REFERAT

HYPOKALEMIA

PRECEPTOR:

dr. Hj. Ihsanil Husna, Sp.PD

BY:

Syalara Fatharani

(2013730108)

MEDICAL PROFESSION PROGRAMME DEPARTMENT OF

INTERNAL MEDICINE
JAKARTA ISLAMIC HOSPITAL CEMPAKA PUTIH
FACULTY OF MEDICINE UNIVERSITY OF
MUHAMMADIYAH JAKARTA
2018

1
 PREFACE

AssalamualaikumWr. Wb.

Alhamdulillah, All praise to Allah SWT the almighty and the most merciful. Shalawat and
salaam to Rasulullah Muhammad Peace be Upon Him which bring us from the darkest of time into
the lights.
The writer also wish to express his deep and sincere gratitude for those who have guided
in completing this referat paper with the tittle “Hypokalemia” to fulfill the criteria for completing
Medical Profession Programme in Internal Medicine Department of Jakarta Islamic Hospital
Cempaka Putih, Faculty of Medicine University of Muhammadiyah Jakarta.

The writer wish this paper to be useful and add another dimension of knowledge for the
writer himself, medical profession student, and anyone else who never stop in learning.

The writer acknowledge in the process of making this paper, there are a lot of mistake and
far from perfect, cause perfection are only belong to Allah SWT. All the critics and advice are
needed for the writer for the better of ourselves in this journey to be the long life learner.

With all pleasure

WassalamualaikumWr. Wb

Jakarta, Juli 2018

Syalara Fatharani

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 CHAPTER I
LITERATURE REVIEW

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

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

3
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.

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

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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

5
  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]

6
  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 CLCNKBgene,
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

7
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 NR3C1gene 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

8
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

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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.

10
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]

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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

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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.

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.

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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).

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.
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.

14
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.

Urine Potassium

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.

15
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.

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:

16
  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)

Treatmen Hypokalemia
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

17
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.

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.

18
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.

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.

19
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

20
 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.

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.
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.

21
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.

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.

22
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