Now, total body potassium can essentially be split into two components— This balance is maintained by the sodium-potassium
odium-potassium pump, which pumps 2
intracellular and extracellular potassium, or potassium inside and outside cells,
respectively.
Now, the vast majority, around 98%, of all of the body’s potassium is intracellular,
or inside of the cells.
In fact, the concentration of potassium inside the cells is about 150 mEq/L whereas
outside the cells it’s only about 4.5 mEq/L.
With hyperkalemia, hyper- means over and -kal- refers to potassium, and -emia
refers to the blood, so hyperkalemia means higher than normal potassium levels in
the blood, generally over 5 mEq/L.
Hyperkalemia
- serum potassium concentration greater than 5 mEq/L (mmol/L)
The ratio of INTRAcellular to EXTRAcellular potassium is important for generation of
action potentials and is essential for normal functions of neurons, skeletal muscles
and cardiac muscles.
This is why potassium levels in the blood are strictly regulated within a narrow
range between 3.5 and 5 mmol/L.
Classifications (based on severity):
1.Mild (5.1-5.9 mEq/L [mmol/L])
2.Moderate (6-7 mEq/L [mmol/L])
3.Severe (above 7 mEq/L [mmol/L])
Epidemiology
- much less common than hypokalemia
- 1% to 10% incidence in hospitalized patients
- Most cases are the result of overcorrection of hypokalemia with IV
potassium supplements
- Severe form occurs more commonly in elderly patients with renal
insufficiency
Keep in mind that these potassium ions carry a charge, so the difference in
concentration also leads to a difference in charge, which establishes an overall
electrochemical gradient across the cell membrane. This is called the internal
potassium balance.
potassium ions in for every 3 sodium ions out, as well as potassium leak channels
and inward rectifier channels that are scattered throughout the membrane.
This concentration gradient is extremely important for setting the resting
membrane potential of excitable cell membranes, which is needed for normal
contraction of smooth, cardiac, and skeletal muscle.
Also, though, in addition to this internal potassium balance, there’s also an external
potassium balance, which refers to the potassium you get externally through the
diet every day.
On a daily basis the amount of potassium that typically gets taken in usually ranges
between 50 mEq/L to 150 mEq/L, which is way higher than the extracellular
potassium concentration of 4.5 mEq/L, so your body has to figure out a way to
excrete most of what it takes in.
This external balancing act is largely taken care of by the kidneys, where excess
potassium is secreted into a renal tubule and excreted in the urine.
Also though, a small amount dietary potassium is also lost via the gastrointestinal
tract and sweat.
Etiology and Pathophysiology
Hyperkalemia develops when
- potassium intake exceeds excretion (true hyperkalemia) (ie, elevated total-
body stores)
- when the transcellular distribution of potassium is disturbed (ie, normal
total-body stores)
Four primary causes of hyperkalemia
1. Increased potassium intake
2. Decreased potassium excretion
3. Tubular unresponsiveness to aldosterone
4. Redistribution of potassium into the extracellular space
So, in order for there to be too much potassium in the blood, or hyperkalemia,
there are many possibilities.
The first is an external balance shift, which is most often caused by a decrease in
sodium excretion in the kidneys, which raises the level of potassium in the blood.
The second is an internal balance shift where potassium moves out of cells, and
into the interstitium and blood.
Associated with Increased Potassium Intake
Common dietary sources associated with the development of hyperkalemia:
- Fresh fruits and vegetables contain large amounts of potassium
- Potassium chloride salt substitute
( contains approximately 10 to 15 mEq (mmol) potassium per gram)
- Over-the-counter herbal and alternative medicine product
Associated with Decreased Renal Potassium Excretion
-When the kidney is unable to excrete potassium appropriately = potassium is
retained
o Most other cases, though have to do with the kidneys, and their ability to
regulate what stays in the blood and gets excreted into the urine.
o Typically for people on a normal diet, more potassium is secreted than
reabsorbed at this stage, and it could be that all of the remaining
potassium is secreted out if it’s simply not needed.
o Now, an important hormone that helps regulate potassium reabsorption or
secretion in the kidneys is aldosterone.
o Aldosterone increases the number of sodium channels and the number of
potassium channels on the lumen side of the principal cell as well as
sodium-potassium pumps on the basolateral side of the principal cells.
o This allows sodium to move from the tubule into the cell, and then to get
pumped into the blood by the sodium-potassium pumps.
o As the pumps collectively move more sodium into the blood under the
influence of aldosterone, more potassium gets pumped into the cell,
which raises the intracellular potassium concentration.
o Having more intracellular potassium and also having more potassium
channels promotes potassium secretion.
o All that being said, in situations where somebody’s unable to produce
enough aldosterone, or hypoaldosteronism or adrenal insufficiency, then
there’s less potassium secretion by the principal cells, and therefore
more potassium is retained, leading to hyperkalemia.
- Medications (ACEIs, ARBs, direct renin inhibitors, K-sparing diuretics &
NSAIDs) that inhibit aldosterone and potassium excretion
o Along the same lines, drugs that reduce the effect of aldosterone can also
cause hyperkalemia, and these are drugs like renin inhibitors, ACE
inhibitors, angiotensin II receptor antagonists, selective aldosterone
blockers, and potassium-sparing diuretics.
o Potassium-sparing diuretics like spironolactone induce mineralocorticoid
or aldosterone resistance, either by competing with aldosterone for
receptor sites- like spironolactone or by directly blocking the sodium
channels in the collecting tubule- like amiloride.
o ACEIs and ARBs: induce hyperreninemic hypoaldosteronism by blocking
the renin- angiotensin- aldosterone system at different levels, such as ACE
inhibitors- like, and angiotensin 2 receptor blockers or ARBs- like
candesartan.
o NSAIDs: induce hyporeninemic hypoaldosteronism, like aspirin and
calcineurin inhibitors- like Cyclosporine or Tacrolimus.
o B- blockers: Propranolol, cause hyperkalemia because they interfere with
beta-2-adrenergic activity, which slows potassium entering the cells. This is
particularly relevant in individuals with renal impairment- because the
excess potassium isn’t excreted properly.
- Diseases (adrenal insufficiency, Addison disease, and selective
hypoaldosteronism) that inhibit aldosterone and potassium excretion
Another cause of hyperkalemia is primary adrenal insufficiency, or Addison’s
disease, which is when the adrenal glands are unable to make sufficient cortisol and
aldosterone.
Adrenal Insufficiency: low sodium and high potassium levels and usually indicate
that the kidneys are not working well. Doctors who suspect adrenal insufficiency
measure cortisol levels, which may be low, and ACTH levels.
This leads to hyperreninemic hypoaldosteronism- because the low levels of
aldosterone will stimulate renin secretion.
NOT SURE: Other drugs: digoxin, cyclosporine, tacrolimus, trimethoprim–
sulfamethoxazole, heparin, and pentamidine
Tubular Unresponsiveness to Aldosterone
Can produce a defect in renal tubular potassium secretion:
1. Sickle cell anemia
2. SLE
3. Amyloidosis
- possibly as the result of an alteration in the aldosterone-binding site.
Redistribution of Potassium into the Extracellular Space
- Efflux of potassium from within the cell into the extracellular space, with
no change in total-body potassium stores
o seen with the presence of metabolic acidosis, diabetes mellitus,
CKD, or lactic acidosis
o One potential cause of an internal potassium balance shift is
insulin deficiency.
 o This is because, after a meal, glucose increases in the blood, and
at the same time, insulin gets released which binds to cells and
stimulates uptake of that glucose.
o Insulin also increases the activity of the sodium/potassium pump,
which pulls potassium into cells.
o NOTE SURE: People with type I diabetes don’t make enough
insulin, so when they eat a meal—especially a meal with a lot of
potassium—that potassium sits in the blood instead of being
taken into cells, and this causes hyperkalemia.
o Another cause of an internal potassium balance shift could be an
acidosis, which is when the blood becomes too acidic, in other
words, there’s a higher concentration of hydrogen ions—which
means a lower blood pH.
o One way the body can increase the blood pH is by moving
hydrogen ions out of the blood and into cells.
o To accomplish this, cells use a complex series of multiple ion
channels, exchangers, and pumps to exchange hydrogen ions for
potassium ions across the cell membrane.
o So in order to help compensate for an acidosis, hydrogen ions
enter cells and potassium ions leave the cells and enter the
blood, which might help with the acidosis, but results in
hyperkalemia.
o Now, this isn’t always the case for acidosis, though. in respiratory
acidosis, potassium levels aren’t affected because CO2 is lipid
soluble and freely moves into cells without being exchanged for
potassium, therefore no hyperkalemia.
o Similarly, when there’s a metabolic acidosis from excess organic
acids like lactic acid and ketoacids, protons can enter cells with
the organic anion rather than having to get exchanged for
potassium ions.
- β-Blockers can also result in a transcellular potassium shift
o Certain catecholamines can also shift potassium out of cells, and
this is via beta-2-adrenergic and alpha-adrenergic receptors on
cell membranes. When activated, beta-2-adrenergic receptors
stimulate the sodium-potassium pump, which pulls potassium
from the blood into cells.
o Meanwhile alpha-adrenergic receptors cause a shift of potassium
out of cells via calcium-dependent potassium channels.
o So, that said, beta-2-adrenergic antagonists, also known as beta
blockers, and alpha-adrenergic agonists, both cause a shift in
potassium out of the cells and into the blood.
- Pseudohyperkalemia - serum potassium concentration can be falsely
elevated
o common in the setting of extravascular hemolysis of red blood
cells: potassium gets released from muscle cells during muscle
contraction, so if a person repeatedly clenches their fist during the
blood draw, then potassium levels can rise
o also occur in conditions of thrombocytosis or leukocytosis:
o thrombocytosis: is marked increase in platelet count. And is one
of the first identified cause of pseudohyperkalemia. It is due to
increased release of potassium from activated platelets during the
process of clotting.
o leukocytosis:
 in chronic lymphocytic leukemia, the lymphocytes are
frail, so they break easily and release potassium. The key
is to simply repeat the serum potassium level and to
obtain a CBC.
- If pseudohyperkalemia is ruled out, then there’s a true hyperkalemia.
- Truly elevated potassium conc are normally associated with other
laboratory abnormalities, like low CO2, or high blood urea nitrogen and
creatinine concentrations.
CLINICAL PRESENTATION:
SCRIPT: Hyperkalemia is often asymptomatic, but it can cause symptoms like
palpitations, paresthesias, and muscle weakness.
Ultimately if hyperkalemia is severe enough, it can lead to a flaccid paralysis
that starts in the lower extremities and ascends upward.
In addition, severe hyperkalemia can affect renal function - causing a person to
become oliguric- meaning their daily urine output can fall below 400 milliliters.
Whenever potassium levels are above 5 mEq/L, the first to do is an EKG.
If the EKG is normal and the individual doesn’t have symptoms of
hyperkalemia, and if there’s no apparent cause of hyperkalemia, then it may be
due to pseudohyperkalemia. This happens when potassium moves out of the
cells during or after a blood draw.
 So, with too much potassium outside the cell, the membrane potential can
become more positive, to the point of even causing contraction. Initially this
might cause mild intestinal cramping.

But eventually, the resting membrane potential gets so high that it’s above the
threshold potential, meaning that once the muscle depolarizes and contracts, it
can’t repolarize to allow another contraction.
In skeletal muscles, this can cause weakness and flaccid paralysis, that starts in
the lower extremities and ascends upward.

Hyperkalemia, though, also affects cardiac muscle contractions, which can lead to
cardiac arrhythmias and cardiac arrest.

Hyperkalemia is diagnosed based on the presence of an elevated potassium levels

A) normal ECG presentation in the blood, generally over 5.5 mEq/L.
(B) Peaking of the T wave [at serum potassium concentrations of ~5.5 to 6
mEq/L (mmol/L) It’s also important to get an electrocardiogram, which typically shows tall, peaked T
(C) Widening of the PR interval waves with a narrow base best seen in the precordial leads V1 through V6, as well
(D) Loss of the P wave as a shortened QT interval, and ST-segment depression.
(E) Widening of the QRS complex
(F) Merging of the QRS complex with the T wave In severe cases, it can also cause a prolonged PR interval, a diminished or absent P
wave, and a widened QRS complex.
everyone with hyperkalemia should be continuously monitored because
ventricular fibrillation can occur anytime. TREATMENT
With severe hyperkalemia, treatment might be done by using
calcium to stabilize the myocardial cell membrane, using
insulin, glucose, beta-adrenergic agonists, and sodium bicarbonate to shift
potassium into the intracellular space, using
resins that bind potassium to promote potassium elimination in the gastrointestinal
tract, using potassium-wasting diuretics to promote potassium elimination in the
kidneys, and in severe cases—dialysis.

Desired Outcomes
- To antagonize adverse cardiac effects
- Reverse signs and symptoms that are present
- Return the serum and total-body stores of potassium to normal

Optimal treatment approach is dependent on:

- Severity of hyperkalemia
Well remember that the concentrations of potassium inside and outside of cells is - rapidity of its development
really—super—important for maintaining the resting cell membrane potential, - patient’s clinical condition
and ultimately for allowing a cell to depolarize and a muscle to contract, and that
includes all muscles—skeletal, smooth, and cardiac.
 Pharmacologic Therapy
Initial treatment should be focused on
- antagonism of the cardiac membrane actions of hyperkalemia (eg, IV Calcium Chloride OR Gluconate
administration of calcium). - for symptomatic patients or in those with severe hyperkalemia: to protect the
cardiac muscle
Secondarily: - Antagonizes the cardiac membrane effect of hyperkalemia
- attempt to decrease extracellular potassium concentration by promoting - Reduces the electrical threshold potential for cardiac myocytes and reverses ECG
its intracellular movement changes within minutes
o with insulin - Should not be given to patients receiving digoxin
o β2-receptor agonists
o sodium bicarbonate Calcium chloride provides approximately three times more calcium than equal
- enhance its removal from the body by hemodialysis: volumes of the gluconate salt; however, it can cause tissue necrosis if extravasation
o the oral administration of cation-exchange resins, and/or the use occurs. For this reason, calcium gluconate is more commonly administered
of loop diuretics Insulin, Dextrose, Sodium bicarbonate, and β2 -adrenergic receptor agonist
- drugs that result in an intracellular shift of potassium
General Approach to Treatment - for rapid correction of hyperkalemia
- IV calcium should be administered to prevent or treat any cardiac
manifestations Rapid acting therapies can help move potassium back into the cells. This doesn’t
- Administer drugs that cause an intracellular shift of potassium, followed by lower total body potassium, but moving the potassium out of the serum and into
the initation of those that increase the elimination of potassium from the the cells, helps to stabilize the cardiac muscle.
body
- May initiate ion exchange resin that results in removal of potassium from In metabolic acidosis, the body tries to raise the pH, by getting the excess hydrogen
the body over several hours to days ions to enter the cells. That’s done by exchanging them with potassium ions which
leave the cells and enter the blood to maintain electroneutrality- resulting in
Nonpharmacologic Therapy hyperkalemia.
If serum potassium is between 5 and 5.4 mEq/L and the individual doesn’t have
any symptoms or EKG changes, then potassium can be lowered through dietary Sodium Bicarbonate
modifications. - for patients with concomitant metabolic acidosis
- causes a rapid intracellular potassium shift + raise the extracellular pH
These individuals should avoid foods that are rich in potassium- especially fruits-
like bananas, oranges, watermelons and vegetables, like eggplants, peas, and should NOTE that: NAHCO3 is much less effective when hyperkalemia is not related
potatoes. to metabolic acidosis as well as in patients with ESRD

Glycyrrhetinic acid Now, to remove potassium from the body there are a few options. In individuals
- the active ingredient in licorice without renal impairment, loop diuretics- such as furosemide- can be used to dump
- inhibits the enzyme 11β-hydroxy-steroid dehydrogenase II = increasing cortisol more potassium into the urine.
availability in the colon
- net result is enhanced potassium elimination in the feces Furosemide
- For patients with normal renal function or those with stage 3 or 4 CKD
Low potassium dialysate - Promote urinary potassium excretion
- enhance the removal of potassium - IV administration at a dosage of 40 to 80 mg
- Oral furosemide; IV:PO dose ratio (1:2) & delayed onset of action
- Required close monitoring of the patient’s volume status and other electrolyte
concentrations
In individuals with impaired renal function, furosemide can be dose-adjusted for
renal function and can be given with isotonic saline solution.
Insulin and Dextrose
- Increases the activity of the Na+-K+-ATPase pump  intracellularly shifting
potassium
- insulin to stimulate the sodium/potassium pump, which normally pushes
potassium back into cells - the potassium levels climb.
Glucose
- Glucose should be given with insulin because hypoglycemia can develop as a result
of the effects of the insulin therapy.
- should be given with insulin unless the serum glucose is above 250 mg/dL
β2 -adrenergic agonists
- Dual mechanism for lowering serum potassium
- Stimulate the Na+-K+-ATPase pump to promote intracellular potassium
uptake
- Stimulate pancreatic β-receptors to increase insulin secretion
-injectable albuterol is not available in the United State
-the doses of inhaled albuterol used for hyperkalemia are at least four times higher
than those typically used for bronchospasm
-should not be used alone for the urgent treatment of hyperkalemia in CKD patients
Most other cases, though have to do with the kidneys, and their ability to regulate
what stays in the blood and gets excreted into the urine.
- The kidney does this by the processes of filtration, reabsorption, and
secretion in the nephron. First off, potassium is freely filtered from the
blood into the urine at the glomerulus.
- After that, about 67% is reabsorbed in the proximal convoluted tubule, and
an additional 20% is reabsorbed in the thick ascending limb, and that
leaves about 13% of the initial amount, right?
- And at this point the distal tubule and collecting ducts of the nephron can
either reabsorb or secrete potassium depending on what the body needs.
- Now, reabsorption in this area is taken care of by the alpha-intercalated
cells, while secretion is controlled by the principal cells.
- Now, acute kidney injury can cause a low glomerular filtration rate, which
is the volume of blood filtered through the kidney over a period of time,
and this can lead to oliguria and hyperkalemia.
- In these situations, the nephron tries to hold on to salt and water, so by
the time filtrate has moved into the distal tubule, there’s very little of both
sodium and water remaining in the lumen. Having little water in the lumen,
creates a relatively high potassium concentration in the lumen.
- In addition to this, because less sodium is in the distal tubule, less of it
moves through the luminal sodium channel into the principal cell and gets
pumped over to the other side by the basolateral sodium-potassium pump.
- And this means less potassium gets into the principal cell, and this leads to
more potassium in the blood and hyperkalemia.
Alright, so there are all these ways to develop hyperkalemia, but what happens
when somebody has hyperkalemia?
Alright, as a quick recap, hyperkalemia describes a high concentration of potassium
in the blood, which can be the result of shifts in internal potassium balance where
potassium moves out of the body’s cells, as well as external potassium balance
problems having to do with the intake of potassium and typically the kidney’s ability
to to regulate its excretion.
Either way, the high potassium levels leads to issues with muscle contractions,
which could be issues with the smooth, skeletal, or cardiac muscles.