S. Faubel and J.

Topf 19 Hyperkalemia

19
19 Hyperkalemia

539
The Fluid, Electrolyte and Acid-Base Companion

Introduction!Hyperkalemia is an elevated plasma potassium

concentration.

Na Cl
Na Mg
+ –

K+ HCO
22.989 24.305

–
19 20
Potassium Calcium

3 K Ca
39.098 40.08

Hyperkalemia is defined as a plasma potassium concentration greater

than 5 mEq/L. Hyperkalemia is a common complication of renal failure.
In the absence of renal failure, hyperkalemia is relatively uncommon be-
cause the kidneys have the ability to excrete large amounts of potassium.
Recognizing hyperkalemia in patients with normal renal function is impor-
tant because it is a flag for systemic disorders that might otherwise go un-
noticed.

Sometimes, it is useful to convert from milligrams to milliequivalents of potassium.

This was
reviewed in Chapter 1,Moles and Water. To convert milligrams to milliequivalents, divide
the milligrams by the molecular weight. For example, one serving of orange juice (8 oz)
contains 450 mg of potassium; 450 mg ÷ 39 is equal to 1 .3 mEq of potassium.

Hyperkalemia is defined as a plasma potassium greater than aaa

______ mEq/L. five

In the absence of _______ ________, hyperkalemia is uncommon. renal failure

Normally, the kidney can effectively __________ a lot of potassi- excrete

um in order to prevent ____________. hyperkalemia

540
S. Faubel and J. Topf 19 Hyperkalemia

Overview: The body has a two-step defense against hyperkale-

mia: intracellular buffering followed by renal excretion.
+
K

compensation
correction
K
+
+
K

K +
K+

+
K

+
K

K
+

1 2
K +

+
K
Movement of potassium into cells com- Renal excretion of potassium cor-
pensates for hyperkalemia. rects hyperkalemia.

Potassium loads are handled in a two-step process consisting of intracel-

lular compensation followed by renal correction.
Compensation. A potassium load is buffered by the movement of potas-
sium into cells. This immediate defense against hyperkalemia is stimulated
by:
• catecholamines
• insulin
• increased plasma potassium
Correction. Hyperkalemia is corrected by the excretion of excess potas-
sium by the kidney. This long-term defense against hyperkalemia is stimu-
lated by:
• elevated plasma potassium
• aldosterone
• increased flow through the distal tubules
The kidney excretes the majority of a potassium load within hours of in-
gestion.

The compensation for a K+ load is the shift of plasma potassium extracellular

into ______________ . cells

The molecular weight of potassium is ______. 39

A bunch of bananas contains about 3 grams of potassium. How

many milliequivalents is this? 77 mEq

541
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Hyperkalemia can be due to increased intake, move-

ment out of cells or decreased renal excretion.

+
K

K
+ K

+
K +

increased intake movement out of cells impaired renal excretion

Hyperkalemia results from three fundamental mechanisms:

• increased potassium intake from diet or medications
• movement of potassium out of cells
• impaired renal excretion of potassium
Acute hyperkalemia is often due to the convergence of multiple etiologies
(e.g., dietary indiscretion in a patient with renal failure). Chronic hyper-
kalemia is always due to impaired renal potassium excretion.

Mechanisms of hyperkalemia can be divided into _______ groups: three

• increased ________ intake
• movement of ____________ potassium to the extracellular intracellular
compartment
• impaired renal __________ of potassium. excretion

Chronic hyperkalemia is always due to impaired potassium excre-

tion by the _________. kidney

542
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Increased intake!Increased oral intake of potassium

causes hyperkalemia only if the ingestion is large and fast.

oj
oj oj oj oj
oj

Increased oral intake of potassium rarely causes hyperkalemia in patients

with normal renal function. Over time, the kidney is able to adapt to in-
creased potassium intake. Because the kidney is so adaptive, only acute
potassium loads are able to cause significant hyperkalemia.
For healthy adults to become significantly hyperkalemic from an oral in-
gestion of potassium, at least 150 milliequivalents must be ingested quickly.
This dose of potassium would require the rapid consumption of three quarts
of Everfresh® Pure 100% Orange Juice from concentrate.
It must be kept in mind that in the presence of renal insufficiency, even
modest ingestions of potassium can result in significant hyperkalemia.

DANGER! Oral citrate and bicarbonate solutions used to treat the chronic acidosis TAof R
or renal failure come in two forms: with or without potassium. Giving citrate with potassium
to a patient with metabolic acidosis and renal failure can be lethal.

Gradual increases in K+ intake do not cause ____________ be- hyperkalemia

cause the kidney is able to __________ its ability to excrete K+. increase

543
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Increased intake!In the hospital, hyperkalemia can

be due to potassium hidden in IV solutions.

old red blood cell transfusion

potassium-containing medicine
(penicillin)

KCl IV fluid

Increased intake of potassium can also occur with IV infusions. The cagey
physician should be aware of some places potassium can hide, especially
when treating patients with renal failure.
Blood transfusions. As packed red blood cells for transfusion
age, intracellular potassium leaks out of the cells. Administration
of old packed RBCs can result in a significant potassium load.
Penicillin G. Penicillin G delivers 1.7 mEq of potassium per one
million units.
Maintenance fluids. Potassium chloride is sometimes added to
maintenance IV fluids.

An embarrassing cause of hyperkalemia is the over-treatment of hypokalemia.

This is a
common cause of hyperkalemia in hospitalized patients.

Potassium can sneak into a patient when giving _________ G or penicillin

red cell _________. transfusions

Increased intake of potassium is especially problematic in pa-

tients with _______ failure. renal

544
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Movement out of cells!The movement of potassi-

um out of cells can cause hyperkalemia.
cell death acidemia
K +

K+
severe exercise
+
K
K
+

lack of insulin

K+

medications: + K
hypertonic plasma
ß-blockers, digoxin

Because 99% of total body potassium is found inside cells, movement of a

small fraction of intracellular potassium into plasma can dramatically change
plasma potassium concentration.
Movement of potassium out of cells can be caused by:
• cell death
• potassium-hydrogen exchange in metabolic acidosis
• lack of insulin
• hypertonic plasma and solute drag
• medications such as `-blockers and digoxin
• severe exercise

99% of the body's potassium is found _________ cells. inside

A small shift of ________ from cells to the plasma can cause potassium
____________. hyperkalemia

The intracellular concentration of potassium is ___________. 140 mEq/L

The extracellular concentration of potassium is ___________. 4 mEq/L

545
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Movement out of cells!Cell death from trauma,

hypothermia or chemotherapy can cause hyperkalemia.

trauma

hypothermia
98.6° F

140 mEq/L

cell death
chemotherapy
tumor lysis syndrome

Because the intracellular concentration of potassium is so high, any in-

sult which destroys cells can cause severe hyperkalemia. There are three
common causes of cell death which can lead to hyperkalemia:
• Massive trauma, especially crush injuries, can cause cell lysis
and increase plasma potassium.
• Hypothermia causes widespread tissue necrosis.
• Cytotoxic chemotherapeutic agents destroy tumor cells, re-
leasing their intracellular contents: potassium, nucleic acids (con-
verted to BUN), uric acid and phosphate. This phenomenon is
known as tumor lysis syndrome.

Because the intracellular concentration of __________ potassium

is high, the destruction of _____ releases a lot of potas- cells
sium.

The three processes which cause cell death and hyper-

kalemia are: __________ trauma
____________ hypothermia
_______ ______ syndrome tumor lysis

546
S. Faubel and J. Topf 19 Hyperkalemia

Tumor lysis syndrome? What’s up with that?

hyperkalemia
tumor cell

hypocalcemia

PO4
hyperphosphatemia
3–
ATP

xanthine
xanthine oxidase
hypoxanthine
xanthine oxidase
uric acid

Tumor lysis syndrome is seen with the rapid destruction of a large

tumor. It occurs most commonly after the initiation of chemotherapy
for Burkitt’s lymphoma or leukemia, but it has been reported to occur
with solid tumors including breast cancer, sarcomas, ovarian cancer
and lung cancer. It is characterized by hyperkalemia, hyperphospha-
temia, hypocalcemia, hyperuricemia and acute renal failure.
The hyperphosphatemia comes from release of intracellular phosphate.
Precipitation of calcium phosphate in the kidney contributes to the acute
renal failure. The phosphate also binds calcium causing hypocalcemia which
can decrease cardiac output and cause arrhythmias.
The hyperuricemia comes from the metabolism of nucleotides. Urate
nephropathy used to be the predominant cause of acute renal failure in
tumor lysis syndrome; however, the use of prophylactic allopurinol has
decreased, but not eliminated, the incidence of this complication. There
is some concern that the elevated xanthine levels seen with allopurinol
may cause xanthiuria and contribute to acute renal failure.
Treatment focuses primarily on prevention of acute renal failure by
using allopurinol to prevent hyperuricemia and maintaining adequate
urine output with IV fluids and diuretics. High urine flow keeps the
urine concentration of uric acid low.
Hemodialysis is an effective treatment for the renal failure or to con-
trol the hyperkalemia, hyperphosphatemia and hyperuricemia of tu-
mor lysis syndrome.

547
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Movement out of cells!When plasma hydrogen con-

centration increases, cells absorb hydrogen and release potassium.

H
+
H+

K+
+
H
140 mEq/L

Think: potassium and hydrogen

walk together.
? hydrogen causes ? potassium
B hydrogen causes B potassium

One of the immediate safeguards against acidemia (increased H+ concen-

tration) is the movement of hydrogen into cells. Inside cells, hydrogen ions
are neutralized by intracellular buffers such as protein, hemoglobin, and
phosphate. As hydrogen ions are absorbed by cells, potassium is secreted in
order to maintain electroneutrality.

A decrease in pH is an increase in the plasma ___________ con- hydrogen

centration.

As hydrogen enters cells, potassium exits in order to maintain

________________. electroneutrality

548
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Movement out of cells!Diabetic ketoacidosis (DKA)

is associated with an extracellular shift of potassium.

K +
K +

K +
K
+
K
+

K +
K +

K +

K +

K + osmotic flow of water K +

K +

K +

K +

3 Na+ 2 K+
ATP

AMP
Hyperglycemia increases plasma osmolality, drawing water out of the intracellular
compartment. The movement of water drags potassium along with it. The lack of
insulin prevents the Na-K-ATPase pump from moving potassium into the cell.

Diabetic ketoacidosis is characterized by massive volume depletion, ke-

toacidosis and hyperglycemia. Upon presentation, plasma potassium is typi-
cally elevated even though total body potassium is low.
Hyperkalemia in DKA is multifactorial:
• Hyperglycemia increases plasma osmolality which causes the
osmotic movement of water out of the cell. As water leaves the
cell, it drags potassium with it. This is called solute drag.
• Normally, insulin stimulates Na-K-ATPase to pump potassium into
the cell. Since DKA is characterized by a lack of insulin, the Na-K-
ATPase pump is unable to pump plasma potassium back into the
cell.

Although the plasma potassium is often increased in DKA, total body potassium is usually
low. During treatment of DKA
with insulin, plasma potassium reenters cells and hyperkale-
mia can quickly turn to hypokalemia.

In DKA, the plasma osmolality is __________ (low/high) because high

of ______________. hyperglycemia

In DKA, water flows out of cells and drags _________ with it. potassium

In DKA, Na-K-ATPase activity is reduced due to a lack of

____________. insulin

549
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Movement out of cells!Two cardiac medications

interfere with the movement of potassium into cells.

beta blocker

K+ K +

ß-2 receptor
2 K+
ATP

AMP
digoxin

Because `<2 receptors stimulate the Because it specifically blocks the

ß-blockers Digoxin

Na-K-ATPase pumps, `<blockers can Na-K-ATPase pumps, digoxin can

increase plasma potassium concen- cause a dose-dependent increase in
tration through antagonism of the `< plasma potassium.
2 receptors. In digoxin toxicity, plasma potas-
Typically, beta-blockers cause only sium concentrations can rise as high
a minor and physiologically insignifi- as 13 mEq/L.
cant rise in the plasma potassium
concentration. Only when superim-
posed on a second defect in potassium
handling does the effect of `<block-
ers become significant.

The Na-K-ATPase pumps move potassium ________ (into/ out of) into
cells.

Because ________ inhibits the activity of Na-K-ATPase pumps, it digoxin

can interfere with the ability of potassium to enter cells, causing
_____________. hyperkalemia

550
S. Faubel and J. Topf 19 Hyperkalemia

Clinical correlation: Potassium movement out of cells while

in the test tube causes pseudohyperkalemia.

leukocytosis thrombocytosis
WBCs >100,000 platelets > 400,000

Pseudohyperkalemia is an elevated measurement of potassium con-

centration when the plasma potassium concentration is actually nor-
mal. Pseudohyperkalemia is due to leakage of potassium out of cells
contained in a blood sample before it is analyzed. It occurs in two situ-
ations:
• Mechanical trauma during or after drawing blood can cause
destruction of RBCs, allowing potassium to leak out. Usually,
the presence of hemolysis (lysis of RBCs) is reported by the lab.
• Measurement of potassium after the sample has clotted in the
setting of leukocytosis or thrombocytosis can cause pseudohyper-
kalemia. Potassium moves out of white blood cells and platelets
during clotting. This is significant only when counts are elevated:
WBC > 100,000 or platelets > 400,000.
The first problem can be avoided by gentle venipuncture without a
tourniquet. The second problem can be avoided by drawing blood into a
heparinized tube (green top) in order to prevent the blood from clotting.
Patients with leukemia can have very high WBC counts and are at risk for pseudohy-
perkalemia. However,before assuming an elevated plasma potassium is due to the
white count, evaluate the patient for tumor lysis syndrome. Patients with high WBC
counts are also at risk for
spontaneoustumor lysis that occurs in the absence of
chemotherapy.
Leukocytosis can also cause pseudo hypokalemia. The mechanism of this phenom-
enon is reviewed in Chapter 18,
Hypokalemia, page 496.

551
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Decreased renal excretion!Excretion of potassi-

um by the kidney is necessary to prevent hyperkalemia.

K
K

K K +

+
+
+

K + + K

The intracellular compartment compensates for acute increases in potas-

sium, but final correction depends on the excretion of potassium by the kid-
ney. All of the causes of hyperkalemia reviewed up to this point cause only
transient hyperkalemia which resolves when the kidney purges the excess
potassium.
If a patient has persistent hyperkalemia, then there is a defect in the renal
excretion of potassium.

Persistent hyperkalemia indicates a __________ in the defect

___________ excretion of potassium. renal

While the ______________ compartment provides an immediate intracellular

buffer against changes in potassium, definitive correction re-
quires the ____________ of potassium by the kidney. excretion

552
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Decreased renal excretion!There are three types

of problems which prevent the kidney from excreting potassium.

Renal failure Effective volume depletion Hypoaldosteronism

R.I.P.

Aldosterone

There are three types of problems which can impair the excretion of po-
tassium by the kidney:
• renal failure
• effective volume depletion
• hypoaldosteronism

___________ types of disorders can prevent the kidney from se- Three
creting potassium: ________ failure, effective circulating volume renal
depletion and _____________. hypoaldosteronism

553
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Decreased renal excretion!Renal failure!

Hyperkalemia in renal failure is due to an insufficient number of
functional nephrons.

K+
+ K

+
K

Hyperkalemia is one of the most worrisome complications of renal fail-

ure. Increased plasma potassium is due to a loss of functional nephrons, not
a specific defect in potassium handling. In fact, each functional nephron
secretes more potassium than normal. The total reduction in functional neph-
rons, however, reduces the total amount of potassium that can be excreted.
If potassium intake exceeds excretion, hyperkalemia develops.
Hyperkalemia in renal failure is associated with advanced disease and is
one of the indications for initiating dialysis.

Hyperkalemia in renal failure is not due to a defect in potassi- tubular

um handling, but rather to a lack of functioning ________. nephrons

Hyperkalemia is an indication to start _______. dialysis

554
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Decreased renal excretion!Volume depletion!

Decreased effective volume impairs potassium excretion by re-
ducing distal flow.
Low effective circulating volume
stimulates sympathetic activity
and the renin-angiotensin II-al-
dosterone system. These sys-
tems reduce distal flow.

Sympathetic activity
reduces GFR by constricting
the afferent arterioles.
low flow

+
Na K
+
+
K

Low distal flow

Angiotensin II Na+
Na+ +
K
+
K
reduces K+ excretion,
increases Na+ resorption in +
even in the presence of
the proximal tubule.
K +
K

+
K aldosterone.

The excretion of potassium is flow-dependent. Increased distal flow in-

creases potassium excretion, while decreased flow reduces potassium excre-
tion. Decreased distal flow can limit potassium excretion even in the pres-
ence of aldosterone. (Aldosterone normally increases potassium excretion.)
Reduced distal flow is most commonly associated with effective volume
depletion which stimulates sympathetic activity and the renin-angiotensin
II-aldosterone system. Together, these systems reduce the delivery of so-
dium and water to the distal nephron. Sympathetic activity decreases GFR
by constricting the afferent arterioles, while angiotensin II increases the
resorption of sodium in the proximal tubule.
Effective volume depletion alone typically does not cause hyperkalemia,
but it can be a contributing factor.
As reviewed in Chapter 4,Volume Regulation, effective circulating volume is compromised
by blood loss, heart failure, liver failure, sequestration of plasma in a third space,
A-V fistu-
las and fluid loss (GI, skin or renal). fective
Ef circulating volume depletion can be associ-
ated with either hypovolemia or hypervolemia.

Effective volume depletion is associated with decreased ef

________ flow. distal

Sympathetic activity decreases _______ through constriction of GFR

the _________ arterioles of the glomerulus. afferent

555
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Decreased renal excretion!Hypoaldosteronism!

Hypoaldosteronism is due to three types of defects.

RENIN
or
ANGIOTENSIN II

ALDOSTERONE

lack of adrenal stimulation inability to produce aldoster- impaired aldosterone action

one

Hypoaldosteronism is a general term indicating decreased aldosterone

activity regardless of cause. Defects in the stimulation, production and ac-
tion of aldosterone all cause hypoaldosteronism.
• Lack of adrenal stimulation is usually due to a lack of renin
(e.g., hyporeninemic hypoaldosteronism) or a lack of angiotensin
II (e.g., ACE inhibitors).
• Inability to produce aldosterone can be due to either a spe-
cific enzyme deficiency (e.g., 21-hydroxylase) or generalized adre-
nal insufficiency (e.g., Addison’s disease).
• Impaired aldosterone action is usually due to potassium-spar-
ing diuretics which block the effect of aldosterone at the distal
nephron.

Type 4 RTA is another disorder associated with hyperkalemia and hypoaldosteronism.

This
disorder is also associated with non-anion gap metabolic acidosis (see Chapter
Non-
12,
anion Gap MetabolicAcidosis).

Hypoaldosteronism results in ___________ because it impairs hyperkalemia

___________ excretion in the distal nephron. potassium

Hypoaldosteronism is caused by _______ fundamental defects: three

• lack of ________ stimulation adrenal
• inability to ________ aldosterone produce
• impaired aldosterone ________ at the distal nephron action

556
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Decreased renal excretion!Hypoaldosteronism!

Hyporeninemic hypoaldosteronism is associated with diabetes
mellitus and renal insufficiency.

angiotensinogen

RENIN

angiotensin I

Angiotensin
Converting ALDOSTERONE
Enzyme

angiotensin II

Hyporeninemic hypoaldosteronism is a poorly understood syndrome

which is associated with hypoaldosteronism and hyperkalemia. This disor-
der most commonly occurs in older patients with diabetes mellitus and mod-
erate renal insufficiency. A variety of disorders which cause renal insuffi-
ciency have been associated with hyporeninemic hypoaldosteronism.
The syndrome is typically characterized by low renin levels which cause
hypoaldosteronism. Despite the name “hyporeninemic hypoaldosteronism,”
some causes of this syndrome are associated with normal renin levels.
Hyperkalemia in this disorder is typically asymptomatic unless a second
defect in potassium excretion is also present.

One cause of decreased aldosterone activity is decreased aaa

____________ for aldosterone release. stimulation

Hyporeninemic hypoaldosteronism strikes older patients with

diabetes mellitus and moderate renal _____________. insufficiency

557
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Decreased renal excretion!Hypoaldosteronism!

Medications can affect the release of aldosterone form the adre-
nal gland.
angiotensinogen

RENIN
Nonsteroidal anti-
inflammatory drugs

angiotensin I

Angiotensin
Converting ALDOSTERONE
Enzyme
ACE inhibitors
angiotensin II

Cyclosporine
Angiotensin II
antagonists

Hypoaldosteronism caused by inadequate adrenal stimulation can also

be due to medications.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are analgesic medi-
cations which block prostaglandin synthesis. Since prostaglandins stimu-
late renin release, NSAIDs can cause hyperkalemia by inhibiting renin release.
ACE inhibitors are antihypertensive medications which prevent angio-
tensin I from being converted to angiotensin II. Angiotensin II is an impor-
tant stimulus for the release of aldosterone. Most patients tolerate ACE
inhibitors with little change in potassium, but a few, especially those with
mild to moderate renal insufficiency, do develop hyperkalemia. The potas-
sium concentration returns to normal after stopping the medication.
Angiotensin II antagonists are antihypertensive medications which
interfere with the activity of angiotensin II at target organs. Inhibition of
activity at the adrenal gland reduces aldosterone production, resulting in
hyperkalemia in some patients.
Cyclosporine, an immunosuppressant, is used in patients with kidney
transplants and has been shown to decrease the release of aldosterone, caus-
ing mild hyperkalemia.
ACE inhibitors block the conversion of angiotensin __ to angiotensin__. I; II

___________ is an immunosuppressant. Cyclosporine

558
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Decreased renal excretion!Hypoaldosteronism!

Primary adrenal insufficiency results in an inability to produce al-
dosterone despite adequate stimulation.
Primary adrenal insufficiency Secondary adrenal insufficiency
adrenal gland destroyed adrenal gland intact

ACTH
ACTH
Angiotensin II
Hyperkalemia

Aldosterone Aldosterone
Adrenal insufficiency refers to a lack of cortisol, a hormone produced in
the adrenal gland. Primary adrenal insufficiency is characterized by a lack
of both cortisol and aldosterone. In secondary adrenal insufficiency, only
cortisol secretion is impaired. Secondary adrenal insufficiency does not cause
hyperkalemia.
Primary adrenal insufficiency, also known as Addison's disease, is
due to destruction of both adrenal glands. This can be caused by infections
(e.g., meningococcemia, HIV, TB), autoimmune diseases or coagulation dis-
orders (e.g., hemorrhage into the adrenal glands).
Secondary adrenal insufficiency is due to decreased ACTH release from a
defect in the anterior pituitary gland. In the adrenal gland, ACTH stimu-
lates the production of cortisol, but has little effect on the production of
aldosterone. Therefore, secondary adrenal insufficiency does not cause hy-
poaldosteronism and is not associated with hyperkalemia. In this disorder,
the intact adrenal gland can respond to the usual stimuli for aldosterone
release: effective volume depletion (angiotensin II) and hyperkalemia.

Adrenal insufficiency can be either _________ or secondary, but primary

only _________ adrenal insufficiency causes hypoaldosteronism. primary

In secondary adrenal insufficiency, __________ secretion from ACTH

the anterior __________ gland is deficient. pituitary

559
The Fluid, Electrolyte and Acid-Base Companion

Etiologies!Decreased renal excretion!Hypoaldosteronism!

21-hydroxylase deficiency causes an inability to produce mineral-
ocorticoids or glucocorticoids.
Cholesterol

Pregnenolone Hydroxypregnenolone Dehydroepiandrosterone

Progesterone Hydroxyprogesterone Androstenedione

21-hydroxylase 21-hydroxylase

Deoxycorticosterone Deoxycortisol Other androgens

Corticosterone Cortisol Estrogens

Aldosterone

While many of the causes of congenital adrenal hyperplasia cause hy-

pokalemia, one type, 21-hydroxylase deficiency, causes hyperkalemia.
Congenital adrenal hyperplasia is characterized by the inability of the
adrenal glands to produce cortisol. Without cortisol feedback, the pituitary
gland over-secretes ACTH. Increased ACTH stimulation of the adrenal glands
enhances production of the metabolites proximal to the enzymatic defect.
In 21-hydroxylase deficiency, the metabolite precursors are converted into
male sex hormones (androgens). In the female fetus, this causes ambiguous
genitalia. In the male, it causes increased muscle mass, deepened voice,
frequent erections and precocious puberty. One-third to two-thirds of pa-
tients with 21-hydroxylase deficiency have hypoaldosteronism. These pa-
tients are termed salt-wasters and are typically hyperkalemic.
21-hydroxylase deficiency is treated with cortisol replacement (to decrease
the ACTH stimulation for androgen synthesis) and fludrocortisone (Flori-
nef®) to provide mineralocorticoid activity.
Congenital adrenal hyperplasia is covered in more detail in ChapterHypokalemia
18, , page
515.

Congenital adrenal _______________ is due to the inability of the adre- hyperplasia

nal gland to synthesize _______________. cortisol

Females with 21-hydroxylase deficiency have ____________ genitalia. ambiguous

560
S. Faubel and J. Topf 19 Hyperkalemia

Etiologies!Decreased renal excretion!Hypoaldosteronism!

Potassium-sparing diuretics interfere with aldosterone action.

spironolactone

Na+ ALDOSTERONE
Na+
Na+
ATP
3 Na+ 2 K+
triamterene AMP
amiloride Cl–
Cl–

K+

The potassium-sparing diuretics interfere with the action of aldosterone

at the distal nephron. There are two classes of potassium-sparing diuretics.
Competitive inhibitors. Spironolactone is a competitive inhibi-
tor of aldosterone.
Sodium channel blockers. These medications inhibit sodium
resorption by antagonizing sodium channels in the distal neph-
ron. Without sodium resorption, the tubule does not become nega-
tively charged which decreases potassium secretion. Triamterene
and amiloride are commonly used diuretics which block sodium
channels.
As in the other causes of medication-induced hyperkalemia, these medi-
cations rarely cause significant hyperkalemia in the absence of renal insuf-
ficiency.

Other medications which have been associated with hyperkalemia include heparin (rare),
high-dose trimethoprim for
Pneumocystis cariniipneumonia (common) and pentamidine.

Potassium-sparing diuretics can interfere with the function of aaa

__________ in the distal nephron. aldosterone

_____________ is a competitive inhibitor of aldosterone. Spironolactone

561
The Fluid, Electrolyte and Acid-Base Companion

Symptoms and signs!Muscle weakness is a clinical conse-

quence of hyperkalemia.

Muscle contraction requires the coordinated electrical depolarization of

cells. Since it is the primary intracellular cation, potassium plays a central
role in muscle activation.
The muscle weakness associated with hyperkalemia typically begins in
the legs and ascends to the trunk, eventually affecting the arms. Hyper-
kalemia must be severe for muscle weakness to occur.

Muscle ___________ is a symptom of hyperkalemia. weakness

562
S. Faubel and J. Topf 19 Hyperkalemia

Symptoms and signs!The cardiac effects of hyperkalemia are

the most worrisome.

potassium 5.0 mEq/L potassium 6.5 mEq/L

potassium 7.0 mEq/L potassium 8.0 mEq/L

The most feared consequence of hyperkalemia is altered cardiac conduc-

tion leading to ventricular fibrillation or asystole. As plasma potassium in-
creases, the EKG tracing changes morphology. The EKG changes reflect the
effect of potassium on myocardial contraction.
• Peaked T waves represent rapid repolarization of the ventricle
after contraction. These typically occur at potassium levels over 6
mEq/L.
• Increased P-R interval represents slowed conduction through
the myocardium.
• Widening of the QRS complex represents delayed depolariza-
tion and activation of the ventricle. This typically occurs at potas-
sium concentrations of 8 mEq/L or greater.
• Loss of the P wave is due to loss of atrial contraction.
The most severe EKG change associated with hyperkalemia is the sinu-
soidal wave form (shown above with a potassium of 8 mEq/L). Patients with
this EKG change are at high risk for developing a fatal cardiac arrhythmia.

The EKG changes associated with hyperkalemia consist of: aaa

___________ T waves peaked
___________ P-R interval increased
___________ QRS complex widened
___________ P wave lost

In severe hyperkalemia, the EKG appears _________ . sinusoidal

563
The Fluid, Electrolyte and Acid-Base Companion

1
Diagnosis!Confirm the potassium measurement and evaluate

Na+ Cl–
for cardiac toxicity.

Is it pseudohyperkalemia or is it real?

K+ HCO
–
3

+
K

K
+
2What is the etiology?

K+
+
K

K+
and/or and/or

K
+ K

+
K +

increased intake movement out impaired renal

of cells excretion

After discovering hyperkalemia, the first step is to verify the measure-

ment and rule out pseudohyperkalemia. As discussed, pseudohyperkalemia
is an elevated potassium measurement caused by the movement of potas-
sium out of cells while in the test tube; it is associated with hemolysis, leu-
kocytosis and thrombocytosis. To prevent hemolysis, a blood sample should
be redrawn with gentle venipuncture without the use of a tourniquet. If the
WBC or platelet count is elevated, the blood should be drawn in a heparin-
ized tube (green top) which prevents the potassium release associated with
blood clotting. While waiting for the results, a 12-lead EKG should be done
to look for characteristic EKG changes.
If true hyperkalemia is confirmed, then the evaluation should proceed
realizing that more than one cause of hyperkalemia is likely to be present.

The first step in the diagnosis of hyperkalemia is to confirm true verifying

hyperkalemia by ____________ the lab. repeating

While waiting for the repeat lab, check a 12-lead _______. EKG

564
S. Faubel and J. Topf 19 Hyperkalemia

Diagnosis!Consider medications, increased intake and redis-

tribution as possible causes. K +

K+
K
+

Medications Increased intake Redistribution

Cardiac Oral Cell death
• `-blockers • diet (rare) • massive trauma
+
• digoxin • oral K supplements • hypothermia
NSAIDs Intravenous • tumor lysis syndrome
Antihypertensives • old blood transfusions Metabolic acidosis
• ACE inhibitors • penicillin G Hyperglycemia
• angiotensin II antagonists • maintenance IVs Severe exercise
Cyclosporine • treatment of hypokalemia
+
K -sparing diuretics
• spironolactone
• triamterene
• amiloride
Trimethoprim (high doses)
Heparin
Pentamidine

The initial evaluation of a patient with hyperkalemia should begin with a

review of medications. Increased potassium intake and the causes of redis-
tribution hyperkalemia should also be evaluated.
Medications known to cause hyperkalemia are listed above. In many
cases, a patient may have mild hyperkalemia that worsens with the initia-
tion of one of these medications. Patients with renal insufficiency or diabe-
tes mellitus are prone to developing hyperkalemia from medications, par-
ticularly diuretics and antihypertensives.
In patients taking digoxin, the plasma level of this medication should be
measured.
Increased intake and redistribution hyperkalemia are easily evalu-
ated by the history (e.g., “did you just ingest three quarts of Everfresh®
orange juice?”), basic labs (e.g., glucose) and clinical picture (e.g., trauma,
hypothermia).

Many medications are known to predispose to hyperkalemia, rare

including nonsteroidal anti-__________ drugs and potassium- anti-inflammatory
sparing diuretics.

Of the three categories listed in the picture, the list of

___________ is the longest. medications

565
The Fluid, Electrolyte and Acid-Base Companion

Diagnosis!Evaluate the patient for impaired renal potassium

excretion.

Renal failure Effective volume depletion Hypoaldosteronism

R.I.P.
Aldosterone

• Hyporeninemic
hypoaldosteronism
• 21-hydroxylase
deficiency
• Primary adrenal
insufficiency

Three major categories of defects can impair renal excretion of potassium.

Renal insufficiency or failure is easily diagnosed by an elevated BUN
and creatinine. Hyperkalemia can result from acute renal failure or an acute
fall in renal function in a patient with long standing renal insufficiency. In
chronic renal failure, patients with stable renal function can become hyper-
kalemic if an additional insult to potassium balance occurs (e.g., a new medi-
cation).
Effective volume depletion is unlikely to be the sole cause of hyper-
kalemia, but can be a contributing factor. The presence of effective volume
depletion should be clear from the history and physical exam; patients are
either hypo- or hypervolemic.
Hypoaldosteronism can be due to a lack of adrenal stimulation, lack of
aldosterone production or resistance of the distal nephron to aldosterone.
Since medications are responsible for most cases of adrenal insufficiency,
the list of the remaining disorders in this category is short. These disorders
are hyporeninemic hypoaldosteronism, congenital adrenal hyperplasia from
21-hydroxylase deficiency and primary adrenal insufficiency.
The presence of hyporeninemic hypoaldosteronism or primary adrenal
insufficiency can be suggested by the clinical situation; for example, hypo-
reninemic hypoaldosteronism typically occurs in diabetics with renal insuf-
ficiency, and 21-hydroxylase deficiency is usually diagnosed in childhood.

The most common cause of _____________ is a decrease in renal hyperkalemia

__________ of potassium. excretion

Renal insufficiency can decrease the excretion of __________. potassium

566
S. Faubel and J. Topf 19 Hyperkalemia

1 2 3
Treatment!The treatment of hyperkalemia follows the same pat-
tern the body does in handling potassium loads.

Stop all potassium intake. Compensation: promote the Correction: Remove potas-
shift of plasma potassium into sium from the body via the kid-
cells. ney, colon and/or dialysis.

+
K

K +

K
+
+
K

K +

The approach to the treatment of hyperkalemia is analogous to the pro-

cess that the body follows when faced with an acute potassium load.
After stopping all potassium intake, treatment consists of compensa-
tion (movement of potassium into cells) and correction (elimination of
potassium from the body).
In addition, calcium is a treatment which specifically suppresses cardiac
arrhythmias. If hyperkalemia is severe, IV calcium is the first medication
that should be given to the patient.

There are _________ main aspects of hyperkalemia therapy: three

stop ingestion, stimulate _____________ shifts and increase transcellular
___________ or _____________ excretion of potassium. renal; GI

567
The Fluid, Electrolyte and Acid-Base Companion

Treatment !Compensation!Insulin, bicarbonate and albuterol

promote the movement of potassium into cells.
K+ insulin (with glucose)

+
K

alkalemia (bicarbonate)

+
K

`-agonist (albuterol nebulizer)

The compensatory treatment of hyperkalemia is the administration of

medications which stimulate the movement of potassium into cells. Three
different medications can be used for this purpose.
Insulin and glucose: 10 units of insulin and an ampule of D50
are given together, intravenously. Insulin promotes the entry of
potassium into cells by stimulating the action of the Na-K-ATPase
pump. Since insulin also causes the movement of glucose into
cells, glucose (D50) is given to prevent hypoglycemia. This insu-
lin dose lowers plasma potassium by 0.5 to 1.5 mEq/L. The effect
occurs in approximately one hour and lasts several hours.
Sodium bicarbonate: 50 mEq given intravenously over five min-
utes decreases plasma potassium by 0.5 to 1.5 mEq/L in as quickly
as 30 minutes. Bicarbonate causes alkalemia which induces the
intracellular exchange of potassium and hydrogen.
ß-2 adrenergic agents: albuterol by nebulizer can lower plasma
potassium within 30 minutes. Because ß-2 agonists are cardiac
stimulants which can predispose to cardiac arrhythmias, the use
of albuterol to treat hyperkalemia is questionable.

In the treatment of hyperkalemia, compensation is achieved through cells

the administration of __________ and glucose, bicarbonate and al- insulin
buterol by __________. nebulizer

Since one ampule of D50 is 50 mL, one ampule of D50 contains _____ 25
mg of glucose and _____ Calories (see pages 13 and 37). 88

568
S. Faubel and J. Topf 19 Hyperkalemia

Treatment!Correction!To correct hyperkalemia, potassium

must be eliminated from the GI tract and/or the kidney.
With normal renal function, in- With impaired renal function,
creasing renal potassium ex- the colon is the best route to
cretion is an effective method promote potassium excre-
to correct hyperkalemia. tion.

Cation exchange resins increase

colonic potassium excretion.

Na+ Na+ K+
te te
Na+ Na+ Na+ K+ K+ Na+
a

a
rene sulfon

rene sulfon
Ka

Ka
Na+ Na+ Na+ Na+ K+ Na+ Na+
yexalate®

yexalate®
Na+ Na+ Na+ K+ K+ Na+
Na+ Na+ Na+ Na+ Na+ K+ Na+
ty

ty
ys

ys
l Na+ Na+ Na+ l Na+ K+ Na+
po po
Na+ Na+ Na+ Na+

Na+ K+ Na+

K+ Na+ K+

Normally, hyperkalemia is corrected by eliminating potassium via the

kidney. Since most patients with hyperkalemia have renal insufficiency, the
corrective treatment of hyperkalemia focuses on eliminating potassium from
the body by other routes. Potassium can be eliminated through the GI tract
or by dialysis.
In the GI tract, cation exchange resins (Kayexalate® ) absorb 1 mEq of
potassium for every gram ingested. The oral dose is 20 grams with 100 mL
of 20% sorbitol. Sorbitol is given to prevent constipation. For patients who
cannot take anything by mouth, cation exchange resins can be given as an
enema. Side effects of the cation exchange resins include sodium retention,
hypokalemia, constipation and nausea.
Loop diuretics can be used to increase excretion of potassium if renal func-
tion is not impaired.

The mainstay of correcting hyperkalemia is getting the excess hyperkalemia

potassium out of the ________. body

The body normally excretes potassium through the __________. kidney

In the face of renal insufficiency, _________ exchange resins can cation

increase the __________ of potassium from the GI tract. excretion

569
The Fluid, Electrolyte and Acid-Base Companion

Treatment!Correction!Dialysis can be used when other meth-

ods of potassium correction fail.

Both hemodialysis and peritoneal dialysis are effective at removing plasma

potassium and lowering its concentration. Hemodialysis is preferred because
it allows for a more rapid decrease in plasma potassium. Dialysis should be
used when the methods previously described fail to correct the potassium.

Both hemodialysis and _______________ dialysis are able to low- peritoneal

er plasma potassium concentration.

570
S. Faubel and J. Topf 19 Hyperkalemia

Treatment!Preventing arrhythmias!Calcium is specifically

used to stabilize cardiac membranes and prevent arrhythmias.

Calcium

The administration of calcium is one of the most important aspects of

treating acute, severe hyperkalemia. If severe hyperkalemia is present (e.g.,
EKG changes, plasma potassium greater than 7.0 mEq/L), calcium should
be the first medication given to the patient. Calcium stabilizes cell mem-
branes and prevents hyperkalemia-induced arrhythmias.
Calcium is given intravenously as either calcium gluconate or calcium
chloride. Calcium chloride is the preferred form because it provides three
times as much calcium, but it can only be given through a central line. Cal-
cium gluconate can be given through a peripheral IV.

Calcium is used in the treatment of severe hyper-__________. kalemia

Calcium comes in two forms: calcium _________ and calcium gluconate

________. chloride

Calcium ________ can only be given through a central line. chloride

This is the _______ chapter in the book. last

571
The Fluid, Electrolyte and Acid-Base Companion

Summary!Hyperkalemia.
Hyperkalemia is defined as a plasma potassium concentration greater
than 5 mEq/L. The body has a two-tiered defense against hyperkalemia:
compensation and correction. Compensation is the shifting of extracellu-
lar potassium into cells. Correction of hyperkalemia occurs through po-
tassium excretion by the kidney.
+
K

K +

K
+

+
K
+
K

+
K

K+

K
+

Ingestion of a po- is initially compensated but correction requires

tassium load… with an intracellular shift… renal excretion.

+
K
Hyperkalemia can be due to increased intake, increased release from cells
or decreased renal excretion. Chronically elevated potassium levels are al-
ways due to impaired renal potassium excretion.

increased intake redistributive hyperkalemia decreased renal excretion

+
K

K
+ K

+
K +

Increased dietary or IV intake of potassium is a rare cause of hyperkale-

mia because the normal kidney readily excretes large potassium loads.
Sources of potassium include old blood transfusions, IV penicillin G and IV
fluids.
The exit of potassium from cells can be caused by numerous factors.

MOVEMENT OF POTASSIUM OUT OF CELLS

• tumor lysis syndrome • acidemia

• trauma (crush injuries) • lack of insulin (DKA)
• hypothermia • hypertonic plasma (solute drag)
• severe exercise • beta-blockers
• pseudohyperkalemia • digoxin

Hyperkalemia is usually due to an inability of the kidney to excrete po-

tassium. A lack of potassium excretion is seen in three clinical situations:
renal failure, effective volume depletion and hypoaldosteronism.

572
S. Faubel and J. Topf 19 Hyperkalemia

Summary!Hyperkalemia.

In acute and chronic renal failure, there is no specific defect in potassium

excretion; in fact, each healthy nephron secretes more potassium than nor-
mal. In renal failure, the reduction in the total number of functional neph-
rons cripples the kidney’s ability to excrete potassium.
In order for the kidney to excrete potassium, sodium and water must be
delivered to the distal nephron. Decreased distal flow is seen with low effec-
tive circulating volume.
Aldosterone is the primary hormone in potassium regulation. Decreased
aldosterone activity decreases the renal excretion of potassium.
Hypoaldosteronism is caused by three fundamental processes: defective
adrenal stimulation, lack of aldosterone production and inhibition of aldos-
terone activity.
Hyporeninemic hypoaldosteronism is a condition found in elderly patients
with diabetes mellitus and renal insufficiency. Several medications can in-
terfere with adrenal stimulation: NSAIDs, ACE-inhibitors, angiotensin II
antagonists and cyclosporine.
Primary adrenal insufficiency (Addison’s disease) is due to the destruc-
tion of the adrenal glands. In primary adrenal insufficiency, both cortisol
and aldosterone cannot be produced. Secondary adrenal insufficiency (loss
of pituitary ACTH) does not cause hypoaldosteronism.

CAUSES OF ADDISON ’ S DISEASE

• meningococcemia • autoimmune destruction
• HIV • coagulation disorder
• MAC infiltration • tuberculosis
• CMV infection

Congenital adrenal hyperplasia is a group of disorders in which a genetic

defect prevents the synthesis of cortisol. In response, the pituitary increases
its excretion of ACTH, driving the overproduction of cortisol precursors. In
21-hydroxylase deficiency, synthesis of aldosterone is blocked.
Medicaitons which affect the ability of aldosterone to act at the distal
nephron include spironolactone (a competitive inhibitor of aldosterone) and
amiloride (a sodium channel blocker).
Determining the cause of hyperkalemia is done by carefully evaluating
the patient for all of the causes of hyperkalemia.

573
The Fluid, Electrolyte and Acid-Base Companion

Summary!Hyperkalemia.
The primary effects of hyperkalemia are muscle weakness and distur-
bances of cardiac electrical conduction.

K+ 5.0 mEq/L K+ 6.5 mEq/L K+ 7.0mEq/L K+ 8.0 mEq/L

Treatment of hyperkalemia follows the pattern the body uses for han-
dling a potassium load: immediate treatment is by shifting potassium into
cells and final correction is by removing potassium from the body.
Calcium specifically suppresses cardiac arrhythmias and is the first medi-
cation that should be given to the patient if hyperkalemia is severe.

STOP INTAKE INDUCE POTASSIUM SHIFT EXCRETE POTASSIUM

• stop all IVF with potassium • insulin and glucose • functional kidneys: furo-
• look for medications con- • bicarbonate semide
taining potassium • albuterol • kidney failure: cation ex-
• eliminate potassium from change resins
TPN and maintenance flu- • severe hyperkalemia: di-
ids alysis

574