REVIEW

Hyperkalemia Associated with Use of Angiotensin-Converting

Enzyme Inhibitors and Angiotensin Receptor Blockers
Marsha A. Raebel1,2
1 Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA
2 University of Colorado, School of Pharmacy, Denver, CO, USA

Keywords
Angiotensin-converting enzyme inhibitor (ACEi);
Angiotensin receptor blocker (ARB);
Hyperkalemia; Hyperpotassemia.
Correspondence
Marsha A. Raebel, PharmD, Institute for Health
Research, Kaiser Permanente Colorado, PO Box
378066, Denver, CO 80237, USA.
Tel.: (303) 614-1260;
Fax: (303) 614-1265;
E-mail: Marsha.A.Raebel@kp.org
doi: 10.1111/j.1755-5922.2010.00258.x
Financial Support: None.
SUMMARY
The aims of this article are to review the current understanding of hyperkalemia associ-
ated with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker
(ARB) therapy. This includes reviewing the pathophysiology of how these agents affect
potassium handling within the kidney, risk factors for developing hyperkalemia, incidence,
clinical signs and symptoms, and providing a practical approach to treatment of the patient
who is either at risk of, or experiencing, hyperkalemia. ACEi and ARB are effective thera-
peutic agents used in a variety of clinical scenarios. However, related to their effects on the
renin–angiotensin–aldosterone system, their use can be associated with hyperkalemia, par-
ticularly in patients who have chronic renal insufficiency. Published incidence estimates of
hyperkalemia associated with ACEi or ARB vary, but up to 10% of patients may experience
at least mild hyperkalemia. Important considerations when initiating ACEi or ARB therapy
include obtaining an estimate of glomerular filtration rate and a baseline serum potassium
concentration, as well as assessing whether the patient has excessive potassium intake from
diet, supplements, or drugs that can also increase serum potassium. Serum potassium mon-
itoring shortly after initiation of therapy can assist in preventing hyperkalemia. If hyper-
kalemia does develop, prompt recognition of cardiac dysrhythmias and effective treatment
to antagonize the cardiac effects of potassium, redistribute potassium into cells, and remove
excess potassium from the body is important.Understanding the mechanism of action of
ACEi and ARB coupled with judicious drug use and clinical vigilance can minimize the risk
to the patient of developing hyperkalemia. Should hyperkalemia occur, prompt recognition
and management can optimize clinical outcome.

The purpose of this article is to review the current understand-

Introduction
Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin
receptor blockers (ARB) are used to lower blood pressure, treat
heart failure, decrease cardiovascular morbidity and death after
myocardial infarction, blunt progression of renal disease in nondi-
abetic patients with chronic kidney disease (CKD), and slow renal
disease progression in patients with type 2 diabetes [1–25]. Un-
fortunately, ACEi or ARB therapy is associated with hyperkalemia
ranging from mild and asymptomatic to clinically evident and life-
threatening [26–33]. National statistics indicate that almost one-
half of 1% of emergency department visits and 2% of hospitaliza-
tions for hyperkalemia end in death [34]. Patients prescribed ACEi
or ARB considered at greatest risk of hyperkalemia include those
with renal insufficiency and diabetes [18,33,35–41]. This poses
a therapeutic challenge because these patient groups comprise a
large proportion of the very patients in whom the drugs are ther-
apeutically indicated.
ing of hyperkalemia associated with ACEi or ARB therapy. The
pathophysiology of how these agents affect potassium handling
within the kidney, risk factors for developing hyperkalemia, in-
cidence, clinical signs and symptoms, and a practical approach to
managing the patient who is at risk of, or experiencing, hyper-
kalemia are discussed.
Potassium, the Kidney, and the
Renin-Angiotensin–Aldosterone System
(RAAS)
Potassium is the most abundant intracellular cation in the body.
It plays crucial functions in maintaining fluid and electrolyte bal-
ance, blood pressure, blunting the effects of excess sodium, and
reducing bone loss and the risk of kidney stones. The diet is the
primary source of potassium. Foods with high potassium contents

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M.A. Raebel
include many fruits and vegetables, dried peas, dairy products,
meat and nuts. In particular, kiwi, bananas, orange juice, potatoes,
avocados, apricots, parsnips and turnips contain high amounts of
potassium.
Dietary potassium is passively absorbed in the small intestine as
long as the potassium concentration is higher in the gastrointesti-
nal tract than in the blood. Small amounts of potassium are ex-
creted in the stool and sweat, but the kidney is the primary organ
of potassium elimination. Potassium is filtered by the glomerulus,
with most being reabsorbed in the proximal tubule and Loop of
Henle (Figure 1). Approximately one-tenth of filtered potassium
reaches the distal nephron to be secreted in the collecting duct
[37].
The RAAS regulates potassium, sodium, and fluid balance, in-
fluencing vascular tone, sympathetic nervous system activity, and
blood pressure [42]. The enzyme renin is secreted by the jux-
taglomerular cells in the walls of afferent arterioles of the kid-
ney (Figure 1). Renin secretion is influenced by intra- and extra-
renal factors such as low renal perfusion pressure, β-adrenergic
stimulation, prostaglandins, angiotensin II, potassium, and sodium
[42,43]. Decreased sodium and chloride delivery to the dis-
tal tubule stimulate renin release. Renin acts on angiotensino-
gen in the blood to form angiotensin I, which is converted
by angiotensin-converting enzyme (ACE) to angiotensin II. An-
giotensin II exerts effects in numerous body tissues (e.g., kidney,
myocardium), including direct pressor effects on peripheral vas-
culature, stimulation of catecholamine release from the adrenal,
and centrally increasing sympathetic nervous system activity
(Figure 1)[42]. Angiotensin II stimulates the release of aldosterone
from zona glomerulosa cells in the adrenal cortex. Aldosterone se-
cretion is also influenced by plasma potassium [44]. Angiotensin II
and potassium act synergistically on aldosterone release [44–46].
Aldosterone directly affects kidney potassium handling. Potas-
sium secretion in the collecting duct is regulated primarily by
serum aldosterone concentrations and the amount of sodium de-
livered to the distal nephron. Aldosterone binds to a receptor in
collecting duct cells and stimulates sodium reabsorption across the
luminal membrane through a sodium channel. As sodium is re-
absorbed, the lumen becomes more electronegative and provides
a favorable environment for potassium secretion through a potas-
sium channel [37].
Effects of ACEi and ARB on the RAAS
By inhibiting formation of circulating angiotensin II or blocking
angiotensin II binding to the adrenal receptor, ACEi or ARB, re-
spectively, interfere with the stimulatory effect of angiotensin II on
aldosterone secretion in the adrenal gland and as a consequence
impair kidney excretion of potassium (Figure 1). There is also ev-
idence that ACEi and ARB interfere with angiotensin II generated
within the adrenal cortex [46].
Diseases and drugs can contribute to impaired potassium ex-
cretion in the presence of ACEi/ARB and increase hyperkalemia
risk (Figure 1, Table 1). Main mechanisms contributing to hyper-
kalemia with ACEi/ARB include decreased aldosterone concen-
trations, decreased delivery of sodium to the distal nephron, ab-
normal collecting tubule function, and excessive potassium intake

c 2011 Blackwell Publishing Ltd
Hyperkalemia with ACEI and ARB
(Table 1). In most patients with hyperkalemia, multiple factors
such as older age, medications, and reduced renal function appear
to contribute to the risk for hyperkalemia. ARBs may have a lesser
effect on potassium in patients with renal failure [47]. Further re-
search, such as that by Johnson and colleagues [48], is needed to
untangle the relative strengths of the various risk factors that con-
tribute to hyperkalemia associated with ACEi/ARB therapy.
For the majority of patients treated with ACEi/ARB, the decline
in serum aldosterone concentration associated with ACEi/ARB
therapy is not sufficient to impair potassium excretion. When hy-
perkalemia develops as a result of decreased aldosterone concen-
trations, aldosterone concentrations have generally decreased be-
fore ACEi/ARB administration due to preexisting disease or drug
effects [37]. When renal perfusion is severely reduced, as in de-
compensated heart failure, proximal sodium reabsorption can be
so great that little reaches the distal nephron; the lack of sodium
can impair potassium secretion [37]. In this situation, reductions
in intraglomerular pressure are not offset by increases in glomeru-
lar perfusion and the serum creatinine rises [49].
When faced with an asymptomatic patient with an elevated
serum potassium concentration, one must also consider the possi-
bility of pseudohyperkalemia. Pseudohyperkalemia is an elevated
serum potassium concentration with a normal plasma potassium.
It is associated with increased release of potassium from cells dur-
ing clotting of the sample, forearm contraction, fist clenching,
tourniquet, cell lysis, thrombocytosis, extreme leukocytosis, or ab-
normal white or red blood cells and requires no treatment [50].
Signs and Symptoms of Hyperkalemia
Mild hyperkalemia (serum potassium 5.5 to 6 mmol/L), mod-
erate/serious hyperkalemia (potassium >6 to 6.9 mmol/L), and
severe hyperkalemia (potassium >7 mmol/L) can present with
life-threatening complications, but can also go unrecognized with
few symptoms prior to cardiac arrest [26,32,33,51,52]. Cardiac
dysrhythmias that are potentially hyperkalemia-associated ini-
tially include peaked T waves, with the following sequence as hy-
perkalemia becomes more severe: Widening PR interval, loss of
P waves, widening QRS complex, merging QRS complex with T
wave resulting in a sine-wave pattern [53]. A variety of atrioven-
tricular (AV) blockades occur with hyperkalemia including intra-
ventricular conduction delays and first-degree AV block, AV dis-
sociation, complete AV block, paroxysmal ventricular tachycardia,
ventricular fibrillation and flutter, bradycardia, and asystole
[32,33,51,54]. Hypotension can also occur [54]. Noncardiac signs
and symptoms include altered mental status, confusion, muscle
cramps and weakness, muscle hypotonia, dyspnea, paresthesia,
flaccid paraplegia, paralysis, and tetany [32,33,51,54].
Definitions and Incidence
of Hyperkalemia among Patients
Prescribed ACEi or ARB
Hyperkalemia occurs in up to 10% of hospitalized patients
[55–57], with 10% of those patients (i.e., up to 1% of hospi-
talized patients) having serum potassium greater than or equal
Cardiovascular Therapeutics 30 (2012) e156–e166 e157
Hyperkalemia with ACEI and ARB M.A. Raebel

Figure 1 The renin–angiotensin–aldosterone system and potassium excretion in the kidney. NSAIDS, nonsteroidal antiinflammatory drugs.

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M.A. Raebel
Table 1 Potential risk factors for hyperkalemia in patients prescribed ACEi or ARB
Risk Factor
Underlying conditions
Increased age
Diabetes
Kidney disease (e.g., acute or chronic
tubulointerstitial renal disease,
diabetic nephropathy, renal
transplants, urinary tract
obstruction; systemic lupus
erythematosus, amyloidosis,
sickle cell disease)
Heart failure (decompensated)
Volume depletion/dehydration
Cell destruction (e.g., rhabdomyolysis,
hemolysis, tumor lysis, trauma,
burns)
Excessive potassium ingestion
Salt substitutes
Diet high in potassium-rich foods
(dried peas, dairy products, meat,
nuts, fruits and vegetables such as
kiwi, bananas, orange juice,
potatoes, avocados, apricots,
parsnips, turnips)
Certain herbal products (e.g., noni
juice, Siberian ginsing, dandelion)
Antimicrobial drugs
Azole antifungals (e.g, ketoconazole)
Trimethoprim (and trimethoprim
combinations such as
trimethoprim-sulfamethoxazole)
Pentamidine
Other drugs
Aliskiren
Potassium-sparing diuretics (e.g.,
spironolactone, eplerenone,
amiloride, triamterene)
β-blockers
Cyclosporine or tacrolimus
Potassium supplements
Nonsteroidal antiinflammatory agents
Heparin
Digoxin

c 2011 Blackwell Publishing Ltd
Hyperkalemia with ACEI and ARB
Mechanism References
Impaired renin release with subsequent hypoaldosteronism (hyporeninemic [82]
hypoaldosteronism)
Diabetic nephropathy; hyporeninemic hypoaldosteronism; impaired ability of the [27,33,37,83,84]
cortical collecting tubule to secrete potassium; insulin deficiency
Impaired ability of the cortical collecting tubule to secrete potassium; hyporeninemic [37]
hypoaldosteronism (can coexist in diabetic nephropathy, renal transplants,
obstruction, systemic lupus erythematosus, amyloidosis, and sickle cell disease)
Decreased delivery of sodium to the distal nephron [37]
Impaired aldosterone release; decreased delivery of sodium to distal nephron [85]
Transcellular shifts [86]
Excess potassium intake relative to potassium excretion, tubular unresponsiveness [53]
to aldosterone, or redistribution of potassium into extracellular space
Excess potassium intake from diet [87]
Contain potassium: excess potassium intake relative to potassium excretion [88–91]
Inhibit biosynthesis of adrenal steroids [37]
Blockade of sodium reabsorption through epithelial sodium channel in the collecting [37,92,93]
duct, that is, abolishing negative potential of the lumen and removing driving
force for potassium secretion
Blockade of sodium reabsorption through epithelial sodium channel in the collecting [37,94]
duct, that is, abolishing the negative potential of the lumen and removing driving
force for potassium secretion
Direct renin inhibition [95]
Impaired ability of cortical collecting tubule to secrete potassium; block the [36,37,96,97]
interaction of aldosterone with the aldosterone receptor (spironolactone,
eplerenone); block the epithelial sodium channel in the collecting duct, that is,
block sodium reabsorption (amiloride, triamterene)
Hyporeninemic hypoaldosteronism induced by effect on both renal renin release and [53,98,99]
adrenal aldosterone release; decrease sodium-potassium ATPase activity thus
interfering with cellular uptake of potassium
Suppress renin release; interfere with secretion of potassium in collecting duct [100,101]
inhibits
Excess potassium intake relative to potassium excretion, tubular unresponsiveness [96]
to aldosterone, or redistribution of potassium into extracellular space
Interfere with stimulatory effect of prostaglandins on renin release; decrease distal [53,102–105]
delivery of sodium; blunt adrenal response to hyperkalemia
Blocks biosynthesis of aldosterone in the adrenal [106,107]
Overdose: Na+ /K+ -ATPase and impairs the uptake of K+ by skeletal muscle [53]
Cardiovascular Therapeutics 30 (2012) e156–e166 e159
Hyperkalemia with ACEI and ARB M.A. Raebel

to 6 mmol/L [58]. ACEi/ARB therapy is considered a contribut-
ing cause in 10% to 38% of hospitalized hyperkalemia cases
[27,57,59,60].
In ambulatory practice, ACEi/ARB therapy also contributes to
hyperkalemia in up to 10% of patients [35,48,58,61], with about
1% of patients with diabetes experiencing serious hyperkalemia
[58]. Furthermore, ACEi/ARB therapy is implicated in hyper-
kalemia in as many as 6% of patients enrolled in clinical trials
[2,37,62,63].
The stated incidence of hyperkalemia among patients prescribed
ACEi/ARB varies [64]. Important contributors to differing hyper-
kalemia rates within published trials and across ambulatory care
environments include prescribing ACEi/ARB to patients with re-
nal insufficiency and diabetes (27, 36, 40), presence/absence of
potassium monitoring [58], differing comorbidities across popula-
tions, prescribing varying dosages of ACEi/ARB, and differences
in use of concomitant medications (Table 1) [37,52,65–68]. Fur-
thermore, incidence of hyperkalemia in the clinical trial setting
should not be compared to incidence in ambulatory care because
of potassium monitoring differences. Patients enrolled in trials re-
ceive potassium evaluation at predefined intervals and increases
are quickly brought to clinical attention. In ambulatory care, both
frequency and timing of potassium evaluation are much less regi-
mented. While information about hyperkalemia risk gleaned from
clinical trials is an accurate reflection of the potential of ACEi/ARB
to increase potassium above some predefined level among patients
enrolled in those trials, such information may not reflect either
risk or severity of hyperkalemia among patients in usual care who
have varying comorbidities, particularly CKD.
Caution must also be used when comparing published estimates
of hyperkalemia because definitions of hyperkalemia applied vary
widely. Most definitions include a lower threshold of serum potas-
sium of 5.5 mmol/L or greater, with or without an accompany-
ing medical visit and/or clinical signs [63]. However, potassium
concentration minimum threshold values used range from as low
as 5.0 mmol/L [27,53,61] to as high as 6.0 mmol/L [58,63,64].
Some have even defined hyperkalemia without reference to spe-
cific potassium concentration, using as the definition “Clinically
important increases in serum potassium” determined through post
hoc-free text search of hospitalization summaries and deaths (in-
tended to identify hyperkalemia associated with drug reduction or
discontinuation) [18].
A recent multisite database study of ambulatory patients with
diabetes newly initiating an ACEi, ARB, or spironolactone high-
lights how hyperkalemia incidence estimates vary with hyper-
kalemia definition [64]. Using a definition that included an ambu-
latory visit, hospitalization, emergency department visit, or death
associated with a coded hyperkalemia diagnosis and/or serum
potassium of greater than or equal to 5.5 mmol/L that cooccurred
within 1 day, the population incidence rate of hyperkalemia was
26.3 per 1000 person-years [64]. When serum potassium data
were not included but other components of the definition re-
mained the same (serum potassium data are often not available
in databases used for observational studies), the population inci-
dence rate was 14.7 per 1000 person-years. When the most re-
strictive definition was used that included only a hospitalization
or emergency department visit associated with a coded diagnosis
(i.e., identifying only serious hyperkalemia events), the popula-
tion incidence rate was further reduced to 9.5 per 1000 person-
years [64].
Potassium Monitoring among Patients
Prescribed ACEi or ARB
Despite widespread agreement that potassium monitoring is a
component of good clinical care for patients prescribed ACEi/ARB,
34% to 39% of ambulatory patients newly initiating ACEi/ARB
and 32% to 38% who initiated ACEi/ARB at least 1 year pre-
viously did not receive potassium and/or creatinine monitoring
[69–71]. Similarly, among patients with diabetes newly initiating
ACEi/ARB therapy, 29% did not have potassium monitoring [58].
While reasons for lack of monitoring are incompletely un-
derstood, there are likely several contributors. These include
clinician and patient nonadherence to test ordering and com-
pletion [72–75], inconsistent recommendations for monitoring
timing and frequency (Table 2)[24,28,36,37,76–79], consensus-
based (rather than evidence-based) monitoring guidelines, and
lack of guidelines tailored to patient-specific risks such as CKD

Table 2 Potassium monitoring recommendations for patients prescribed ACEi or ARB

Drugs Monitoring frequency Year (reference)

ACEi or ARB Within 1 to 2 weeks of initiating drug in patients with chronic kidney disease 2003 [28]
ACEi or ARB Within 1 week of starting drug/increasing dose; monitor based on results 2004 [37]
ACEi Within 1 week of initiating therapy in “vulnerable elders” 2001 [76]
ACEi, ARB, Diuretics Annual 2006 [77]
ACEi or ARB 3 to 5 days after initiation of therapy and with each dose increment, followed by 2007 [53]
another measurement 1 week later
ACEi, ARB, Spironolactone “Serial monitoring of serum electrolytes and renal function” in patients with chronic 2001[79]
heart failure
ACEi + Spironolactone “Monitored closely” 2001 [36]
ACEi + Spironolactone At 1, 4, and 8 weeks after beginning concomitant therapy 1996 [78]

e160 Cardiovascular Therapeutics 30 (2012) e156–e166 

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M.A. Raebel
[24,28,37,76,79]. The relative contributions of clinician nonad-
herence to ordering and patient noncompletion of ordered tests
deserve further study to elucidate appropriate targets for interven-
tions to improve monitoring.
Raebel and colleagues recently demonstrated that, among
27,355 patients with diabetes newly initiating an ACEi, ARB, or
spironolactone, those who received monitoring were 50% less
likely to experience hyperkalemia (adjusted relative risk [RR] 0.50
[95% confidence interval 0.37, 0.66]) than similar patients who
did not receive monitoring [58]. In the subset of 2176 patients
who had both diabetes and CKD, patients who received monitor-
ing were 71% less likely to experience hyperkalemia (adjusted RR
0.29 [95% confidence interval [0.18, 0.46])[58]. This study was
the first to offer concrete evidence in support of published guide-
lines that recommend monitoring potassium in patients newly
starting an ACEi/ARB. These findings should not be extrapolated
beyond the patient population studied (i.e., patients with dia-
betes). Evidence-based monitoring guidelines for additional pa-
tient populations are needed.
Approach to Patients at Risk
of Hyperkalemia
In patients to be started on an ACEi/ARB, the most important
actions to minimize risk of hyperkalemia are to evaluate esti-
mated glomerular filtration rate (eGFR) and baseline serum potas-
sium concentration [37]. If the patient has an eGFR less than or
equal to 59 mL/min/1.73 m2 (stage 3 CKD), then additional vig-
ilance for hyperkalemia is important. Among patients with CKD,
coprescribing an ACEi and an ARB or an ACEi or ARB with a
potassium-sparing diuretic should be avoided. If spironolactone
must be coprescribed, dosage should not exceed 25 mg/day [53].
Prior to initiating the ACEi/ARB, patients should be asked about
concomitant medications, diet, and use of supplements and salt
substitutes that contain potassium and can contribute to hyper-
kalemia (Table 1). If appropriate, these can be discontinued or
changed to agents less likely to interfere with potassium han-
dling. If a patient is currently receiving a diuretic that increases
potassium excretion (i.e., loop or thiazide), it should be continued.
ACEi/ARB therapy should be started with a low dosage of a single
agent. Serum potassium should be monitored within the first week
of therapy and again after any dosage increase. If the serum potas-
sium increases above 5.5 mmol/L, the ACEi/ARB should be dis-
continued and, depending on clinical signs and symptoms, the pa-
tient should at a minimum have serum potassium checked within
2 or 3 days or treatment for hyperkalemia should be initiated (see
below). In situations where the potassium increases above base-
line, but is less than or equal to 5.5 mmol/L, assessment of po-
tential contributing factors is important. In this situation, either
the ACEi/ARB dosage can be reduced or the drug withheld until
serum potassium has returned to normal. Often the ACEi/ARB can
be reinitiated at a lower dosage without serum potassium increase.
When ACEi/ARB is reinitiated, serum potassium should again be
measured within the first week.
In addition to monitoring potassium, checking renal func-
tion, judiciously choosing ACEi/ARB dosage, and carefully using
concomitant drugs, other strategies proposed to reduce occur-

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Hyperkalemia with ACEI and ARB
rence of hyperkalemia include low-potassium diet, newly pre-
scribing diuretics that increase potassium elimination, switching
to an ACEi/ARB that is not totally dependent on renal excre-
tion, and prescribing intermittent use of a potassium binding resin
[24,28,36,37,79]. However, these strategies have not been sys-
tematically evaluated to determine whether they decrease the fre-
quency of hyperkalemia-associated adverse outcomes.
Treatment of ACEi- or ARB-Associated
Hyperkalemia
Clinical suspicion of hyperkalemia and prompt recognition and
treatment cannot be overemphasized. Freeman and colleagues re-
cently observed that, among patients presenting to an emergency
department with serious hyperkalemia, median time to treatment
initiation was 117 min, with the chief complaint of “unrespon-
sive” being most likely to lead to early treatment [54]. Moore et al.
also documented that treatment is frequently suboptimal, with
over one-third of patients not having any ECG performed, up to
one-half not receiving any acute treatment, and one-fourth not
having any follow-up of hyperkalemia [80].
When a patient receiving an ACEi or ARB presents with hyper-
kalemia, the first priority is to determine whether ECG changes
and/or serum potassium greater than 6 mmol/L are present. If
either is detected, acute hyperkalemia management should be ini-
tiated [53] and continued until the serum potassium decreases be-
low 5 mmol/L and ECG abnormalities resolve. Acute management
includes continuous ECG monitoring and immediate treatment.
Urgent management of hyperkalemia often includes admission to
the hospital, but there is little guidance on specific indications for
hospitalization, in part because of the many factors that influ-
ence risk of hyperkalemia-associated cardiac and neuromuscular
sequelae such as the patient’s acid-base status, serum calcium con-
centration, rapidity of rise of the serum potassium, and comorbid
disease states [53].
Treatment of ACEi/ARB-associated hyperkalemia includes
three general principles: Antagonizing cardiac effects of potassium,
redistributing potassium into cells, and removing excess potassium
from the body. Situations where each of these approaches is ap-
plicable are discussed below. A comprehensive patient workup
must be completed, with intent to identify and treat additional
contributing factors (e.g., additional medications, diet, CKD, de-
hydration). Importantly, with hyperkalemia in a patient receiving
an ACEi or ARB, temporary discontinuation or dosage reduction
of the ACEi or ARB is indicated. Laboratory tests obtained dur-
ing patient workup of moderate or severe hyperkalemia should
include eGFR or serum creatinine, serum electrolytes, serum glu-
cose, serum osmolality, calcium and magnesium, complete blood
count, and urine pH and osmolality [53].
Treatment approach in general depends on how rapidly potas-
sium must be removed from the body. However, even though
calcium does not lower either serum or total body potassium,
if an abnormal ECG is present, intravenous calcium—as cal-
cium gluconate—should be administered to antagonize the car-
diac effects of potassium by raising the cardiac threshold potential
(Table 3)[53,81].This is true even in the presence of normal serum
calcium levels. Calcium rapidly, reliably reverses arrhythmias, is
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Hyperkalemia with ACEI and ARB M.A. Raebel

Table 3 Treatment of hyperkalemia associated with ACEi or ARB therapy [53,81]

Onset of Action; Peak

Medication/Treatment Dosage; Route of Administration Activity Duration of Action Comments

Antagonize cardiac effects of potassium

Calcium gluconate 1 g (10 mL ampule of 10% solution); 1 to 2 min; 10 mL of 10% calcium gluconate
intravenous over 5 to 10 min 2 to 10 min; contains 89 mg (2.2 mmol) elemental
∼ 30 min calcium. Administer with continuous
ECG monitoring. Administer with
caution in patients taking digoxin;
hypercalcemia potentiates toxic
effects of digoxin on myocardium (can
dilute calcium gluconate in 100 mL of
5% dextrose in water and infuse over
20 to 30 min)
Shift potassium into cells
Regular insulin 5 to 10 units; 20 to 30 min; Usually administered with 10%
intravenous or subcutaneous 30 to 60 min; dextrose infusion (see below) or as
2 to 6 h bolus followed immediately by 50 mL
of 50% dextrose.
Administer without dextrose if
hyperglycemia is present; reduces
serum potassium by 0.5 to 1.2 mmol/L
Dextrose 10% 500 to 1000 mL; 20 to 30 min; Do not administer without insulin
intravenous over 1 to 2 h 30 to 60 min;
2 to 6 h
Dextrose 50% 50 mL (25 g); 20 to 30 min; Do not administer without insulin
intravenous over 5 min 30 to 60 min;
2 to 6 h
Sodium bicarbonate 50 to 100 mEq; 30 min; Use is controversial; consider only if
intravenous over 2 to 5 min variable; acidosis is present
2 to 6 h
Albuterol (i.e., β-adrenergic agonist) 10 to 20 mg; 30 min; Reduces serum potassium by 0.5 to
nebulize over 10 min 90 min; 1.0 mmol/L; dosage is higher than
Nebulize in 4 mL of normal saline about 2 h dosage for asthma; monitor for
tachycardia
Remove excess potassium from the body
Sodium polystyrene sulfonate (i.e., cation 15 to 60 g; 1 h; Each gram of resin binds ∼ 1 mEq of
exchange resin) oral or rectal 4 to 24 h; potassium in exchange for 1 mEq of
Oral administration should be with variable sodium, usually removing 0.5 mEq
sorbitol to prevent constipation potassium per gram of SPS; SPS can
be administered chronically; it is
marketed as a suspension containing
15 g resin per 60 mL
Hemodialysis Hours; Immediate; Use in presence of severe
not applicable 3 h; hyperkalemia
until end of dialysis
Furosemide 20 to 40 mg; 5 to 15 min; Not the treatment of choice for
intravenous ∼ 45 min; ACEi/ARB-associated hyperkalemia
4 to 6 h

short acting, and can be repeated if there is little change in ECG or
if ECG abnormalities reoccur [53].
Rapid correction of moderate-to-severe hyperkalemia can be
achieved with administration of drugs that shift potassium intra-
cellularly that is, insulin with dextrose, albuterol, and/or sodium
bicarbonate. Insulin plus glucose and albuterol all reliably decrease
serum potassium; bicarbonate use is controversial. Insulin low-
ers serum potassium primarily by shifting potassium into skeletal
muscle and hepatocytes. Insulin can be administered with dex-
trose as an intravenous infusion, bolus, or subcutaneous injection

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M.A. Raebel Hyperkalemia with ACEI and ARB

(Table 3) and can be repeated. Hypoglycemia may occur (even
when insulin is administered with dextrose), usually about 1 h
after insulin infusion, and blood glucose should be monitored.
In hyperglycemic patients, insulin should be administered with-
out glucose and with close blood sugar monitoring. Combining
insulin and albuterol treatment can reduce the magnitude of hy-
poglycemia (as well as lower potassium).
Albuterol is a selective β 2 -agonist that is an underused, effective
treatment for acute hyperkalemia. It shifts potassium into hepato-
cytes and skeletal muscle cells [53]. Although both oral and in-
haled albuterol are available, only the inhaled drug is effective in
lowering serum potassium, with albuterol administered by nebu-
lization reducing serum potassium concentrations about twice as
much (Table 3) as metered-dose inhaler administration.
Definitive hyperkalemia treatment is removal of potassium from
the body using hemodialysis, diuretics, or exchange resins. In se-
vere hyperkalemia, when urgent lowering of both serum and total
body potassium is needed, dialysis is most rapidly effective, reduc-
ing both extra- and intracellular potassium. While all modes of
renal replacement therapies are effective [53], hemodialysis is pre-
ferred. The greatest amount of potassium is removed during the
first hour of hemodialysis and serum potassium usually reaches its
lowest value after about 3 h, but removal continues throughout
the entire session [53]. Caution is needed with hemodialysis be-
cause arrhythmias can worsen during hemodialysis and a rebound
increase in serum potassium can occur after hemodialysis is com-
pleted [53].
Diuretics are not the treatment of choice for ACEi/ARB-
associated hyperkalemia, but can be useful in the setting of
moderate-to-severe hyperkalemia in patients with hyporeninemic
hypoaldosteronism and selected kidney potassium secretion prob-
lems (e.g., pentamidine). Furosemide is usually the diuretic ad-
ministered (Table 3).
Sodium polystyrene sulfonate (SPS, Kayexalate) is a cation-
exchange resin useful in treating asymptomatic patients with mild-
to-moderate hyperkalemia. It is also used as follow-up to acute hy-
perkalemia treatment. SPS onset of action is slow (Table 3). Each
gram of resin exchanges about 1 mEq of sodium for 1 mEq of
potassium in the colon, thereby increasing fecal potassium excre-
tion [81]. The usual oral dosage is 15 to 30 g of SPS powder in
70% sorbitol one to four times daily. Sorbitol promotes excretion
of potassium by inducing diarrhea. SPS can also be administered
as a retention enema (retained 30 to 60 min, followed by cleans-
ing enema) using 30 to 50 g of resin in warm water every 6 h [53],
however, oral is better tolerated and more effective.
In patients with mild asymptomatic hyperkalemia, discon-
tinuing the ACEi/ARB until serum potassium decreases below
5 mmol/L can sometimes be sufficient treatment, in addition
to efforts to identify potential contributing factors. Often the
ACEi/ARB can be restarted at a lower dosage with no hyper-
kalemia recurrence.
Conclusion
ACEi and ARB are effective therapeutic agents that can rarely
cause moderate to severe, life-threatening hyperkalemia, particu-
larly among patients with underlying chronic renal insufficiency.
To minimize hyperkalemia risk in patients in whom an ACEi/ARB
is initiated, baseline eGFR and serum potassium should be ob-
tained, and use of concomitant medications, diet, and supple-
ments that increase risk of hyperkalemia should be assessed. If
hyperkalemia occurs, prompt administration of definitive ther-
apy to antagonize the adverse cardiac effects of potassium and re-
turn both serum and total body potassium to normal can optimize
outcomes.
Conflict of Interest
The author has no conflict of interest.
Acknowledgments
I thank Laura Palmer for her assistance with the illustration.

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