Potassium Disorders:
`Hypokalemia and Hyperkalemia
`
`ANTHONY J. VIERA, MD, MPH, and NOAH WOUK, MD, University of North Carolina
`at Chapel Hill School of Medicine, Chapel Hill, North Carolina
`
`Hypokalemia and hyperkalemia are common electrolyte disorders caused by changes in potassium intake, altered
`excretion, or transcellular shifts. Diuretic use and gastrointestinal losses are common causes of hypokalemia, whereas
`kidney disease, hyperglycemia, and medication use are common causes of hyperkalemia. When severe, potassium
`disorders can lead to life-threatening cardiac conduction disturbances and neuromuscular dysfunction. Therefore, a
`first priority is determining the need for urgent treatment through a combination of history, physical examination,
`laboratory, and electrocardiography findings. Indications for urgent treatment include severe or symptomatic hypo-
`kalemia or hyperkalemia; abrupt changes in potassium levels; electrocardiography changes; or the presence of certain
`comorbid conditions. Hypokalemia is treated with oral or intravenous potassium. To prevent cardiac conduction dis-
`turbances, intravenous calcium is administered to patients with hyperkalemic electrocardiography changes. Insulin,
`usually with concomitant glucose, and albuterol are preferred to lower serum potassium levels in the acute setting;
`sodium polystyrene sulfonate is reserved for subacute treatment. For both disorders, it is important to consider poten-
`tial causes of transcellular shifts because patients are at increased risk of rebound potassium disturbances. (Am Fam
`Physician. 2015;92(6):487-495. Copyright © 2015 American Academy of Family Physicians.)
`
`More online
`at http://www.
`aafp.org/afp.
`
`CME This clinical content
`conforms to AAFP criteria
`for continuing medical
`education (CME). See
`CME Quiz Questions on
`page 441.
`
`Author disclosure: No rel-
`evant financial affiliations.
`
`Patient information:
`A handout on this topic,
`written by the authors of
`this article, is available
`at http://www.aafp.org/
`afp/2015/0915/p487-s1.
`html.
`
`Potassium disorders are common.
`
`Hypokalemia (serum potassium
`level less than 3.6 mEq per L [3.6
`mmol per L]) occurs in up to 21%
`of hospitalized patients and 2% to 3% of
`outpatients.1-3 Hyperkalemia (serum potas-
`sium level more than 5 mEq per L [5 mmol
`per L] in adults, more than 5.5 mEq per L
`[5.5 mmol per L] in children, and more than
`6 mEq per L [6 mmol per L] in neonates)
`occurs in up to 10% of hospitalized patients
`and approximately 1% of outpatients.4,5 The
`body’s plasma potassium concentration is
`closely regulated by a variety of mechanisms.
`
`Causes of Hypokalemia
`Hypokalemia results from abnormal losses,
`transcellular shifts, or
`insufficient
`intake
`(Table 1).6-8 Abnormal losses are most com-
`mon.9 Because the kidney can significantly
`lower potassium excretion in response to
`decreased intake, insufficient intake is rarely the
`sole cause of hypokalemia, but it often contrib-
`utes to hypokalemia in hospitalized patients.9
`
`RENAL LOSSES
`
`Diuretic use is a common cause of renally
`mediated hypokalemia.10 When given in the
`
`same dosage, chlorthalidone is more likely to
`induce hypokalemia than hydrochlorothia-
`zide, which is more often implicated because
`of its widespread use.11,12 Diuretic-induced
`hypokalemia is dose-dependent and tends to
`be mild (3 to 3.5 mEq per L [3 to 3.5 mmol
`per L]), although it can be more severe when
`accompanied by other causes (e.g., gastroin-
`testinal [GI] losses).13
`
`GI LOSSES
`
`GI losses are another common cause of
`hypokalemia, particularly among hospital-
`ized patients.9 The mechanism by which
`upper GI losses induce hypokalemia is indi-
`rect and stems from the kidney’s response to
`the associated alkalosis. As a portion of daily
`potassium is excreted in the colon, lower
`GI losses in the form of persistent diarrhea
`can also result in hypokalemia and may be
`accompanied by hyperchloremic acidosis.6
`
`Evaluation and Management
`of Hypokalemia
`GENERAL PRINCIPLES
`Hypokalemia is often asymptomatic. Evalu-
`ation begins with a search for warning signs
`or symptoms warranting urgent treatment
`
`September 15, 2015 ◆ Volume 92, Number 6
`
`www.aafp.org/afp
`
`American Family Physician 487
`
`Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright © 2015 American Academy of Family Physicians. For the private, noncom-
`mercial use of one individual user of the website. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2021, Page 1
`
`

`

`Table 1. Causes of Hypokalemia
`
`Abnormal losses
`Medications
`Diuretics
`Laxatives and enemas
`Corticosteroids
`Gastrointestinal losses
`Renal losses
`Osmotic diuresis
`Mineralocorticoid excess
`Types I and II renal tubular acidosis
`Polydipsia
`Intrinsic renal transport defects
`Hypomagnesemia
`Dialysis/plasmapheresis
`Transcellular shifts
`Medications
`Insulin overdose
`Beta2 sympathomimetics
`Decongestants
`Xanthines
`Amphotericin B
`Verapamil intoxication
`Chloroquine (Aralen) intoxication
`Barium intoxication
`Cesium intoxication
`
`NOTE: Listed in approximate order of frequency.
`
`Information from references 6 through 8.
`
`Transcellular shifts
`(continued)
`Alkalosis
`Refeeding syndrome
`Increased beta2 adrenergic
`stimulation
`Delirium tremens
`Head injury
`Myocardial ischemia
`Thyrotoxicosis
`Familial hypokalemic periodic
`paralysis
`Hypothermia
`Inadequate intake
`Anorexia
`Dementia
`Starvation
`Total parenteral nutrition
`Pseudohypokalemia
`Delayed sample analysis
`Significant leukocytosis
`(> 75,000 cells per mm3
`[75.0 × 109 per L])
`
`(Figure 1).7,14 These include weakness or pal-
`pitations, changes on electrocardiography
`(ECG), severe hypokalemia (less than 2.5
`mEq per L [2.5 mmol per L]), rapid-onset
`hypokalemia, or underlying heart disease
`or cirrhosis.7,15 Most cases of hypokalemia-
`induced rhythm disturbances occur
`in
`individuals with underlying heart disease.10
`Early identification of transcellular shifts is
`important because management may differ.
`Identification and treatment of concurrent
`hypomagnesemia are also important because
`magnesium depletion impedes potassium
`repletion and can exacerbate hypokalemia-
`induced rhythm disturbances.16,17
`
`HISTORY AND PHYSICAL EXAMINATION
`
`A focused history includes evaluation for
`possible GI losses, review of medications,
`and assessment
`for underlying cardiac
`comorbidities. A history of paralysis, hyper-
`thyroidism, or use of insulin or beta agonists
`suggests possible transcellular shifts leading
`to redistributive hypokalemia. The physical
`examination should focus on identifying
`cardiac arrhythmias and neurologic mani-
`festations, which range from generalized
`weakness to ascending paralysis.
`
`LABORATORY ANALYSIS AND ECG
`
`The diagnosis should be confirmed with a repeat serum
`potassium measurement. Other laboratory tests include
`serum glucose and magnesium levels, urine electrolyte
`and creatinine levels, and acid-base balance. The most
`accurate method for evaluating urinary potassium excre-
`tion is a 24-hour timed urine potassium collection; nor-
`mal kidneys excrete no more than 15 to 30 mEq per L
`(15 to 30 mmol per L) of potassium per day in response to
`hypokalemia. A more practical approach is calculation of
`the urine potassium-to-creatinine ratio from a spot urine
`specimen; a ratio greater than 1.5 mEq per mmol (13 mEq
`per g) is indicative of renal potassium wasting.18 If no
`cause is identified with the initial workup, assessment of
`thyroid and adrenal function should be considered.
`Typically, the first ECG manifestation of hypokale-
`mia is decreased T-wave amplitude. Further progression
`can lead to ST-interval depression, T-wave inversions,
`PR-interval prolongation, and U waves. Arrhythmias
`associated with hypokalemia include sinus bradycar-
`dia, ventricular tachycardia or fibrillation, and torsade
`de pointes.19 Although the risk of ECG changes and
`
`arrhythmias increases as serum potassium concentra-
`tion decreases, these findings are not reliable because
`some patients with severe hypokalemia do not have
`ECG changes.20
`
`Treatment of Hypokalemia
`The immediate goal of treatment is the prevention of
`potentially life-threatening cardiac conduction distur-
`bances and neuromuscular dysfunction by raising serum
`potassium to a safe level. Further replenishment can pro-
`ceed more slowly, and attention can turn to the diagnosis
`and management of the underlying disorder.15 Patients
`with a history of congestive heart failure or myocardial
`infarction should maintain a serum potassium concen-
`tration of at least 4 mEq per L (4 mmol per L), based on
`expert opinion.15
`Careful monitoring during treatment is essential
`because supplemental potassium is a common cause
`of hyperkalemia in hospitalized patients.21 The risk of
`rebound hyperkalemia is higher when treating redis-
`tributive hypokalemia. Because serum potassium con-
`centration drops approximately 0.3 mEq per L (0.3
`mmol per L) for every 100-mEq (100-mmol) reduction
`in total body potassium, the approximate potassium
`
`488 American Family Physician
`
`www.aafp.org/afp
`
`Volume 92, Number 6 ◆ September 15, 2015
`
`Potassium Disorders
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2021, Page 2
`
`

`

`Potassium should not be given in dextrose-containing
`solutions because dextrose-stimulated insulin secretion
`can exacerbate hypokalemia.
`Nonurgent hypokalemia is treated with 40 to 100 mmol
`of oral potassium per day over days to weeks. For the pre-
`vention of hypokalemia in patients with persistent losses,
`
`Evaluation of Hypokalemia
`
`Potassium < 3.6 mEq per L (3.6 mmol per L)
`Check magnesium and replace if low
`
`Warning signs present?*
`
`Yes
`
`No
`
`Pseudohypokalemia?
`
`Yes
`
`No further action
`
`Urgent
`therapy
`
`No
`
`Evidence of decreased intake
`or transcellular shifts?
`
`No
`
`Yes
`
`Urine potassium-
`to-creatinine ratio
`
`Treat according
`to etiology of
`transcellular shifts
`
`deficit can be estimated in patients with abnormal losses
`and decreased intake. For example, a decline in serum
`potassium from 3.8 to 2.9 mEq per L (3.8 to 2.9 mmol per L)
`roughly corresponds to a 300-mEq (300-mmol) reduc-
`tion in total body potassium. Additional potassium will
`be required if losses are ongoing. Concomitant hypomag-
`nesemia should be treated concurrently.
`For hypokalemia associated with diuretic
`use, stopping the diuretic or reducing its
`dosage may be effective.15 Another strategy,
`if otherwise indicated to treat a comor-
`bid condition, is use of an angiotensin-
`converting
`enzyme
`(ACE)
`inhibitor,
`angiotensin receptor blocker (ARB), beta
`blocker, or potassium-sparing diuretic
`because each of these drugs is associated
`with an elevation in serum potassium.
`It is appropriate to increase dietary
`po tassium in patients with low-normal and
`mild hypokalemia, particularly in those
`with a history of hypertension or heart
`disease.15 The effectiveness of increased
`dietary potassium is limited, however,
`because most of the potassium contained in
`foods is coupled with phosphate, whereas
`most cases of hypokalemia involve chloride
`depletion and respond best to supplemen-
`tal potassium chloride.6,15
`Because use of intravenous potassium
`increases the risk of hyperkalemia and
`can cause pain and phlebitis, intravenous
`potassium should be reserved for patients
`with severe hypokalemia, hypokalemic
`ECG changes, or physical signs or symp-
`toms of hypokalemia, or for those unable
`to tolerate the oral form. Rapid correction
`is possible with oral potassium; the fastest
`results are likely best achieved by combin-
`ing oral (e.g., 20 to 40 mmol) and intrave-
`nous administration.22
`When intravenous potassium is used,
`standard administration is 20 to 40 mmol
`of potassium in 1 L of normal saline.
`Correction typically should not exceed
`20 mmol per hour, although higher rates
`using central venous catheters have been
`successful in emergency situations.22 Con-
`tinuous cardiac monitoring is indicated if
`the rate exceeds 10 mmol per hour. In chil-
`dren, dosing is 0.5 to 1.0 mmol per L per kg
`over one hour (maximum of 40 mmol).23
`
`≤ 1.5 mEq per mmol
`(13 mEq per g)
`
`Extrarenal losses
`(e.g., gastrointestinal,
`inadequate intake,
`discontinued diuretic,
`transcellular shifts)
`
`Acidosis (e.g., types
`I and II renal tubular
`acidosis)
`
`> 1.5 mEq per mmol
`
`Renal losses
`
`Yes
`
`Elevated blood
`pressure or
`hypervolemia?
`
`No
`
`Check acid-base status
`
`Evaluate for conditions associated
`with mineralocorticoid excess
`(e.g., primary and secondary
`hyperaldosteronism, renal artery
`stenosis, Cushing syndrome,
`congenital adrenal hyperplasia)
`
`Variable (e.g.,
`hypomagnesemia)
`
`Alkalosis (e.g., emesis,
`diuretic use, Bartter and
`Gitelman syndromes†)
`
`*—Symptoms of hypokalemia, changes on electrocardiography, severe hypokalemia (less
`than 2.5 mEq per L [2.5 mmol per L]), rapid-onset hypokalemia, or underlying heart dis-
`ease or cirrhosis.
`†—Autosomal recessive disorders of renal tubular transport.
`
`Figure 1. Suggested algorithm for the evaluation of hypokalemia.
`Information from references 7 and 14.
`
`September 15, 2015 ◆ Volume 92, Number 6
`
`www.aafp.org/afp
`
`American Family Physician 489
`
`Potassium Disorders
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2021, Page 3
`
`

`

`Table 2. Causes of Hyperkalemia
`
`Impaired excretion
`Acute kidney injury/chronic
`kidney disease
`Medications
`Angiotensin-converting
`enzyme inhibitors and
`angiotensin receptor blockers
`Nonsteroidal anti-inflammatory
`drugs
`Potassium-sparing diuretics
`Trimethoprim
`Heparin
`Lithium
`Calcineurin inhibitors
`Decreased distal renal flow
`Acute kidney injury/chronic
`kidney disease
`Congestive heart failure
`Cirrhosis
`Hypoaldosteronism
`Hyporeninemic
`hypoaldosteronism
`Adrenal insufficiency
`Adrenocorticotropic hormone
`deficiency
`Primary hyporeninemia
`Primary renal tubular defects
`Sickle cell disease
`Systemic lupus erythematosus
`Obstructive uropathy
`Hereditary tubular defects
`Amyloidosis
`
`Transcellular shifts
`Insulin deficiency/resistance
`Acidosis
`Hypertonicity
`Hyperglycemia
`Mannitol
`Medications
`Beta blockers
`Digoxin toxicity
`Somatostatin
`Succinylcholine (Anectine)
`Cell breakdown/leakage
`Hyperkalemic periodic paralysis
`Increased intake
`Potassium supplementation
`Red blood cell transfusion
`Foods high in potassium*
`Potassium-containing salt substitutes
`Protein calorie supplements
`Penicillin G potassium
`Certain forms of pica
`Pseudohyperkalemia
`Hemolysis
`Tourniquet use
`Fist clenching
`Blood sample cooling
`Intravenous fluids with potassium
`Cell hyperplasia
`Significant leukocytosis (> 75,000
`cells per mm3 [75.0 × 109 per L])
`Erythrocytosis
`Thrombocytosis
`Familial pseudohyperkalemia
`
`NOTE: Listed in approximate order of frequency.
`
`*—Dietary-induced hyperkalemia usually involves concurrent renal insufficiency.
`
`Information from references 8 and 24.
`
`as with ongoing diuretic therapy or hyper-
`aldosteronism, 20 mmol per day is usually
`sufficient.15
`
`Causes of Hyperkalemia
`Hyperkalemia is caused by excess potassium
`intake, impaired potassium excretion, or
`transcellular shifts (Table 2).8,24 The etiology
`of hyperkalemia is often multifactorial, with
`impaired renal function, medication use,
`and hyperglycemia as the most common
`contributors.25 Because healthy individuals
`can adapt to excess potassium consumption
`by increasing excretion, increased potas-
`sium intake is rarely the sole cause of hyper-
`kalemia, and underlying renal dysfunction
`is common.24
`
`IMPAIRED POTASSIUM EXCRETION
`
`Renally mediated hyperkalemia results from
`derangement of one or more of the following
`processes: rate of flow in the distal nephron,
`aldosterone secretion and its effects, and
`functioning potassium secretory pathways.
`Hyperkalemia secondary to decreased distal
`delivery of sodium and water occurs with
`congestive heart failure, cirrhosis, acute kid-
`ney injury, and advanced chronic kidney
`disease. Conditions that cause hypoaldoste-
`ronism, such as adrenal insufficiency and
`hyporeninemic hypoaldosteronism (a com-
`mon complication of diabetic nephropathy
`and tubulointerstitial diseases), can lead to
`hyperkalemia.
`
`TRANSCELLULAR SHIFTS
`
`Various mechanisms promote the exit of potassium
`from cells or impede its entrance, thereby raising the
`plasma potassium concentration (redistributive hyper-
`kalemia). Increased plasma osmolality, such as with
`uncontrolled diabetes mellitus, establishes a concentra-
`tion gradient wherein potassium follows water out of
`cells. Relative insulin deficiency or insulin resistance,
`which also occurs in persons with diabetes, prevents
`potassium from entering cells. In response to acidosis,
`extracellular hydrogen is exchanged for intracellular
`potassium, although the net result is highly variable
`and depends in part on the type of acidosis; metabolic
`acidosis produces the greatest effect.26 Because 98% of
`total body potassium is intracellular, any process that
`increases cell turnover, such as rhabdomyolysis, tumor
`
`lysis syndrome, or red blood cell transfusions, can result
`in hyperkalemia.
`
`MEDICATION-INDUCED HYPERKALEMIA
`
`Medication use is a common cause of hyperkalemia,
`particularly in patients with baseline renal dysfunction
`or hypoaldosteronism.27 Medication-induced hyperkale-
`mia is most often a result of the medication interfering
`with potassium excretion. Also, the administration of
`potassium to treat or prevent hypokalemia can inadver-
`tently cause hyperkalemia.19
`ACE inhibitors contributed to one-half of all cases of
`drug-induced hyperkalemia in one sample, and approxi-
`mately 10% of outpatients who start an ACE inhibitor or
`an ARB will develop hyperkalemia within one year.23,28
`
`490 American Family Physician
`
`www.aafp.org/afp
`
`Volume 92, Number 6 ◆ September 15, 2015
`
`Potassium Disorders
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2021, Page 4
`
`

`

`Evaluation of Hyperkalemia
`
`Potassium > 5 mEq per L (5 mmol per L)
`
`Warning signs present?*
`
`Yes
`
`Urgent therapy (Figure 3)
`
`No
`
`Pseudohyperkalemia?
`
`Yes
`
`No further action
`
`No
`
`Evidence of increased intake
`or transcellular shifts?
`
`No
`
`Yes
`
`Urine sodium > 25 mEq
`per L (25 mmol per L)?
`
`Treat according to etiology
`of transcellular shifts
`
`No
`
`Decreased distal renal flow (e.g., acute
`kidney injury/chronic kidney disease,
`congestive heart failure, cirrhosis)
`
`Yes
`
`Low serum aldosterone?
`
`No
`
`Medication use, pseudohypoaldosteronism,
`amyloidosis, systemic lupus erythematosus,
`sickle cell disease, primary renal tubular defects
`
`Yes
`
`Low serum renin?
`
`No
`
`Yes
`
`Primary adrenal insufficiency
`Medication use (e.g., angiotensin-
`converting enzyme inhibitors,
`angiotensin receptor blockers, heparin)
`
`Hyperglycemia, primary renal tubular
`defects, medication use (e.g., nonsteroidal
`anti-inflammatory drugs, beta blockers)
`
`*—Symptoms of hyperkalemia, changes on electrocardiography, severe hyperkalemia (greater than 6.5 mEq per L [6.5 mmol per L]), rapid-onset
`hyperkalemia, or underlying heart disease, cirrhosis, or kidney disease.
`
`Figure 2. Suggested algorithm for the evaluation of hyperkalemia.
`Information from references 14 and 30.
`
`The incidence of hyperkalemia associated with use of
`potassium-sparing diuretics has risen since adding spi-
`ronolactone to standard therapy was shown to reduce
`morbidity and mortality in patients with congestive
`heart failure.29 Dual treatment with an ACE inhibitor
`and an ARB increases the risk of harmful adverse effects,
`including hyperkalemia, and should be avoided.11 Other
`commonly used medications known to cause hyperka-
`lemia include trimethoprim, heparin, beta blockers,
`digoxin, and nonsteroidal anti-inflammatory drugs.3
`
`Evaluation and Management of Hyperkalemia
`GENERAL PRINCIPLES
`As with hypokalemia, the immediate danger of hyper-
`kalemia is its effect on cardiac conduction and muscle
`strength, and initial efforts should focus on determin-
`ing the need for urgent intervention (Figure 2).14,30
`
`The absence of symptoms does not exclude severe hyper-
`kalemia, because hyperkalemia is often asymptomatic.
`Because of their increased risk of developing hyperka-
`lemia, patients with underlying renal dysfunction merit
`special attention.22
`
`HISTORY AND PHYSICAL EXAMINATION
`
`Severe hyperkalemia (more than 6.5 mEq per L [6.5 mmol
`per L]) can cause muscle weakness, ascending paralysis,
`heart palpitations, and paresthesias. Chronic kidney dis-
`ease, diabetes, heart failure, and liver disease all increase
`the risk of hyperkalemia. Clinicians should review
`patients’ medications to identify those known to cause
`hyperkalemia, and ask patients about the use of salt sub-
`stitutes that contain potassium. The physical examina-
`tion should include assessment of blood pressure and
`intravascular volume status to identify potential causes
`
`September 15, 2015 ◆ Volume 92, Number 6
`
`www.aafp.org/afp
`
`American Family Physician 491
`
`Potassium Disorders
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2021, Page 5
`
`

`

`Management of Hyperkalemia
`
`Potassium > 5 mEq per L (5 mmol per L)
`
`Potassium 5 to 5.9 mEq
`per L (5 to 5.9 mmol per L)
`and no risk factors?*
`
`Yes
`
`No
`
`Potassium > 6 mEq per L
`(6 mmol per L) or risk factors?*
`
`ECG changes present?
`
`No
`
`Yes
`
`Evaluate potential
`causes (Figure 2)
`Consider dietary
`modification
`Consider medication
`adjustments
`Consider sodium
`polystyrene sulfonate
`(Kayexalate)†
`
`Administer intravenous
`calcium in addition to A
`
`A
`
`Administer insulin with
`glucose, with or without
`nebulized albuterol
`Consider dialysis
`Serial ECG and continuous
`cardiac monitoring
`
`Monitor serum potassium, glucose
`
`Potassium < 6 mEq per L?
`
`No
`
`Return to A
`
`Yes
`
`Continue to monitor potassium
`Consider more continuous cardiac
`monitoring
`Evaluate potential causes (Figure 2)
`Consider dietary modifications
`Consider medication adjustments
`Consider sodium polystyrene
`sulfonate†
`
`NOTE: See Table 3 for a summary of medication therapy for hyperkalemia.
`
`include measurement of serum blood
`urea nitrogen and creatinine, measure-
`ment of urine electrolytes and creatinine,
`and assessment of acid-base status. Fur-
`ther evaluation may include measurement
`of serum glucose to evaluate for hypergly-
`cemia, and measurement of serum renin,
`aldosterone, and cortisol to further inves-
`tigate kidney and adrenal function.
`ECG should be considered if the potas-
`sium level is greater than 6 mEq per L; if
`there are symptoms of hyperkalemia; if
`there is suspicion of rapid-onset hyperka-
`lemia; or among patients with underlying
`kidney disease, heart disease, or cirrhosis
`who have a new case of hyperkalemia. Find-
`ings on ECG are neither sensitive nor spe-
`cific for hyperkalemia. Therefore, although
`ECG changes should trigger urgent treat-
`ment, treatment decisions should not be
`based solely on the presence or absence of
`ECG changes.32
`Peaked T waves are the prototypical,
`and generally the earliest, ECG sign of
`hyperkalemia. Other ECG changes include
`P-wave flattening, PR-interval prolon-
`gation, widening of the QRS complex,
`and sine waves.19 Hyperkalemia-induced
`arrhythmias include sinus bradycardia,
`sinus arrest, ventricular tachycardia, ven-
`tricular fibrillation, and asystole.19
`
`*—Symptoms of hyperkalemia, rapid-onset hyperkalemia, or underlying heart disease,
`cirrhosis, or kidney disease.
`†—Avoid in patients with or at risk of developing abnormal bowel function.
`
`Figure 3. Suggested algorithm for the management of hyperkalemia.
`(ECG = electrocardiography.)
`
`of kidney hypoperfusion, which can lead to hyperkale-
`mia. Neurologic signs of hypokalemia include general-
`ized weakness and decreased deep tendon reflexes.11
`
`LABORATORY ANALYSIS AND ECG
`
`Repeat measurement of serum potassium can help iden-
`tify pseudohyperkalemia, which is common and typi-
`cally results from potassium moving out of cells during
`or after sample collection.31 Other laboratory studies
`
`Treatment of Hyperkalemia
`GENERAL PRINCIPLES
`The goals of acute treatment are to pre-
`vent potentially life-threatening cardiac
`conduction and neuromuscular dis-
`turbances, shift potassium into cells,
`eliminate excess potassium, and resolve
`the underlying disturbance. Patients
`with chronic hyperkalemia should be
`counseled to reduce dietary potassium.
`Although redistributive hyperkalemia is uncommon, a
`cautious approach is warranted because treatment may
`not involve attempts to eliminate potassium, and cor-
`rection of the underlying problem can provoke rebound
`hypokalemia. Indications for prompt intervention are
`symptoms of hyperkalemia, changes on ECG, severe
`hyperkalemia (greater than 6.5 mEq per L), rapid-
`onset hyperkalemia, or underlying heart disease, cir-
`rhosis, or kidney disease.24,30,33-35 Potassium should be
`
`492 American Family Physician
`
`www.aafp.org/afp
`
`Volume 92, Number 6 ◆ September 15, 2015
`
`Potassium Disorders
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2021, Page 6
`
`

`

`Table 3. Medications for the Treatment of Hyperkalemia
`
`Medication
`
`Dosage
`
`Onset
`
`Duration
`
`Approximate
`potassium-
`lowering effect Mechanism
`
`Cautions
`
`Acute treatment
`Calcium
`Calcium chloride,
`10 mL of 10%
`solution IV over
`5 to 10 minutes, or
`calcium gluconate,
`30 mL of 10%
`solution IV over 5
`to 10 minutes
`
`Insulin
`
`Regular insulin, 10
`units IV followed
`immediately by
`50 mL of 50%
`glucose (25 g) IV
`
`Immediate
`
`30 to 60
`minutes
`
`—
`
`May potentiate digoxin
`toxicity; calcium chloride
`can cause phlebitis and
`tissue necrosis
`
`Stabilizes cardiac
`muscle cell
`membrane; no
`effect on serum
`potassium
`or total body
`potassium
`
`15 minutes
`
`≥ 2 hours
`
`0.7 to 1 mEq
`per L
`(0.7 to 1
`mmol per L)
`
`Shifts potassium
`into cells; no
`effect on total
`body potassium
`
`May cause hypoglycemia;
`glucose is unnecessary if
`serum glucose level is
`> 250 mg per dL (13.9
`mmol per L); additive
`effect when combined
`with albuterol
`
`Can cause tachycardia and
`thus should be used with
`caution in patients with
`underlying heart disease;
`potassium-lowering
`effect not reliable in all
`patients; additive effect
`when combined with
`insulin
`
`Association with
`gastrointestinal
`complications,
`particularly when
`combined with sorbitol;
`should be avoided
`in patients at risk of
`abnormal bowel function
`
`Albuterol
`
`10 to 20 mg
`nebulized
`
`30 minutes
`
`≥ 2 hours
`
`0.5 to 1 mEq
`per L
`(0.5 to 1
`mmol per L)
`
`Shifts potassium
`into cells; no
`effect on total
`body potassium
`
`Subacute treatment
`Sodium
`Oral: 15 g, 1 to 4
`polystyrene
`times daily
`sulfonate
`Rectal: 30 to 50 g
`(Kayexalate)
`every 6 hours in a
`retention enema
`
`2 to 24 hours
`
`Variable
`
`Variable
`
`Binds potassium
`in exchange for
`sodium; lowers
`total body
`potassium
`
`IV = intravenously.
`
`Information from references 22, 30, and 36.
`
`monitored often because patients are at risk of rede-
`veloping hyperkalemia until the underlying disorder is
`corrected and excess potassium is eliminated. Figure 3 is
`an algorithm for the management of hyperkalemia, and
`Table 3 22,30,36 summarizes medications used in the treat-
`ment of the condition.
`
`URGENT TREATMENT
`
`Intravenous Calcium. Intravenous calcium, which helps
`prevent life-threatening conduction disturbances by
`stabilizing the cardiac muscle cell membrane, should
`be administered if ECG changes are present.24,25,35 Intra-
`venous calcium has no effect on plasma potassium
`concentration. If after five minutes, follow-up ECG con-
`tinues to show signs of hyperkalemia, the dose should
`
`be repeated.37 Clinicians should be aware that intrave-
`nous calcium has a short duration, ranging from 30 to
`60 minutes.
`Insulin and Glucose. The most reliable method for
`shifting potassium intracellularly is administration of
`glucose and insulin. Typically, 10 units of insulin are
`administered, followed by 25 g of glucose to prevent
`hypoglycemia.37 Because hypoglycemia is a common
`adverse effect even with the provision of glucose, serum
`glucose levels should be monitored regularly. Patients
`with a serum glucose level of more than 250 mg per dL
`(13.9 mmol per L) typically do not require coadministra-
`tion of glucose.
`Inhaled Beta Agonists. Albuterol, a beta2 agonist,
`is an underutilized adjuvant for shifting potassium
`
`September 15, 2015 ◆ Volume 92, Number 6
`
`www.aafp.org/afp
`
`American Family Physician 493
`
`Potassium Disorders
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2021, Page 7
`
`

`

`SORT: KEY RECOMMENDATIONS FOR PRACTICE
`
`Clinical recommendation
`
`Evidence
`rating
`
`References
`
`Patients with a history of congestive heart failure or myocardial infarction should maintain a serum
`potassium concentration of at least 4 mEq per L (4 mmol per L).
`Intravenous potassium should be reserved for patients with severe hypokalemia (serum potassium
`< 2.5 mEq per L [2.5 mmol per L]), hypokalemic ECG changes, or physical signs or symptoms of
`hypokalemia, or for those unable to tolerate the oral form.
`Prompt intervention and possible ECG monitoring are indicated for patients with severe hypokalemia
`(serum potassium < 2.5 mEq per L) or severe hyperkalemia (serum potassium > 6.5 mEq per L
`[6.5 mmol per L]); ECG changes; physical signs or symptoms; possible rapid-onset hyperkalemia; or
`underlying kidney disease, heart disease, or cirrhosis.
`Intravenous calcium should be administered if hyperkalemic ECG changes are present.
`Intravenous insulin and glucose, inhaled beta agonists, and dialysis are effective in the acute
`treatment of hyperkalemia.
`Sodium polystyrene sulfonate (Kayexalate) may be effective in lowering total body potassium in the
`subacute setting.
`
`C
`
`C
`
`C
`
`C
`B
`
`C
`
`15
`
`22
`
`7, 15, 24, 30,
`33-35
`
`24, 25, 35
`39
`
`25
`
`ECG = electrocardiography.
`
`A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
`oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.
`org/afpsort.
`
`intracellularly.24,37 All forms of administration (i.e.,
`inhaled, nebulized, and intravenous where available)
`are effective. It should be noted that the recommended
`dose of nebulized albuterol (10 to 20 mg) is four to eight
`times greater than the typical respiratory dose. There is
`an additive effect when albuterol is combined with insu-
`lin.38 Albuterol’s potassium-lowering effect is mitigated
`in some patients, particularly those with end-stage kid-
`ney disease; therefore, albuterol should not be used as
`monotherapy.30
`Sodium Bicarbonate. Although sodium bicarbonate is
`often used to treat hyperkalemia, the evidence to sup-
`port this use is equivocal, showing minimal to no ben-
`efit.39 Therefore, sodium bicarbonate should not be used
`as monotherapy. It may have a role as adjuvant therapy,
`particularly among patients with concurrent metabolic
`acidosis.24,39,40
`
`LOWERING TOTAL BODY POTASSIUM
`
`Potassium can be removed via the GI tract or the kid-
`neys, or directly from the blood with dialysis. Dialysis
`should be considered in patients with kidney failure or
`life-threatening hyperkalemia, or when other treatment
`strategies fail.23,37 Other modalities are not rapid enough
`for urgent treatment of hyperkalemia.39
`Currently available cation exchange resins, typi-
`cally sodium polystyrene sulfonate (Kayexalate) in the
`United States, are not beneficial for the acute treatment
`of hyperkalemia but may be effective in lowering total
`body potassium in the subacute setting.25,39 Because
`sodium polystyrene sulfonate can be constipating, many
`formulations include sorbitol for its laxative effects.
`However, case reports linking the concomitant use of
`
`sodium polystyrene sulfonate and sorbitol to GI injury
`prompted a U.S. Food and Drug Administration boxed
`warning.41,42 More recent reports implicate sodium poly-
`styrene sulfonate alone.43 Therefore, use of the drug with
`or without sorbitol should be avoided in patients with or
`at risk of abnormal bowel function, such as postopera-
`tive patients and those with constipation or inflamma-
`tory bowel disease.42
`There is no evidence supporting the use of diuret-
`ics for the acute treatment of hyperkalemia. However,
`diuretics, particularly loop diuretics, may play a role in
`the treatment of some forms of chronic hyperkalemia,
`such as that caused by hyporeninemic hypoaldosteron-
`ism.39,44 Fludrocortisone is an option for hyperkalemia
`associated with mineralocorticoid deficiency, including
`hyporeninemic