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. 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.

A model of transport mechanisms

in the distal convoluted tubule. Sodium-chloride (NaCl) enters the cell via the apical thiazide-
sensitive NCC and leaves the cell through the basolateral Cl channel (ClC-Kb), and the
Na+/K+-ATPase. Indicated also are the recently identified magnesium channel TRPM6 in the
apical membrane, and a putative Na/Mg exchanger in the basolateral membrane. These
transport mechanisms play a role in familial hypokalemia-hypomagnesemia or Gitelman
syndrome.

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.

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]

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).
 A model of transport mechanisms
in the distal convoluted tubule. Sodium-chloride (NaCl) enters the cell via the apical thiazide-
sensitive NCC and leaves the cell through the basolateral Cl channel (ClC-Kb), and the
Na+/K+-ATPase. Indicated also are the recently identified magnesium channel TRPM6 in the
apical membrane, and a putative Na/Mg exchanger in the basolateral membrane. These
transport mechanisms play a role in familial hypokalemia-hypomagnesemia or Gitelman
syndrome.

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 deficiencysyndrome

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

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 nonpotassium-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.

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).

Prognosis
The prognosis for patients with hypokalemia depends entirely on the conditions 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.

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.

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.

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).

Diagnostic Considerations
Pseudohypokalemia may be seen with sampling errors, particularly if a blood sample is taken
upstream of an infusion of saline, dextrose, or other fluids that contain little or no potassium.
Clues to sampling errors include other serum-level abnormalities that reflect sampling of a
mixture of blood and the fluid that is being infused.

Measurement of urine potassium is essential to establishment of the pathophysiologic

mechanism of hypokalemia and, thus, to determination of the differential diagnosis.

Differential Diagnoses
Bartter Syndrome
Hyperthyroidism and Thyrotoxicosis
Hypocalcemia
Hypochloremic Alkalosis
Hypomagnesemia
Iatrogenic Cushing Syndrome
Metabolic Alkalosis

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 Mnchhausen or Mnchhausen-by-proxy syndrome. An elevated serum insulin level
without an appropriately elevated C-peptide level suggests exogenous insulin administration.

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]

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.

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-totubular 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 osmolalitythat is, the urine is concentrated
relative to the serumand (2) the urine sodium is greater than 20 mEq/Lthat 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.

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.
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.

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.

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

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.

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.

Addressing the Cause of Hypokalemia

Determine the underlying cause of the patients 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.

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

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.

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.

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.

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.

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.

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]

Electrolytes
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.

Potassium chloride (K-Dur, Klor Con, Klor-Con M, KTab, MicroK, Kaon CL

10, K-Lyte Cl, Kay Ciel)

View full drug information

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.
Urinary Alkalinizing Agents
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.

Potassium citrate (Urocit K)

View full drug information

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.

ACE Inhibitors
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.

Captopril (Capoten, Captoril)

View full drug information

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.

Enalapril (Vasotec)

View full drug information

Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing

aldosterone secretion and increasing renin secretion.

Fosinopril

View full drug information

Fosinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor,

resulting in lower aldosterone secretion and increased renin secretion.
Ramipril (Altace)

View full drug information

Ramipril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor,

resulting in lower aldosterone secretion.

ARBs
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.

Valsartan (Diovan)

View full drug information

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.

Candesartan (Atacand)

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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.

Losartan (Cozaar)

View full drug information

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.

Diuretics, Potassium-Sparing
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.

Triamterene (Dyrenium)

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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).

Amiloride (Midamor)

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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.

Aldosterone Antagonists, Selective

Class Summary

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

Spironolactone (Aldactone)

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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.

Eplerenone (Inspra)

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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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