticipated for the patient (eg, a patient on long-term diuresis for hypertension), then ensuring that the prescribed daily potassium supplement is adequate to maintain a normal serum potassium level is important.

Cardiac evaluation

Electrocardiographic (ECG) monitoring is imperative for severe hypokalemia (< 2 mEq/L in otherwise healthy individuals or < 3 mEq/L in patients with known or suspected cardiac disease). With a sudden shift of potassium into the cells (eg, with insulin therapy for diabetic ketoacidosis), even individuals with healthy hearts can develop lethal arrhythmias. Continuously monitor patients on digoxin or those with digoxin toxicity.

Further evaluation

Once a cause has been determined for hypokalemia and the condition has been treated as per the diagnosis, ensuring that treatment plans are adequate is imperative. Evaluate for more unusual secondary causes. If an unusual cause of hypokalemia is suggested, either by specific clinical features or failure to respond to initial therapy, evaluation can at least begin while the patient is hospitalized. However, evaluation often can be completed in an outpatient setting.

If covert diuretic or laxative use is suspected, establishing proof of this is best accomplished in the hospital, with patients in a relatively controlled environment. In this setting, 24-hour urine measurements of sodium and potassium excretion, measurement of serum potassium at frequent intervals, and supervision of intake and output are possible. Ongoing potassium losses in the face of a negative urine and serum screen for diuretics suggest another diagnosis.

If the patient has hypertension, then the next steps would be as follows:

• Determine serum renin activity and aldosterone and cortisol levels
• Obtain a 24-hour urine measurement for aldosterone, cortisol, sodium, and potassium
• Consider an imaging study (eg, renal vascular Doppler, captopril renal scan, or computed tomography [CT] angiography) to investigate the possibility of renal artery stenosis;^[46] perform a CT scan of the abdomen to investigate for a possible adrenal adenoma.

A high cortisol level suggests Cushing syndrome. Evaluate for pituitary or adrenal causes. If renin and aldosterone levels are both elevated, this points more strongly to renal artery stenosis. If the index of suspicion is high enough, perform a renal arteriogram and renal vein renin determination to look for significant renal artery stenosis as a cause of hypertension and hypokalemia.

A high aldosterone level with low renin activity suggests primary hyperaldosteronism. If the patient is hypertensive but the aldosterone level is low, this suggests one of the more unusual congenital forms of hypertension, such as Liddle syndrome, in which a mutation in the epithelial sodium channel produces uncontrollable sodium reabsorption or glucocorticoid-remediable hypertension. This scenario also could be produced by licorice ingestion or ingestion of a steroid with mineralocorticoid activity, such as prednisone or fludrocortisone.

If the patient is not hypertensive but has hypokalemic metabolic alkalosis, and diuretic use and bulimia have been excluded, then possibilities include Bartter syndrome and Gitelman syndrome. If patients have metabolic acidosis, the most common cause is diarrhea. If this is not present, then the most likely possibility is a distal renal tubular acidosis, as might be seen with amyloid or amphotericin use or with glue sniffing.

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Outpatient Care

For otherwise healthy patients undergoing what appears to be an acute episode, such as severe diarrhea, causing hypokalemia, no further follow-up care is required. For patients who are likely to develop hypokalemia again (eg, those requiring long-term diuretic therapy), periodic monitoring of serum potassium levels is essential. If not performed during hospitalization, then outpatient follow-up care with tests such as 24-hour urine cortisol and aldosterone is acceptable.

Patients taking drugs that can alter serum potassium levels require periodic follow-up care. The greater the number of medical problems and the greater the number of drugs, the more frequent the follow-up care should be. Failure to check potassium levels after alteration of 1 of these drugs could allow the patient to develop a lethal complication. Bear in mind that the combination of potassium supplements, ACE inhibitors, angiotensin receptor blockers, and potassium-sparing diuretics has the potential to produce severe hyperkalemia.

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Deterrence and Prevention

Some authors advocate the routine use of potassium supplementation in patients with congestive heart failure. Undoubtedly, most patients will require potassium supplementation because they will be taking loop diuretics. However, recall the caveats concerning the use of potassium supplements, ACE inhibitors, and potassium-sparing diuretics in patients with subclinical renal failure.

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Medication Summary

Potassium

Oral potassium chloride is the usual choice for replenishment of potassium levels and for maintenance of potassium levels in patients with ongoing potassium loss (eg, those on thiazide diuretics). Potassium chloride is absorbed easily and can be given several times per day if needed, especially if high-dose diuretic therapy is required.

In patients with hypokalemia and diabetic ketoacidosis, part of the potassium dose should be administered as potassium phosphate.

ACE inhibitors

ACE inhibitors have gained significantly in popularity because of their excellent tolerability and benefit in a variety of disease conditions. In particular, these drugs have demonstrable clinical benefit for the treatment of hypertension, heart failure, and a variety of kidney diseases, including diabetic nephropathy.

Because they inhibit renal potassium excretion, ACE inhibitors can ameliorate some of the hypokalemia that can occur with use of thiazide or loop diuretics.

Cough is the most common complaint with ACE inhibitors. Other types of adverse effects commonly seen with other antihypertensives (eg, exercise intolerance, fatigue, dry mouth, impotence, drowsiness) are not reported as commonly with ACE inhibitors.

Caution

Often, individuals with cirrhosis or chronic heart failure have subtle decreases in renal function that may not be apparent from routine laboratory studies. In addition, patients with heart failure often are treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), classes of drugs that inhibit renal potassium excretion.

In patients with mild renal insufficiency, the combination of an ACE inhibitor, a potassium-sparing diuretic, and a potassium supplement can very easily result in life-threatening hyperkalemia. Frequent follow-up is necessary to avoid this outcome.

Selective aldosterone antagonists

Potassium-sparing diuretics are generally used only in patients with normal renal function who are prone to significant hypokalemia. Some evidence indicates that spironolactone is particularly useful in patients with cirrhosis and in those with heart failure. Exercise caution in using potassium-sparing diuretics in either of these populations. Frequent determination of potassium levels is mandatory.

Treatment with the more selective aldosterone receptor inhibitor eplerenone is associated with fewer side effects than treatment with spironolactone and may be more effective for hypertension related to primary hyperaldosteronism.^[47] Eplerenone in patients with chronic heart failure after acute myocardial infarction has been associated with improved mortality and a low incidence of hyperkalemia.^[48]

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Potassium chloride (K-Dur, Klor Con, Klor-Con M, KTab, MicroK, Kaon CL 10, K-Lyte Cl, Kay Ciel)

• Dosing, Interactions, etc.

Clinical Context:  Potassium chloride is the preferred salt for patients with preexisting alkalosis. It is the first choice for IV therapy. Oral preparations include 8 mEq slow-release tablets, 20 mEq elixir, 20 mEq powder, and 25 mEq tablets. Any of these forms may irritate the stomach and cause vomiting; consequently, they should be taken with food or after meals to minimize gastrointestinal discomfort.

Unflavored liquid potassium chloride has an unpleasant taste, so pills may be conducive to better compliance. Long-acting supplements often are not as well absorbed, but microencapsulated forms often are better tolerated. Tailor the dose to the patient's needs.

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Class Summary

Potassium is essential for transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity, skeletal and smooth muscles, and maintenance of normal renal function. Gradual potassium depletion may occur via renal excretion, through gastrointestinal loss, or because of low intake. In general, a 1 mEq/L drop in potassium correlates to a loss of 100-200 mEq of total body potassium. However, hypokalemia may result from the movement of potassium into cells without loss of potassium from the body.

Electrolytes can be used as oral or parenteral therapy for potassium replacement. Most patients respond well to low-dose supplements.

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Potassium citrate (Urocit K)

• Dosing, Interactions, etc.

Clinical Context:  This is an oral preparation with a base instead of an acid anion. Potassium citrate is generally used for patients who form calcium stones or for those with severe metabolic acidosis. It is not as effective as potassium chloride for replacement in the general population. Tailor the dose to the patient's needs.

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Class Summary

Potassium citrate is an orally administered alkalinizing agent. This and other potassium salts may be used as supplements to maintain potassium homeostasis; however potassium chloride is usually the drug of choice.

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Captopril (Capoten, Captoril)

• Dosing, Interactions, etc.

Clinical Context:  This agent prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion and increased renin activity. Captopril is the shortest-acting ACE inhibitor; it must be given 2 or 3 times daily, while other drugs in this class can be taken once daily.

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Enalapril (Vasotec)

• Dosing, Interactions, etc.

Clinical Context:  Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion and increasing renin secretion.

• References

Fosinopril

• Dosing, Interactions, etc.

Clinical Context:  Fosinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion and increased renin secretion.

• References

Ramipril (Altace)

• Dosing, Interactions, etc.

Clinical Context:  Ramipril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

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Class Summary

These agents inhibit the production of aldosterone and decrease renal potassium losses. All of the drugs in this category work in the same way. Differences are in the duration of action and the ability to inhibit locally produced and circulating ACE.

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Valsartan (Diovan)

• Dosing, Interactions, etc.

Clinical Context:  Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Valsartan may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema. It can be used as an alternative therapy, especially in patients who are unable to tolerate ACE inhibitors.

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Candesartan (Atacand)

• Dosing, Interactions, etc.

Clinical Context:  Candesartan produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

This agent may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema. It can be used as an alternative therapy, especially in patients unable to tolerate ACE inhibitors.

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Losartan (Cozaar)

• Dosing, Interactions, etc.

Clinical Context:  Losartan is an angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema. It can be used as an alternative therapy, especially in patients unable to tolerate ACE inhibitors.

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Class Summary

ARBs competitively inhibit the ability of angiotensin II to interact with and stimulate angiotensin II receptors. This action results in decreased aldosterone secretion and, consequently, decreased renal potassium excretion.

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Triamterene (Dyrenium)

• Dosing, Interactions, etc.

Clinical Context:  Triamterene is a potassium-sparing diuretic with relatively weak natriuretic properties. It exerts a diuretic effect on the distal renal tubule, inhibiting reabsorption of sodium in exchange for potassium and hydrogen. It is not a competitive antagonist of mineralocorticoids, and a potassium-conserving effect is observed in patients with Addison disease (ie, without aldosterone).

• References

Amiloride (Midamor)

• Dosing, Interactions, etc.

Clinical Context:  This agent is a pyrazine-carbonyl-guanidine unrelated chemically to other known antikaliuretic (potassium-sparing) or diuretic agents. It is a potassium-sparing drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity.

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Class Summary

Potassium-sparing diuretics are excellent for adjunctive therapy when ongoing renal losses are anticipated. These agents may be used in conjunction with thiazide or loop diuretics.

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Spironolactone (Aldactone)

• Dosing, Interactions, etc.

Clinical Context:  Spironolactone is used to manage edema resulting from excessive aldosterone excretion. It competes with aldosterone for receptor sites in distal renal tubules, resulting in increased water excretion and retention of potassium and hydrogen ions.

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Eplerenone (Inspra)

• Dosing, Interactions, etc.

Clinical Context:  Eplerenone selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, renal) and nonepithelial (eg, heart, blood vessel, and brain) tissues; thus, it decreases blood pressure and sodium reabsorption. It is more selective for mineralocorticoid receptors than spironolactone and thus has a lower incidence of side effects associated with androgen antagonism, such as gynecomastia.

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Class Summary

These agents selectively block aldosterone binding at mineralocorticoid receptors. They may be used as potassium-sparing diuretics.

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