1. REVIEW
The Management of Hyperkalemia in Patients with
Cardiovascular Disease
Apurv Khanna, MD, William B. White, MD
Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of
Medicine, Farmington, Conn.
ABSTRACT
The development of hyperkalemia is common in patients with cardiac and kidney disease who are administered
drugs that antagonize the renin-angiotensin-aldosterone system (RAAS). As the results of large-scale clinical
trials in hypertension, chronic kidney disease, and congestive heart failure demonstrate benefits of RAAS
blockade alone or, in some cases, in combination therapies, the incidence of hyperkalemia has increased in
clinical practice. Although there is potential for adverse events in the presence of hyperkalemia, there also are
potential benefits of RAAS blockers that support their use in high-risk patient populations. Management of
hyperkalemia may be improved by identifying the levels of potassium that may potentially induce harm and
using appropriate strategies to avert the levels that may be dangerous or life threatening.
© 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 215-221
KEYWORDS: Antihypertensive drug therapy; Cardiovascular disease; Chronic kidney disease; Hyperkalemia
The benefits of angiotensin-converting enzyme (ACE) in- patients who lack preexisting factors for its development. In
hibitors and angiotensin receptor blockers (ARBs) are es- contrast, patients with heart disease, congestive heart fail-
tablished in patients with hypertension, congestive heart ure, severe hypertension, and diabetes often have renal
failure, coronary artery disease, and diabetic nephropa- insufficiency, putting them at increased risk for hyperkale-
thy.1-3 Hyperkalemia caused by therapy with agents that mia.1 Renal insufficiency also is recognized as a robust
interfere with the renin-angiotensin-aldosterone system independent predictor of death in patients with cardiovas-
(RAAS), including ACE inhibitors, ARBs, aldosterone an- cular disease.4 Thus, the typical patients who might derive
tagonists, and direct renin inhibitors, occurs infrequently in the most benefit from use of a RAAS-blocking agent are
those at enhanced risk for development of hyperkalemia.
Because of the increasingly common use of antihyper-
Funding: This work was supported in part by funding from US De-
tensive and cardiovascular treatment strategies that often
partment of Defense DAMDW81XWH-05-10060, NIH R01 AG022092,
and an unrestricted educational grant from Boehringer-Ingelheim Pharma- include multiple levels of blockade of the RAAS, we
ceuticals. present a current review on the evaluation and management
Conflict of Interest: Dr White discloses that he has received research of hyperkalemia in patients with underlying cardiovascular
funding during the previous 12 months from the National Institutes of disease.
Health, the Catherine and Patrick Donaghue Foundation, Astra-Zeneca
Pharmaceuticals, Inc, Boehringer-Ingelheim Pharmaceuticals, Inc, Novar-
tis, Inc, and Pfizer, Inc. Dr White serves as a safety consultant to Gilead, CASE PRESENTATION
Inc, Nicox, Inc, Palatin Technologies, Takeda Research Development A 73-year-old woman with hypertension, type 2 diabetes
Group, and Teva Neurosciences, Inc. Dr Khanna discloses he has received
an unrestricted educational grant from Boehringer-Ingelheim Pharmaceu- mellitus, and chronic heart failure was determined to have a
ticals. serum potassium of 6.1 mEq/L at an outpatient visit. Her
Authorship: All authors had access to the data and played a role in medications included hydrochlorothiazide 25 mg daily,
writing this manuscript. metoprolol XL 100 mg daily, perindopril 8 mg daily, and
Requests for reprints should be addressed to Apurv Khanna, MD, spironolactone 25 mg daily. Three months earlier on the
Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun
Cardiology Center, University of Connecticut Health Center, 263 Farm- very same regimen, her serum potassium had been 4.8
ington Avenue, Farmington, CT 06030-3940. mEq/L. On examination, her seated blood pressure was
E-mail address: akhanna@uchc.edu 128/76 mm Hg. Repeated serum potassium was 6.2 mEq/L,
0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2008.10.028

2. 216 The American Journal of Medicine, Vol 122, No 3, March 2009
serum creatinine was 1.0 mg/dL, estimated glomerular fil- manifested by only minor elevations in the serum Kϩ,
tration rate (GFR) was 43 mL/min, and urinalysis showed because the kidney is usually able to compensate by increas-
normal results. The electrocardiogram demonstrated sinus ing urinary excretion of potassium.11 This effect can be
rhythm at 64 beats/min, with normal conduction intervals problematic in patients with chronic kidney disease or when
and normal morphology of the P and T waves. there is concomitant use of other RAAS blockers. ␤1-
Questions of clinical importance Selective adrenergic blockers
for this patient include the follow- are less likely to reduce cellular
ing: What are the likely causes of uptake of Kϩ than nonselective
CLINICAL SIGNIFICANCE
hyperkalemia in this patient? How ␤-blockers when used in low
should the hyperkalemia observed ● Hyperkalemia is increasingly common be- doses.12
in this patient be managed acutely? cause of the use of drugs affecting the
How should the hyperkalemia ob- renin-angiotensin-aldosterone system. Digoxin Toxicity
served in this patient be managed The Naϩ-Kϩ ATPase receptor
over the long term? ● The use of these drugs is, however, of has been found to be highly spe-
proved benefit in patients with congestive cific for digoxin, which inhibits
REGULATION OF heart failure and chronic kidney disease. the activity of the pump in a
● Hyperkalemia can be safely managed in
dose-dependent manner.13 The
POTASSIUM HOMEOSTASIS increase in plasma Kϩ associated
Potassium stores in the adult are patients by dietary restriction, regular
with digoxin on this mechanism of
approximately 3500 mEq, making review of medication lists, and use of cellular transport is usually not at
it the most abundant cation in diuretics, cation-exchange resins, and levels of clinical importance. How-
5
the human body. Potassium is sodium bicarbonate. ever, after ingestion of large
mainly distributed in the intra- amounts of digoxin, severe hyper-
cellular space. This intracellular-
ϩ kalemia has been reported.14
extracellular K gradient is main-
tained by the Naϩ-Kϩ adenosine triphosphatase (ATPase)
pump, which transports 3 Naϩ ions out of the cell in ex-
change for 2 Kϩ ions into the cell.6 Potassium stores are
Table 1 Common Foods Rich in Potassium
determined by dietary intake and renal excretion of potas-
sium. Most potassium filtered in the glomeruli is reabsorbed Fruits
at the proximal tubule. The distal nephron accounts for only Apricot
ϩ Avocado
a small percentage of the K reabsorbed, but the secretion
ϩ Banana
of K distally is under the control of the RAAS and becomes
ϩ 7 Cantaloupe
the major determinant of plasma K concentration.
Grapefruit
Hyperkalemia can occur as the result of 1 or more of 3
Orange
processes: increased potassium intake; impaired movement Prunes
of potassium from the extracellular to the intracellular Raisins
space; or impaired renal excretion of potassium. Vegetables
Acorns
Baked beans
INCREASED POTASSIUM INTAKE Carrots
Increased potassium intake is an uncommon cause of hy- Lentils
perkalemia unless it is accompanied by an underlying im- Legumes
pairment of renal function. Oral intake of large amounts of Potatoes
potassium in a single dose (eg, Ͼ160 mEq of Kϩ) can Pumpkins
increase plasma Kϩ concentrations to more than 7.0 to 8.0 Spinach
mmol/L, even in patients with a normal GFR.8 Excessive Tomatoes
potassium intake also can occur as the result of blood Other Foods
Bran
transfusions, potassium-containing “salt substitutes,”9 and
Chocolate
low-sodium foods that may contain potassium (Table 1).10 Milk
Nuts and seeds
Peanut butter
IMPAIRED MOVEMENT OF POTASSIUM
Salt substitutes
INTO CELLS Yogurt
Snuff
␤-Adrenergic Blockade
Adapted from the National Kidney Foundation website, http://www.
␤-Adrenergic– blocking drugs can induce hyperkalemia by
kidney.org/ATOZ/atozItem.cfm. Accessed October 14, 2008.
reducing the cellular uptake of Kϩ. This process is typically

3. Khanna and White Hyperkalemia in Cardiovascular Diseases 217
Cardiopulmonary Bypass Renin-angiotensin Blockers
Hyperkalemia has been described during cardiopulmonary Administration of ACE inhibitors or ARBs does not typi-
bypass using warm blood cardioplegia15 and is caused by cally result in hyperkalemia in most patients.15 The mean
washout of ischemic areas of the myocardium that were increase in plasma Kϩ concentration after ACE inhibition is
previously underperfused and develop restoration of blood less than 0.3 to 0.4 mEq/L if renal function is normal.22
flow. Clinically important hyperkalemia could occur if patients
are coadministered Kϩ supplements or aldosterone antago-
nists, or have chronic kidney disease.22,23
Metabolic Acidosis
In metabolic acidosis, there is Kϩ movement into the extra-
cellular compartment. This movement occurs to preserve elec-
Aldosterone Antagonists
troneutrality in exchange for excess Hϩ ions, which then Aldosterone antagonists induce hyperkalemia by impairing
moves back across cell membranes into the cytosol. The in- the ability of the distal nephron to excrete potassium. Drugs
crease in the plasma Kϩ concentration ranges from 0.2 to 1.7 such as spironolactone and eplerenone block the interaction
mEq/L for every 0.1 unit reduction in the arterial pH.16 of aldosterone with its mineralocorticoid receptor.24 In a
retrospective cohort study of 100 patients with heart failure,
Cruz and colleagues25 compared the rates of hyperkalemia
TYPES OF IMPAIRED EXCRETION OF POTASSIUM (serum Kϩ Ն 5.5 meq/L) for patients receiving an ACE
inhibitor versus those receiving both the ACE inhibitor and
Chronic Kidney Disease an aldosterone antagonist over a period of several years. In
The kidney has a great capacity for excreting potassium; all, 16 patients receiving the combination treatment devel-
consequently, in a non-oliguric patient, hyperkalemia is oped a serum Kϩ more than 5.5 mEq/L versus 1 patient
manifested only with a GFR less than 15 mL/min. However, receiving the ACE inhibitor alone. The proportion who
in patients who have oliguria with concurrent use of RAAS developed a serum Kϩ greater than 6.0 meq/L in patients
blockade, elevated plasma Kϩ levels may be induced in taking spironolactone was 14% versus 0% for patients tak-
earlier stages of chronic kidney disease.17 The retention of ing ACE inhibitors alone.
Kϩ in chronic kidney disease occurs because of an inade-
quate number of nephrons.18 Other Potassium-Sparing Diuretics
The potassium-sparing diuretics amiloride and triamterene
Congestive Heart Failure impair distal Kϩ secretion by closing the Naϩ channel in the
luminal membrane of the collecting tubular cell.26 Data
Decreases in cardiac output lead to diminished renal perfu-
from case-control studies in older patients show that those
sion and urinary excretion of potassium. In addition to renal
admitted to the hospital because of hyperkalemia were 20
dysfunction in patients with heart failure, the risk of hyper-
times more likely to be taking a potassium-sparing diuretic
kalemia is increased because most of these patients also are
in combination with an ACE inhibitor than those taking an
maintained on RAAS blockers. In a case-control study
ACE inhibitor alone.27
involving 938 patients with heart failure, Ramadan and
colleagues19 showed that diabetes mellitus (odds ratio
[OR] ϭ 2.42), reduced creatinine clearance (OR ϭ 8.36), Heparin
use of spironolactone (OR ϭ 4.18), and use of ACE inhib- Heparin can lead to decreased renal excretion of potassium
itors (OR ϭ 2.55) were all independent risk factors for the in patients with underlying chronic kidney disease. Hyper-
development of hyperkalemia. kalemia occurs in approximately 7% of patients who receive
Inhibition of aldosterone as a cause of hyperkalemia has long-term heparin. Heparin is a potent inhibitor of aldoste-
assumed increasing relevance after the Randomized Aldac- rone secretion via attenuation of the affinity and number of
tone Evaluation Study (RALES) demonstrated that spirono- angiotensin II receptors.28 It is recommended that monitor-
lactone improved outcomes in patients with chronic heart ing for hyperkalemia be performed at 3- to 4-day intervals
failure.20 The incidence of hyperkalemia in patients ran- in patients receiving prolonged heparin, including deep ve-
domized to spironolactone in RALES was 2%, but patients nous thrombosis prophylaxis.
with serum creatinine more than 2.5 mg/dL and serum Kϩ
concentration more than 5 mmol/L were excluded. Nonsteroidal Anti-inflammatory Drugs
A prospective cohort study of more than 1000 patients Nonsteroidal anti-inflammatory drugs (NSAIDs) might
with heart failure done after publication of the RALES trial cause hyperkalemia and renal insufficiency, particularly in
showed that spironolactone had a survival benefit (relative patients with underlying chronic kidney disease and heart
risk 0.09; confidence interval 0.02-0.39) even in a popula- failure.29 By inhibiting both prostaglandin E and prostacy-
tion in whom 78% of the patients did not meet RALES clin synthesis, NSAIDs decrease renin secretion and renal
eligibility criteria. However, 25% of patients had spirono- blood flow, and impair natriuresis.30 In patients with normal
lactone withdrawn because of side effects. Only 1 patient kidney function, the mean increase in plasma Kϩ is typi-
developed serum Kϩ greater than 6 mmol/L.21 cally on the order of 0.2 mEq/L. However, in patients with