0905 (1) When Cardiovascular Medications Become Toxins

September 2005
Volume 7, Number 9
Authors
Beth Y Ginsburg, MD
Fellow, Medical Toxicology, Department of Emergency
Medicine, New York University School of Medicine
New York, NY.
Ruben Olmedo, MD
Director, Division of Toxicology, Department of
Emergency Medicine, Mount Sinai Medical Center
New York, NY.
Peer Reviewers
Frank LoVecchio, DO, MPH, FACEP
Medical Director, Banner Good Samaritan Regional
Poison Center; Research Director, Maricopa Medical
Center, Department of Emergency Medicine; Associate
Professor, AZ College of Osteopathic Medicine.
Richard D Shih, MD
Program Director, Morristown Memorial Hospital;
Associate Professor, New Jersey Medical School
Morristown, NJ.
CME Objectives
Upon completing this article, you should be able to:
discuss the pathophysiology and pharmaco-
kinetics of digoxin, -blockers, and CCBs in
therapeutic and overdose amounts;
describe the unique symptoms of overdose
among each of these cardiovascular agents;
anticipate the systemic effects, in addition to the
cardiovascular effects, of CV toxicity; and
recognize and treat patients poisoned by CV
toxins, based on properties of the specic
agent(s) involved.
Date of original release: September 21, 2005.
Date of most recent review: September 12, 2005.
See Physician CME Information on back page.
1.
2.
3.
4.
EMERGENCY MEDICINE PRACTICE
A N E V I D E N C E - B A S E D A P P R O A C H T O E ME R G E N C Y ME D I C I N E
EMPRACTICE.NET
When Cardiovascular
Medications Become Toxins:
Managing -Blocker, CCB,
And Digoxin Overdoses
A 29-year-old man with a history of hypertension presents to the ED 6 hours after
an overdose with Cardizem
SR. At presentation he has normal vital signs and

mental status, and you begin his treatment by administering a dose of activated
charcoal. Then, 14 hours after the initial ingestion, the patients blood pressure (BP)
drops to 85/P and his heart rate (HR) to 30. You then treat with 2 amps CaCl and 2
mg glucagon, which results in normalization of his BP and HR. He is subsequently
admitted to the CCU.
Based on the recommendations from a toxicology consultation with the local
poison control center, whole bowel irrigation is started and a glucagon drip is kept
at 2 mg/hr intravenously. Despite these measures, 16 hours after ingestion, the
patients BP and HR drop again, and he is found to be in PEA. He is treated with
IV uids and 3 amps CaCl, and the glucagon drip is increased to 5, 7, and then 10
mg/hr, without BP response. Simultaneously with CPR, a norepinephrine drip is
started. A transvenous pacemaker is placed, and insulin (80 U) and glucose (1 g/kg)
are administered intravenously. BP returns to 90/P 30 minutes later.
The patient remains in the CCU for 48 hours for continued hemodynamic
monitoring. A CT scan of the brain and an EEG reveal anoxic brain damage. The
patient dies on day 6 of hospitalization.
C
ARDIOVASCULAR medications are widely used in the United States
to treat hypertension, angina, dysrhythmias, and congestive heart fail-
ure. Their role in saving lives and improving quality of life is enormous.
Yet cardiovascular medications also ranked fourth among the most common
pharmaceutical agents involved in poisoning fatalities in the US in 2004,
according to the American Association of Poison Control Centers. Calcium
channel blockers (CCBs), -blockers, and digoxin accounted for 95% of the
agents involved in these fatalities. These medications in particular pose
Editor-in-Chief
Andy Jagoda, MD, FACEP, Professor
and Vice-Chair of Academic
Affairs, Department of Emergency
Medicine; Residency Program
Director; Director, International
Studies Program, Mount Sinai
School of Medicine, New York, NY.
Associate Editor
John M Howell, MD, FACEP, Clinical
Professor of Emergency Medicine,
George Washington University,
Washington, DC; Director of
Academic Affairs, Best Practices,
Inc, Inova Fairfax Hospital, Falls
Church, VA.
Editorial Board
William J Brady, MD, Associate
Professor and Vice-Chair,
Department of EM, University of
Virginia, Charlottesville, VA.
Peter DeBlieux, MD, LSUHSC
Professor of Clinical Medicine;
Director of Faculty and Resident
Development, LSU Health Science
Center, New Orleans, LA.
Wyatt W Decker, MD, Chair and
Associate Professor, Department
of EM, Mayo Clinic College of
Medicine, Rochester, MN.
Francis M Fesmire, MD, FACEP,
Director, Heart-Stroke Center,
Erlanger Medical Center; Assistant
Professor of Medicine, UT College
of Medicine, Chattanooga, TN.
Valerio Gai, MD, Professor and Chair,
Department of EM, University of
Turin, Italy.
Michael J Gerardi, MD, FAAP, FACEP,
Clinical Assistant Professor,
Medicine, UMDNJ; Director,
Pediatric EM, Childrens Medical
Center, Atlantic Health System;
Department of EM, Morristown
Memorial Hospital, NJ.
Michael A Gibbs, MD, FACEP, Chief,
Department of EM, Maine Medical
Center, Portland, ME.
Steven A Godwin, MD, FACEP,
Assistant Professor and Residency
Director, Department of EM,
University of Florida HSC/
Jacksonville, Jacksonville, FL.
Gregory L Henry, MD, FACEP, CEO,
Medical Practice Risk Assessment,
Inc; Clinical Professor of EM,
University of Michigan, Ann
Arbor, MI.
Keith A Marill, MD, Instructor,
Department of EM, Massachusetts
General Hospital, Boston, MA.
Charles V Pollack, Jr, MA, MD,
FACEP, Chairman, Department
of EM, Pennsylvania Hospital,
University of Pennsylvania Health
System, Philadelphia, PA.
Michael S Radeos, MD, MPH,
Assistant Professor of Emergency
Medicine, Weill Cornell College
of Medicine; Lincoln Medical and
Mental Health Center, Bronx, NY.
Robert L Rogers, MD, FAAEM, ,
Assistant Professor and Program
Director, Combined EM / IM
Residency Program, University
of Maryland School of Medicine,
Baltimore, MD.
Alfred Sacchetti, MD, FACEP,
Assistant Clinical Professor,
Department of EM, Thomas
Jefferson University, Philadelphia,
PA; Research Director, Our Lady of
Lourdes Medical Center, Camden,
NJ.
Corey M Slovis, MD, FACP, FACEP,
Professor and Chair, Department
of EM, Vanderbilt University Medical
Center; Medical Director, Metro
Nashville EMS, Nashville, TN.
Jenny Walker, MD, MPH, MSW,
Assistant Professor; Division Chief,
Family Medicine, Department
of Community and Preventive
Medicine, Mount Sinai Medical
Center, New York, NY.
Ron M Walls, MD, Chairman,
Department of Emergency
Medicine, Brigham & Womens
Hospital; Associate Professor of
Medicine (Emergency), Harvard
Medical School, Boston, MA.
Research Editors
Jack Choi, MD, Mount Sinai
Emergency Medicine Residency.
Beth Wicklund, MD, Regions Hospital
Emergency Medicine Residency,
EMRA Representative.
Emergency Medicine Practice 2005 2 EMPractice.net September 2005
an ongoing challenge to the emergency physician, when
patients present with symptoms of severe toxicity.
We know that digoxin, -blockers, and CCBs cause
hypotension and bradydysrhythmias. Based on the most
recent literature, we nd that regular-release formulations
do so within the rst 6 hours of ingestion, while extended-
release formulations result in delayed toxicity and require
24-hour observation. In addition to supportive care and
decontamination, there are specic antidotal treatments
for these medications: digoxin-specic Fab antibody frag-
ments for digoxin toxicity, glucagon for -blocker toxicity,
and calcium (Ca
++
) salts for CCBs. High-dose insulin with
glucose should also be considered for -blocker and CCB
toxicity. Other treatments that are useful in this setting
include catecholamines, phosphodiesterase inhibitors, and
mechanical support of circulation.

Critical Appraisal Of The Literature
A search of Ovid MEDLINE
was conducted using the key

words digoxin, -blocker, CCB, poisoning, overdose, and
toxicity, spanning the period from 1980 to the present. In
addition, current textbooks of toxicology and pharmacol-
ogy, and classical articles dating from before 1980, were re-
viewed. These resources yielded several hundred articles
and chapters, of which 138 were selected for inclusion in
this review. In this issue of Emergency Medicine PRACTICE,
the 138 references cited provide a basis for our discussion
of the epidemiology, pathophysiology, diagnosis, and
treatment of digoxin, -blocker, and CCB toxicity, followed
by evidence-based management recommendations.
Etiology, Pharmacokinetics, Pathophysiology
Over the past 100 years, there have been numerous cardio-
vascular agents developed for the treatment of hyperten-
sion, dysrhythmias, and congestive heart failure. Many
of these agents have their effects directly on the cardio-
vascular system. However, many of them have additional
systemic effects, which are markedly present in the setting
of an overdose. In 2004 the American Association of Poi-
son Control Centers (AAPCC) reported that, as a class of
medications, cardiovascular agents were the fourth most
common pharmaceutical agent involved in poisoning
fatalities in the US. Only analgesics, sedative-hypnotics/
antipsychotics, and antidepressant medications were more
common. Among cardiovascular agents, CCBs, -blockers,
and digoxin were the most commonly involved in fatali-
ties, accounting for 60%, 17 %, and 17% of the reported fa-
talities, respectively.
1
In order to understand the toxicity of
these 3 agents, we will review their pathophysiology and
the clinical manifestations of overdose, as well as provide
treatment recommendations.

Cardiac Glycosides
Cardiac glycosides became widely accepted as a medical
treatment for heart failure in 1785, when a manuscript
detailing their effects on the heart was rst published.
2

Cardiac glycosides have since been used for the treatment
of chronic heart failure and for ventricular rate control
in atrial tachydysrhythmias. Digoxin, derived from the
foxglove plant Digitalis lanata, is the most commonly pre-
scribed cardiac glycoside in the US. Other pharmaceutical
preparations including digitoxin, rarely seen in the US
are still used worldwide. Although the pharmacokinet-
ics differ among the various cardiac glycoside prepara-
tions, the clinical effects are similar.
Many plants contain cardiac glycosides. Aside from
foxglove, other examples include milkweed, lily of the
valley, oleander, yellow oleander, dogbane, and squill.
3

Toxicity may occur following ingestion of seeds, leaves,
or other parts of these plants. In addition, poisoning
can occur from teas, herbal products that contain plant
components, or even food cooked on skewers made from
the branches of these plants.
2
Cardiac glycoside toxicity
has also occurred after ingestion of topical aphrodisiacs
containing bufadienolides. And the naturally occurring
cardiac glycosides are not limited to plants they have
been found in the venom of the Bufo toad, as well. (Table
1)
-blockers
After the discovery in the 1960s that the effects of cat-
echolamines were mediated by the activation of - and
-adrenergic receptors, -blockers were soon developed.
5

Table 1. Plants And Animals That Contain Cardiac Glycosides.
Common Name Latin Name Glycoside
Foxglove Digitalis lanata
Digitalis purpurea
Digoxin
Digitoxin
Lily of the valley Convallaria majalis Convallatoxin
Oleander Nerium oleander
Thevetia peruviana
Oleandrin and others
Milkweed Asclepias spp Asclepiadin and others
Red squill Urginea indica
Urginea maritima
Scillaren A & B and others
Dogbane Apocynum cannabinum Apocynein, Apocynin
Bufo toad venom Bufo marinus and others Bufalin and others
3 Emergency Medicine Practice 2005 September 2005 EMPractice.net
Table 2. Calcium Channel Blockers: Classes And Extended-Release Preparations.
Class Medication Extended-Release Preparations (Brands)
Phenylalkylamine Verapamil Calan SR, Isoptin SR, Covera HS, Verelan PM
Benzothiazepine Diltiazem Cardizem SR, Cardizem CD, Cardizem LA, Taztia XT, Cartia XT, Dilt-CD
Dihydropyridine Nifedipine Procardia XL
Nicardipine Cardene SR
Isradipine DynaCirc CR
Nisoldipine Sular
Propranolol, the prototypical -adrenergic receptor
antagonist, was rst synthesized in 1962.
6
Its use led to de-
creased morbidity and mortality in patients with angina,
due to its ability to decrease myocardial oxygen demands.
7

Today, at least 15 different -blockers are commonly used
in the US. They have proven effective for the treatment
of ischemic heart disease, hypertension, congestive heart
failure, and certain dysrhythmias.
8
Other indications for
their use include hyperthyroidism, glaucoma, prevention
of variceal bleeding in the setting of portal hypertension,
migraine prophylaxis, and for the control of acute panic
symptoms.
8-12
Propranolol is an example of a nonspecic -ad-
renergic receptor antagonist that blocks both
1
and
2

receptors. Others include nadolol, sotalol, and timolol. On
the other hand, atenolol, metoprolol, and the short-act-
ing esmolol are selective for
1
receptors, although this
selectivity is not absolute and is often lost in the setting
of overdose.
13
Labetalol and carvedilol are nonspecic -
blockers that also block
1
receptors.

CCBs
CCBs were also developed in the 1960s, following the
realization that drugs can alter cardiac and smooth muscle
contraction by preventing the entry of Ca
++
into myo-
cytes.
14
Due to their negative inotropic and chronotropic
effects, CCBs are used for the treatment of hypertension,
dysrhythmias, and exertional and variant angina.
15-18
Non-
cardiac indications for CCBs include Raynauds disease,
migraine headache prophylaxis, cerebral vasospasm fol-
lowing cerebral aneurysm rupture, and premature uterine
contractions.
16,19
Today there are 10 CCBs approved for clinical use in
the US, each belonging to 1 of 4 classes: the phenylalkyl-
amine class (verapamil), the benzothiazepine class (diltia-
zem), the diarylaminopropylamine class (bepridil), and
the dihydropyridine class (nicardipine, nifedipine, isradip-
ine, amlodipine, felodipine, nisoldipine, and nimodipine).
There is an additional class of CCB the diphenylpipera-
zine; however, there are currently no approved drugs.
(Table 2)
Pharmacokinetics
Digoxin
Digoxin is typically dosed orally at 0.125 to 0.5 mg/day,
following oral or intravenous loading. It is well absorbed
orally, with a bioavailability of about 70 to 80%.
20
Appar-
ent resistance to standard oral dosing of digoxin may be
due to the enteric bacterium Eubacterium lentum, which is
found in roughly 10% of the population and can convert
digoxin into an inactive metabolite. This effect may be
reversed by the administration of antibiotics.
21
Clarithro-
mycin, erythromycin, and tetracycline alter gut ora and
may lead to elevated serum levels of digoxin.
22
Serum di-
goxin levels may also be increased by drugs that decrease
intestinal motility and lead to increased absorption, such
as diphenoxylate and propantheline.
22
Drugs that decrease
absorption, such as antacids, cholestyramine, metoclo-
pramide, and neomycin, may also lead to decreased serum
digoxin levels.
22
Distribution of digoxin follows a 2-compartment
model. There is rapid distribution to the intravascular
compartment, with peak serum concentrations occurring
within 2 to 3 hours. This is followed by a slower distribu-
tion to cardiac tissue over a period of 6 to 8 hours. Onset of
action following oral dosing may be as soon as 90 minutes,
with maximal effect seen within 4 to 6 hours.
2
(See Table 3
on page 4.) Digoxin is approximately 25% protein-bound.
2

It has a volume of distribution in adults of 6 to 7 L/kg,
but can be decreased to 4 to 5 L/kg in patients with renal
failure.
2
Digoxin is metabolized to a very small extent via
hydrolysis, oxidation, and conjugation. About 50 to 70%
is excreted unchanged by the kidney, and dosing should
be adjusted according to the patients creatinine clearance.
Smaller amounts of the drug are excreted in bile, with en-
terohepatic recycling occurring. Serum digoxin levels may
be decreased in the setting of concomitant use of drugs
that reduce its clearance or volume of distribution, such
as alpraxolam, amiodarone, indomethacin, propafenone,
quinidine, and verapamil.
22
Nonrenal clearance may be en-
hanced by rifampin.
22
The elimination half-life ranges from
36 to 51 hours, though this has been reported to decrease
in the setting of an overdose, to as low as 15 hours.
23

-blockers and CCBs
Pharmacokinetic parameters, such as oral bioavailability,
lipid solubility, protein binding, elimination half-life, and
metabolism, vary greatly among the different -blockers
and calcium channel blockers.
8,24
As a result, onset and
duration of action are dependent upon the individual
-blocker or CCB taken. However, following a pure
overdose of a nonsustained-released -blocker or CCB,
symptoms typically occur within 6 hours.
25-27
While there
is also large variation in the volume of distribution among
-blockers, it is almost uniformly greater than 1 L/kg.
24

Most -blockers are taken orally, with the exception of
timolol. This agent is a liquid solution that is used topi-
cally for the treatment of glaucoma. -blocker toxicity can
develop with its use.
Although absorption is nearly complete following
oral administration of CCBs, bioavailability is reduced due
to rst-pass hepatic metabolism via the CYP3A subgroup
of the cytochrome P450 enzyme system.
28,29
Onset of action
following an oral dose of an immediate-release prepara-
tion usually occurs within 30 to 60 minutes.
28
All CCBs are
highly protein-bound, and most have large volumes of
distribution.
28,29
Elimination half-lives range from 1.3 to 64
hours.
28
An increased elimination half-life may develop in
the setting of an overdose, when hepatic enzymes become
saturated, or in the setting of chronic ingestion of a drug
that is either a substrate or inhibitor of the same hepatic
enzyme.

Pathophysiology
In order to understand the toxicity of digoxin, -blockers,
and CCBs, a review of the normal physiology of cardiac
myocyte depolarization and myobril contraction is
important.
During the initial phase of the cardiac myocyte action
potential, positively charged sodium ions (Na
+
) enter the
cell and lead to membrane depolarization. As a result,
voltage-gated L-type Ca
++
channels open, leading to an in-
ux of Ca
++
. An increased intracellular Ca
++
concentration
stimulates the release of additional Ca
++
into the cytosol
from sarcoplasmic stores, via the ryanodine receptor on
the sarcolemma. Ca
++
binds to troponin C and ultimately
allows for the binding of actin and myosin, thereby pro-
ducing muscle contraction. In smooth muscle, the inux
of Ca
++
stimulates the phosphorylation of myosin. This
activated myosin then binds to actin, causing a contrac-
tion. (Figure 1)
A Na
+
gradient across the cell membrane needs to be
reestablished for the next cellular depolarization to occur.
The Na
+
-K
+
-ATPase is responsible for regenerating this
gradient. The Na
+
gradient then drives the Na
+
-Ca
++
chan-
nel exchanger, which is responsible for moving Ca
++
out of
the cell. A portion of Ca
++
is also reabsorbed into the sarco-
plasmic reticulum via a Ca
++
-ATPase on the sarcolemma.
Cardiac conduction and contractility, and vasogenic
muscle tone, are under the inuence of the sympathetic
and parasympathetic nervous systems via specic cell
membrane receptors. In cardiac myocytes,
1
receptors are
linked to G proteins that activate adenylate cyclase when
Table 3. Digoxin Pharmacokinetics.
Route Onset of Action Time to Peak Level Time to Peak Effect
Oral 1.5-6 h 2-3 h 4-6 h
Intravenous 5-30 min Intermediate 1.5-3 h
Figure 1. Mechanism Of Myocardial Cell
Muscle Contraction.
A. -adrenergic agonists bind to the -adrenergic receptors and
activate adenyl cyclase to produce cAMP from ATP. -blockers
competitively inhibit agonist binding.
B. cAMP activates slow L Ca
++
channels and increase intracellular
Ca
++
. CCBs act on these channels to impede Ca
++
inux.
C. Elevated intracellular Ca
++
causes release of Ca
++
from the
sarcoplasmic reticulum.
D. And causes muscle contraction.
E. cAMP is metabolized to 5MP by phosphodiesterase. PDE
inhibitors increase intracellular Ca
++
by inhibiting cAMP metabo-
lism.
stimulated. This results in the intracellular production of
cyclic AMP (cAMP), which, via protein kinases, phosphor-
ylates several myocyte proteins.
30
Ca
++
channel phosphory-
lation increases the inux of Ca
++
during each depolariza-
tion cycle.
31,32
Adrenergic stimulation of the heart via
1

receptors leads to cardiac myocyte depolarization and
results in increased contractility. It also increases cardiac
conduction velocity and excitability, leading to increased
heart rate and induction of automaticity.
8,24
Noncardiac
effects of
1
receptor agonism include renal artery dilation,
increased renin secretion, decreased intestinal motility and
tone, and the secretion of antidiuretic hormone from the
posterior pituitary.
33

2
receptors are predominantly located in the vascu-
lature particularly in skeletal muscle and the smooth
muscle of bronchioles.
2
receptors are linked to G proteins
that activate adenylate cyclase and mediate relaxation.
33

Receptor stimulation leads to vasodilation and bronchodi-
lation. Other effects of
2
receptor agonism include ciliary
muscle relaxation, decreased stomach and intestinal motil-
ity and tone, gallbladder and gallbladder duct relaxation,
detrusor muscle relaxation in the urinary bladder, uterine
muscle relaxation, increased glycogenolysis in skeletal
-blockers
-blockers are competitive antagonists of endogenous cat-
echolamines for the adrenergic receptor. This effect causes
a decrease in heart rate and inotropy.
CCBs
CCBs impair Ca
++
inux into cardiac and smooth muscle
myocytes. Similar to -blockers, the effect of CCBs on car-
diac myocytes is a decrease in contractility. By impairing
Ca
++
inux in the cardiac conduction system, CCBs impair
spontaneous depolarization of the action potential. This
action slows heart rate and causes AV conduction block-
ade. In smooth muscle, CCBs cause vasodilation and lead
to hypotension.
Table 4. Distribution Of -Adrenoreceptor Subtypes Within Organs.
1
Heart Increase contractility, automaticity, and conduction velocity
Adipose tissue Activate lipolysis
Posterior pituitary ADH secretion
2
Vascular and respiratory smooth muscle Relaxation/dilatation
Skeletal muscle Relaxation
Glycogenolysis
Promote K
+
reuptake
Liver Glycogenolysis & Gluconeogenesis
Gallbladder and ducts Relaxation
Pancreas (Islets cells) Increased secretion
Eye Ciliary muscle relaxation
Kidney Renin secretion
Bladder Detrusor muscle relaxation
Uterus Muscle relaxation
Figure 2. Mechanism Of Cardiac Glycosides.
A. Cardiac glycosides inhibit the Na
+
-K
+
-ATPase, causing a rise
in intracellular Na
+
.
B. Ca
++
is prevented from exiting cell via antiporter.
C. Elevated intracellular Ca
++
causes release of Ca
++
from the
sarcoplasmic reticulum.
D. And enhances cardiac inotropy.
muscle and liver, increased hepatic gluconeogenesis,
stimulation of K
+
uptake into cells, and increased insulin
secretion from pancreatic islet -cells.
33
(Table 4)

Digoxin
Digoxins primary site of action is cardiac tissue, where
it inhibits the Na
+
-K
+
-ATPase. It exerts a positive inotro-
pic effect, which is benecial in the setting of congestive
heart failure, by increasing intracellular concentrations of
Ca
++
. Enhanced Ca
++
entry is achieved either secondary
to increased intracellular Na
+
concentration, or as a result
of reduced Ca
++
efux through the Na
+
-Ca
++
exchanger,
or both.
34,35,36
Digoxin itself may also increase intracellular
Ca
++
via interactions with L-type Ca
++
channels and the
ryanodine receptor.
2,35,37
Some incremental Ca
++
is taken up
into the sarcoplasmic reticulum and is then available for
release, thereby producing an augmented contractile re-
sponse in the subsequent depolarization cycle.
20
(Figure 2)
Digoxin has another important mechanism of action
it mediates an increase in vagal tone by increasing
the release of acetylcholine from parasympathetic nerve
bers.
38,39
At therapeutic drug levels, conduction through
the sinoatrial (SA) and atrioventricular (AV) nodes is
decreased, and the refractory period is prolonged.
40
This
effect contributes to digoxins utility as an antidysrhyth-
mic agent. However, at increased concentrations, this may
lead to sinus bradycardia or AV conduction abnormalities.
Supratherapeutic concentrations of digoxin increase
sympathetic nervous system activity and increase cardiac
automaticity, thereby contributing to the generation of
either atrial or ventricular dysrhythmias.
20
Delayed after-
depolarizations, caused by excessive increases in intracel-
lular Ca
++
and increased sympathetic tone, may reach the
threshold for generation of an action potential and initiate
contractions.
41
The simultaneous increase in automaticity
and depression of conduction in the His-Purkinje and ven-
tricular muscle bers may lead to ventricular tachycardia
or brillation.
20
these patients may develop severe toxicity following a
very large overdose. Conditions that require sympathetic
activity in order to maintain heart rate and cardiac output,
such as congestive heart failure and conduction defects,
increase the likelihood of becoming symptomatic follow-
ing an overdose.
24
The coingestion of another cardioactive
compound, such as CCBs, tricyclic antidepressants, or
neuroleptics, is considered to be the single most important
factor associated with the development of cardiovascular
morbidity.
26
Bradycardia (heart rate less than 60 beats per minute)
with associated hypotension (systolic blood pressure less
than 80 mm Hg) due to inhibition of cardiac chronotropy
and inotropy characterizes severe -blocker and CCB
toxicity. In addition to bradycardia, patients may develop
conduction abnormalities, including SA and AV nodal
dysfunction.
43
Patients may present with varying degrees
of heart block. First-degree AV block has been found to
be the most common ECG nding among symptomatic
-blocker exposures.
43
In addition to sinus bradycardia,
high-degree AV block and prolonged QRS and QTc inter-
vals may be found in some cases.
24,43
Lipophilic -blockers, particularly propranolol and
acebutolol, have membrane-stabilizing effects on cardiac
myocytes via Na
+
channel blockade or altered Ca
++
ux.
44,45

As a result, ventricular depolarization is prolonged and
manifested on the ECG as a wide QRS interval. These pa-
tients are at risk for developing ventricular dysrhythmias
and asystole.
24
Sotalol is the only -blocker with the ability
to block the delayed rectier K
+
current responsible for
repolarization.
24
With sotalol toxicity, the action potential
becomes prolonged, leading to a prolonged QTc interval
on the ECG.
46
These patients are at risk for developing
torsades des pointes. Patients with underlying congestive
heart failure may develop worsening symptoms.

CCBs
The clinical effect of a CCB depends on its relative afnity
for myocardial versus smooth muscle calcium channels,
although in severe overdose channel selectivity is lost.
47

The dihydropyridines selectively inhibit Ca
++
channels
in the vasculature and produce signicant vasodilation.
48

These agents are often used for the treatment of hyperten-
sion. They do not typically affect cardiac conduction and
cause little or no decrease in myocardial contractility.
49

Verapamil has a signicant inhibitory effect on cardiac
Differential Diagnosis
All of the agents under consideration here digoxin,
-blockers, and CCBs are capable of producing toxic
effects directly on the heart, of course; but other systems
are affected, as well. (For a comparison of ECG ndings
among these agents in overdose amounts, see Table 5.
Noncardiovascular ndings are shown in Table 6.)

Cardiovascular Effects
Digoxin
The cardiac toxicity from a digoxin overdose is related to
digoxins effects on both the sympathetic and parasym-
pathetic innervation of the heart. Consequently, digoxin
poisoning may result in almost any type of cardiac dys-
rhythmia, including sinus bradycardia, atrial tachycardia,
brillation or utter with slow ventricular response, all
degrees of AV block, junctional tachycardia, and ventricu-
lar tachycardia or brillation. However, rapidly conducted
supraventricular tachydysrhythmias cannot occur, due to
inhibition of AV nodal conduction. Bidirectional ventricu-
lar tachycardia is considered to be pathognomonic for
digoxin toxicity and is caused by alterations of intraven-
tricular conduction, junctional tachycardia with aberrant
intraventricular conduction, or alternating ventricular
pacemakers.
2
However, the most commonly seen cardiac
conduction abnormalities are premature ventricular con-
tractions,
42
often the rst indication of digoxin poisoning.
Electrocardiographic manifestations of digoxin
toxicity are due to decreased conduction accompanied
by increased automaticity and a shortened repolariza-
tion interval. Electrocardiogram (ECG) ndings include
an increased PR interval, AV nodal block, and QT seg-
ment shortening. Scooping of the ST segment, commonly
referred to as Salvador Dalis mustache, may be found
in patients with therapeutic digoxin levels and is due to ST
segment and T-wave forces in an opposing direction to the
major QRS forces.
2

-blockers
-blockers prevent the normal physiologic responses
to adrenergic stimulation of receptors. In overdose,
cardiovascular toxicity is of primary concern. -adrenergic
receptor antagonism is often well tolerated in young and
healthy persons who do not rely on sympathetic tone to
maintain their heart rate or cardiac output.
24
However,
Table 5. Differences In Evaluating The ECG In Patients With Acute Digoxin, -blocker, And
CCB Toxicity.
Digoxin -Blocker CCB
Atrial tachycardia +
Wide QRS + +/
High-degree AV block + + +
Biventricular tachycardia +
indicates absent; and + indicates present
reported, but does not occur frequently and is probably
limited to susceptible patients.
24,25,58

Insulin release from pancreatic islet -cells is regulat-
ed by Ca
++
inux through a slow Ca
++
channel.
59
Hypogly-
cemia may occur in children following an overdose from
-blockers, but has not been reported in adults unless they
have diabetes.
27,60,61
The primary endocrine effect of CCB
toxicity is hyperglycemia. In the setting of an overdose,
CCBs lose their selectivity and inhibit the Ca
++
channels in
pancreatic cells, thereby reducing the release of insulin.
29
In the overdose setting, other signs and symptoms
may be present, depending on the degree of hypotension
and cardiac compromise.
29
Neurologic symptoms include
dizziness, lightheadedness, fatigue, lethargy, confusion,
syncope, focal neurologic decit, seizure, and coma.
29,62-
64
Intestinal ileus and ischemia, elevated transaminases,
acute renal failure, and metabolic acidosis have also been
reported following -blocker and CCB overdose.
65-69
Rhab-
domyolysis may occur in conjunction with acute renal
failure.
65
Respiratory effects are uncommon, but mild to
severe pulmonary edema and acute lung injury have been
reported in the setting of CCB overdose.
70-74

Potassium Abnormalities
Digoxin
Digoxin toxicity is associated with hyperkalemia, which
can be found after an acute overdose and is a marker of
the severity of digoxin toxicity. A 1973 study of 91 patients
demonstrated that the K
+
level is an accurate predictor of
outcome in adults following acute digitoxin overdose.
75

This study did not include patients with chronic digoxin
toxicity and was done prior to the availability digoxin-
specic antibody fragments (Fab). The authors found
that 50% of patients with a K
+
level between 5.0 and 5.5
mEq/dL survived, while all patients with a level less than
5.0 mEq/dL survived, and all patients with a level greater
than 5.5 mEq/dL died. Hyperkalemia probably results
from inhibition of the Na
+
-K
+
-ATPase, but may also be due
to increased release of K
+
from tissue, including the liver,
and inhibition of the of K
+
uptake by muscle.
2
Patients with chronic digoxin toxicity are often
hypokalemic. This is not a direct effect of digoxin, but
rather is often secondary to diuretic use, potassium bind-
ing resins, or diarrhea. Hypomagnesemia may occur for
pacemaker cells and myocytes.
49
It produces a negative
chronotropic and inotropic effect. Diltiazem has greater
afnity for cardiac rather than vascular channels, as well.
However, it has a more moderate cardiodepressant effect
compared to verapamil.
49
Both verapamil and diltiazem
have similarly moderate vasodilatory effects.
49,50
Hypotension is the most common nding follow-
ing a CCB overdose.
51
In the setting of a dihydropyridine
overdose, hypotension may be accompanied by a reex
tachycardia.
52
Bradycardia may develop only after very
large ingestions.
53
Verapamil and diltiazem toxicity may
produce myocardial conduction abnormalities, including
sinus bradycardia and varying degrees of AV nodal block-
ade, and lead to the development of junctional or ventricu-
lar dysrhythmias.
51,54
Verapamil and diltiazem toxicity are
also associated with negative inotropy and may even lead
to complete inhibition of ventricular contraction in severe
overdose.
55
Noncardiovascular Effects
Digoxin
Digoxin toxicity is also manifested by noncardiac symp-
toms. Gastrointestinal effects are common and include
nausea, vomiting, and anorexia. Central nervous system
(CNS) symptoms include confusion and delirium, particu-
larly in the elderly. Digoxin toxicity is also associated with
visual disturbances, including blurring and scotomas,
as well as aberrations of color vision, often described as
yellow halos around lights.
56
However, these visual nd-
ings are less commonly seen than in the past, as digoxin
manufacturing processes have improved the purity of
this pharmaceutical agent. Impurities are believed to be
responsible for the visual side effects.
-blockers and CCBs
Since receptors are found throughout the body, -blocker
toxicity affects many other organ systems. -blocker over-
dose may lead to signicant CNS depression. An overdose
of one of the more lipophilic agents, such as propranolol,
may produce delirium, seizures, and coma, even in the
absence of hypotension.
27
Respiratory depression follow-
ing overdose typically occurs in patients who are hypoten-
sive and have CNS depression. However, it has also been
reported in an awake patient.
57
Bronchospasm has been
Table 6. Differences In Evaluating Patients With Acute Digoxin, -Blocker, And CCB Toxicity.
Mental status changes +
GI symptoms ++
Blood pressure Normal Decreased Decreased
Heart rate Decreased Decreased Decreased
Potassium Increased Mildly increased No effect
Glucose No effect Decreased Increased
indicates absent; and + indicates present.
the same reasons, as well. Hypokalemia may inhibit the
Na
+
-K
+
-ATPase and reduce its functional capability.
76
In
addition, chronic hypokalemia reduces the number of
Na
+
-K
+
-ATPase units in skeletal muscle. This may decrease
digoxins volume of distribution.
2
Hypokalemia is also
known to increase cardiac automaticity. The combined
effects of digoxin poisoning and hypokalemia predispose
patients to more signicant dysrhythmias at lower digoxin
levels.
-blockers
Serum K
+
levels have been shown to increase slightly with
-blocker use.
77
However, signicant hyperkalemia rarely
complicates an acute overdose.
24

Prehospital Care
Prehospital care of patients with an overdose of cardiovas-
cular toxin should follow the same guidelines as those for
patients who have an overdose of unknown origin. Care
must be taken to inspect the scene where the patient was
picked up, with special attention given to all the house-
hold medications. Patients are often asymptomatic and
have normal vital signs on initial medical contact. Never-
theless, because of the nature of cardiovascular toxins, it is
important to continuously monitor the airway, breathing,
and circulation. The patient should be attached to an ECG
monitor, and an IV line should be started. In the symp-
tomatic patient, ACLS guidelines should be followed, with
adequate airway management and prompt use of calcium
salts. In these cases, the admitting hospital should be noti-
ed of the patients status and expected time of arrival.
ED Evaluation And Management
In the initial evaluation of those who have possibly taken
a digoxin, -blocker, or CCB overdose, patients should
be attached to a cardiac monitor, and an ECG should be
obtained emergently to determine if conduction abnor-
malities are present. The initial management should also
include a rapid determination of blood glucose level and
serum electrolytes. Helpful laboratory tests include basic
electrolytes and arterial blood gas measurements. Serum
or urine -blocker or CCB levels do not play a role in the
clinical management of these patients. A chest radiograph
is useful to evaluate for pulmonary edema and/or acute
lung injury.
Digoxin levels should be obtained to conrm expo-
sure to digoxin. A correlation between elevated digoxin
levels and digoxin toxicity does exist. Typically, patients
with digoxin toxicity have digoxin levels above 2 ng/mL.
2
However, the diagnosis of digoxin toxicity is not based
solely on an elevated serum level. Monoclonal assays
will detect the presence of digoxin, but not other cardiac
glycosides. Polyclonal assays will detect the presence of
plant or animal cardiac glycosides, but to varying degrees.
The detection of digoxin on an assay in suspected cardiac
glycoside poisoning should only help to conrm a diag-
nosis. Conversely, an elevated digoxin level is not always
associated with toxicity. In a study of 1269 patients on di-
goxin, 58 (4.6%) were found to have digoxin levels greater
than 3.0 ng/mL.
78
Premature blood sampling accounted
for the elevated digoxin level in 10 of these patients. Only
11 patients had clinical evidence of digoxin toxicity. Note
that digoxin levels should be obtained at least 6 hours
after oral dosing, as this drug follows a 2-compartment
distribution model.
Digoxin, -blockers, and CCBs all cause bradycardia,
which may be accompanied by conduction delays. How-
ever, there are some subtle differences among these agents.
Diagnosis of digoxin toxicity should be suspected in any
patient presenting with signs of increased cardiac automa-
ticity, such as atrial or ventricular tachycardias, particular-
ly when accompanied by conduction delays. The diagno-
sis is especially challenging in patients who have not been
prescribed digoxin, but were exposed to another form of
cardiac glycoside, such as an herbal or plant source. These
patients may present with nonspecic gastrointestinal or
neurological complaints, or hyperkalemia.
Diagnosis of a -blocker or CCB overdose should
be suspected in the setting of bradycardia with associ-
ated hypotension. Reex tachycardia may be seen in an
overdose of a dihydropyridine CCB. CNS depression,
mild hypoglycemia, and mild hyperkalemia may make
the diagnosis of -blocker toxicity more likely than CCB or
digoxin overdose. Patients presenting with CCB toxicity
may be hyperglycemic and often have a normal mental
status despite hypotension. The development of neuro-
logical symptoms in the setting of a CCB overdose usually
corresponds to worsening toxicity. Patients with digoxin
poisoning may have an altered mental status and are less
likely to be hypotensive. (See Table 6 on page 7.)
Special consideration should be given to patients
presenting following an overdose from sustained-release
preparations. In these cases, patients may be asymptomat-
ic on presentation. Toxicity may be delayed for more than
12 hours postingestion, with subsequent rapid symptom
progression and possible severe toxicity.
54
Therefore, these
patients should be admitted, even if they are initially
asymptomatic.
Treatment
In the setting of digoxin, -blocker, and CCB overdoses,
general supportive care is immediately aimed at the
patients cardiovascular status. Attention should then be
turned to gastrointestinal and neurologic symptoms, with
equal consideration given to any electrolyte abnormalities.
Specic treatment modalities will be discussed below.
Decontamination
Decontamination with syrup of ipecac is contraindicated
in these cases, since there may be a rapid decline in the
patients level of consciousness, resulting in a signicant
risk of aspiration. In addition, vomiting may induce vagal
stimulation and worsen bradycardia.
79
Orogastric lavage is
recommended for patients presenting with severe toxicity,
if the drug is expected to still be in the stomach.
24
It should
also be considered following life-threatening overdoses
or coingestions, or in asymptomatic patients who present
early and are expected to become clinically unstable and
who have not already vomited. In the setting of digoxin
overdose, gastric lavage is less useful for several reasons.
Removing drug from the stomach by gastric emptying
may be limited, since vomiting is common in this setting.
In addition, orogastric lavage may increase vagal tone and
worsen bradydysrhythmias. Moreover, a safe and effective
antidote already exists.
Activated charcoal (AC) should be administered oral-
ly following an overdose with any of these agents the
oral dose of AC is 1 g/kg for patients who have a normal
mental status. Clearance of digoxin may be improved with
the use of multiple doses of activated charcoal (MDAC),
which is believed to interrupt enterohepatic and entero-
enteric recirculation of drug.
80
Since digoxin is cleared
renally, this may be particularly useful in the setting of
renal failure.
81
MDAC doses should also be considered in
the setting of sustained-release preparations of -blockers
and CCBs.
29
The dose is 0.5 g/kg, after the initial loading
dose of 1.0 mg/kg, for no more than 3 doses.
Whole bowel irrigation (WBI) with polyethylene
glycol may be the most effective means of decontamina-
tion for sustained-release products.
82
In adults, 1 to 2 L/h
of polyethylene glycol should be administered until the
rectal efuent is clear. It is important to consider decon-
tamination with MDAC and WBI following all overdoses
of sustained-release preparations, even in patients who are
asymptomatic on their initial presentation.
Endotracheal intubation should precede orogastric
lavage and/or the administration of activated charcoal,
via nasogastric or orogastric tube, in patients with an
altered mental status or in those patients whose level
of consciousness is expected to rapidly decline. Prior to
undergoing laryngoscopy for endotracheal intubation or
orogastric lavage, patients may need to be pretreated with
standard doses of atropine, since these procedures might
also induce vagal stimulation and worsen bradycardia.
24

Atropine
Patients who present with bradycardia and hypotension
should be initially managed with atropine and intra-
venous uid boluses. Atropine has been useful in the
management of severe supraventricular bradydysrhyth-
mias or high degrees of AV block in the setting of digoxin
toxicity.
83
In the setting of CCB toxicity, however, atropine
is usually ineffective.
84
In adults, 1 mg of atropine may
be given and repeated twice, for a total dose of 3 mg. In
infants, children, and adolescents, 0.02 mg/kg per dose of
atropine may be given. The maximum total dose is 1 mg
in infants and children, and 2 mg in adolescents. A dose of
less than 0.1 mg may cause paradoxical bradycardia.
Potassium Abnormalities
Hyperkalemia is common in acute digoxin toxicity and is a
sign of severe toxicity, rather than a mechanism of toxicity.
The correction of hyperkalemia by conventional methods
in the setting of digoxin toxicity has not been shown to
improve survival.
75
Denitive treatment of digoxin toxicity
with digoxin-specic Fab will often lead to resolution of
hyperkalemia.
If hyperkalemia is suspected to be the cause of the
bradydysrhythmia, insulin and glucose and/or Na
+

bicarbonate may be administered rst. The administration
of Ca
++
, which is often used in the treatment of hyperkale-
mia, is contraindicated in the setting of digoxin toxicity. A
change in the ECG with this treatment will assure the di-
agnosis of hyperkalemia as the cause of the dysrhythmia.
If there is no change in the ECG, digoxin immunotherapy
may be administered next, prior to the administration of a
Ca
++
salt.
-blocker toxicity causes a mild elevation in K
+
that, if
present, is only helpful for diagnostic evaluation.
Hypokalemia exacerbates chronic digoxin toxicity and
K
+
should be repleted in this setting. Hypomagnesemia
should be corrected, as well, since hypokalemia may be
refractory to treatment in the setting of hypomagnesemia.
Antidotal Treatment
Digoxin
Digoxin-specic Fab
The mainstay of treatment for digoxin toxicity is the
administration of digoxin-specic Fab. These antibodies
have a high afnity for digoxin, but they have sufcient
cross-reactivity to be useful for the treatment of toxicity
secondary to other cardiac glycosides.
4
A study of 125 pa-
tients with digoxin toxicity found that 90% had a response
to digoxin-specic Fab within minutes to several hours of
administration.
85
In addition, complete resolution of symp-
toms occurred in 80% of patients, with partial resolution
in an additional 10%. Among the 15 patients who did not
respond, 14 were severely ill, and some were found not to
have digoxin toxicity. This study also found digoxin-spe-
cic Fab to be very safe, and no signicant adverse effects
related to its administration were noted.
Digoxin-specic Fab works by binding intravascular
free digoxin immediately following intravenous adminis-
tration. It subsequently diffuses into the interstitial space
and binds digoxin there, as well. A concentration gradient
is established, and digoxin moves from its binding sites in
tissue (such as the heart) to the interstitial and intravascu-
lar compartment, where it is then bound to digoxin-spe-
cic Fab.
86
Following administration of digoxin-specic
Fab, free digoxin has been shown to drop to an undetect-
able level within 1 hour.
87
A rise in the serum digoxin level
following administration of antibody should not cause
concern, assuming the patient has clinically improved.
Most health care facilities measure total digoxin, which
includes free and antibody-bound digoxin, rather than
just free digoxin. Therefore, it is not clinically useful to
measure digoxin levels after therapy with digoxin-specic
Fab, unless the assay measures free digoxin.
Treatment should be initiated in any patient manifest-
ing clinical signs of digoxin toxicity. This includes patients
Continued on page 11

The evidence for recommendations is graded using the following scale. For complete denitions, see back page. Class I: Denitely
recommended. Denitive, excellent evidence provides support. Class II: Acceptable and useful. Good evidence provides support. Class III:
May be acceptable, possibly useful. Fair-to-good evidence provides support. Indeterminate: Continuing area of research.
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending
upon a patients individual needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright 2005 EB Practice, LLC. 1-800-249-5770. No part of this publication may be reproduced in any for-
mat without written consent of EB Practice, LLC.
Suspected overdose with bradycardia and hypotension?

ABCD
IV line/uid bolus
Cardiac monitoring
Laboratory
BP normalizes?
Bradycardia and hypotension? Physical Exam
Atrial tachycardia with AVB
or biventricular tachycardia
Signs of hyperkalemia
(No P waves, peaked T waves,
wide-sinusoidal QRS)
ECG normalizes
Digoxin toxicity likely,
continue reassessment
Clinical Pathway: Treatment Of Possible Digoxin,

-blocker, Or CCB Overdose
Continue reassessment
SLUDGE
(Atropine, until no secretions)
ECG
Apply pacing pads
Miosis, bradypnea
Atropine: 1-3 mg IVP
Digoxin toxicity likely
Digoxin Fab:
10 vials if acute OD, 5
vials if chronic
Insulin, 10U IV
D50 glucose, 1 amp IV
Sodium bicarbonate, 1 amp IV
Hyperkalemia likely,
continue reassessment
ECG normalizes
Hypotension resolves
Hemodialysis: Hx of acebutolol
or atenolol ingestion
Continue reassessment External/Intravenous Pacing ECG normalizes
Catecholamines: Isoproterenol (to correct HR in beta-blocker OD):
0.1 g/kg/min, titrate to effect, or norepinephrine (for BP): 8-12
g/min IV, then titrate to BP
Glucagon:
3-5 mg IV (50-150 g/kg)
Ca: 1 amp 10% CaCl
2
or
2-3 amp 10% Ca Gluconate IV over 5 min
10-20 mg/kg CaCl
2
IV
Insulin: 10-20 U IVP, followed by 0.2-1.0 IU/kg/hr-
Glucose: 1 amp D50, then 0.5 g/kg/h (euglycemia)
Phosphodiesterase inhibitor (PDI):
Milrinone: Bolus 50 g/kg IV, then 0.25-1.0 g/kg/min
or Amrinone: Bolus 0.75 mg/kg IV, then 5-10 g/kg/min IV infusion
Mechanical BP support: Intra-aortic
balloon pump/ECMO
Continuing reassessment, no change in ECG?
(Invasive cardiac
monitoring)
(Start
infusion at
dose that
produced
response)
each vial contains 0.5 mg of digoxin-specic Fab. Digoxin
levels reported in mmol/L can be converted to ng/mL, by
multiplying by a factor of 0.8. Alternatively, if the amount
of digoxin ingested acutely is known, the total body load
can be determined by multiplying by 80% the bioavail-
ability of digoxin. For patients who display signicant
signs of digoxin toxicity, treatment should not be delayed
while waiting for the results of the serum digoxin level.
The empiric dose for an acute overdose in an adult or
child is 10 vials.
86
In cases of chronic toxicity, the empiric
dose is 3-6 vials for adults, and 1-2 vials for children.
86
(See
Table 7 on page 12.)
In the event that digoxin-specic Fab is unavailable,
lidocaine may be helpful in the management of ventricular
dysrhythmias. Lidocaine combats enhanced cardiac auto-
maticity without slowing cardiac conduction.
88
It should
be given as a 1-1.5 mg/kg intravenous push, followed
by a maintenance infusion of 1-4 mg/min.
89
For refrac-
tory dysrhythmias, additional boluses of 0.5-0.75 mg/kg
can be given over 3-5 minutes, or the infusion rate can be
increased to a maximum of 4 mg/min.
89
In the past, phe-
nytoin was used for refractory cardiotoxicity secondary
presenting with life-threatening dysrhythmias. In the set-
ting of digoxin toxicity, a K
+
level greater than 5.0 mEq/dL
is a marker for an increased risk of mortality and should
prompt treatment with digoxin-specic Fab. In a patient
presenting with symptoms suggesting poisoning by either
digoxin, a -blocker, or a CCB, treatment with digoxin-
specic Fab should be considered early. A diagnosis of
digoxin toxicity can be made if symptoms resolve follow-
ing antibody administration.
Dosing of digoxin-specic Fab depends on the total
body load of digoxin, which can be calculated by multi-
plying the serum digoxin concentration, in ng/mL, by the
volume of distribution of digoxin and the patients weight
in kilograms. The number of vials needed equals the total
body load of digoxin in milligrams multiplied by 2, as
each vial of digoxin-specic Fab binds 0.5 mg of digoxin.
A quick estimation of the number of vials needed equals
the serum digoxin concentration (in ng/mL) multiplied by
the patients weight (in kg) divided by 100.
86
This calcula-
tion assumes a volume of distribution of 5 L/kg and that
Ten Pitfalls To Avoid
6. We didnt start high-dose insulin therapy until all other
medications we had given failed.
Though the information on high-dose insulin therapy is
based on case reports, it takes approximately 1 hour for this
therapy to work. Starting high-dose insulin late in a severely
poisoned patient may jeopardize their outcome.
7. I thought that reversing the patients digoxin level would
put him into acute pulmonary edema or atrial brillation.
Digoxin is a mild inotropic agent. For patients with CHF, it is
principally used to invigorate their daily activities. Digoxin
administration does not reverse acute pulmonary edema.
Atrial brillation may be managed with CCBs or -blockers.
8. I didnt think the patient was on digoxin, so I treated the
bradycardia with isoproterenol.
Isoproterenol may induce lethal ventricular dysrhythmias in
the setting of acute digoxin toxicity.
9. I didnt think that calcium chloride was going to
damage the babys arm to the extent of necessitating an
amputation.
When administered peripherally, calcium chloride can
cause severe sclerosing of the vasculature. If the only
access available is peripheral, calcium gluconate should be
administered instead.
10. On recheck, the digoxin level after we had treated the
patient with digoxin Fab was greater than 30, so we treated
the patient again.
Although there is no medical harm from administering large
doses of digoxin Fab, there is no need for further treatment
after appropriate initial treatment.
1. I wanted to wait for a digoxin level before treating the
patient with digoxin Fab.
Dont wait. A patients cardiodynamic status may worsen
during the wait for completion of a digoxin level.
2. I always perform gastric lavage on every poisoned
patient.
Gastric lavage has many associated risks and should be
reserved for life-threatening overdoses, when the toxin is
still expected to be in the stomach.
3. Whole bowel irrigation has never worked in any other
patient I have treated.
Although based only on case reports, whole bowel irrigation
is generally recommended for body-packers and those cases
where sustained-release preparations have been ingested,
since this mode of decontamination is safe and may turn a
lethal ingestion into a survivable one.
4. We administered calcium chloride because we were
following ACLS guidelines for hyperkalemia. We didnt
know the patient was on digoxin.
ACLS guidelines were not written for overdose patients.
The administration of calcium salts in the setting of digoxin
toxicity may induce systolic cardiac arrest, an entity known
as stone heart.
5. Our patient may have overdosed on digoxin. We placed
a transvenous pacer after atropine administration, in
conformity with ACLS guidelines for bradycardia.
Acute digoxin toxicity sensitizes the myocardium.
Introducing a transvenous pacer induces ventricular
arrhythmias in 50% of patients with digoxin toxicity.
Continued from page 9
Table 7. Calculation Of Dose Of Digoxin-Specic Immunotherapy.
Calculation or Empiric Dose Number of Vials
Known amount ingested Amount ingested (mg) x 0.8 (bioavailability of digoxin) / 0.5 mg (amount of digoxin Fab per vial)
Known serum digoxin level Serum digoxin level (ng/mL) x patients weight (kg) / 100
Empiric, acute overdose 10 vials (adult or child)
Empiric, chronic toxicity 3-6 vials (adult)
Empiric, chronic toxicity 1-2 vials (child)
*Source: Howland MA. Digoxin-specic antibody fragments. In: Goldfranks Toxicologic Emergencies. 7th ed. 2002;735-740. See Reference 86.
positive chronotropic and inotropic cardiac effect despite
-blockade.
97
Evidence supporting the use of glucagon in
the management of patients with -blocker overdose is
limited to animal studies.
98
Theoretically, glucagon should
not be effective for CCB toxicity, because the mechanism of
toxicity is downstream of its effect.
29
However, both in vi-
tro and in vivo animal studies of CCB toxicity have shown
some improvement in bradycardia, heart block, cardiac
output, or hypotension with glucagon use.
99-104
There are
numerous case reports that demonstrate the efcacy of
glucagon in -blocker toxicity, and it is a widely accepted
antidote for this type of overdose.
98
Similarly, human data
demonstrating improvements in heart rate or blood pres-
sure following glucagon therapy after CCB overdose are
limited to case reports.
65,105-107

Glucagon has no role in the management of digoxin
toxicity. In fact, since glucagon elevates intracellular cal-
cium, it may have a deleterious effect in this setting.
Appropriate dosing of glucagon for -blocker toxicity
includes both an intravenous bolus dose and a mainte-
nance infusion.
24
The initial adult dose is 3-5 mg over 1-2
minutes. If there is no response to the initial dose, addi-
tional doses may be repeated every 5-10 minutes, until a
total of 10 mg has been given. Once a response has been
achieved, an infusion should be started at an hourly rate
equal to the amount of glucagon that produced a response.
Patients not achieving the desired response following the
maximum bolus dose of glucagon should be started on
an infusion of 10 mg/h. The dose for children is 50-150
g/kg, followed by an infusion of 50 g/kg/h, up to the
maximum adult dose. Side effects may be dose-dependent
and include nausea, vomiting, hyperglycemia, and hypo-
kalemia.
108,109
(Table 8)
Other Treatment Modalities
-blockers and CCBs
Catecholamines
Patients who are refractory to the preceding treatment op-
tions usually require a catecholamine infusion. A -agonist
would be a logical choice in the setting of -blocker toxic-
ity. Isoproterenol is a pure -agonist and has been dem-
onstrated to be more effective than glucagon in reversing
-blocker toxicity in animal models.
110
However, this
effect has not been demonstrated in a review of human
case reports.
111
Isoproterenol was shown to be effective in
to acute digoxin poisoning. Its use should be considered
when digoxin-specic Fab is unavailable and lidocaine has
not been successful.
-blockers and CCBs
Calcium
Treatment with intravenous Ca
++
should be initiated in
patients with refractory hypotension and bradycardia sec-
ondary to -blocker or CCB toxicity. The administration of
exogenous Ca
++
increases extracellular Ca
++
concentration.
This may help drive Ca
++
through any unblocked channels
down an increased concentration gradient.
29
Animal stud-
ies have demonstrated the efcacy of Ca
++
in improving
blood pressure and inotropy in the setting of -blocker or
CCB toxicity.
90,91
In reports of human -blocker and CCB
toxicity, Ca
++
reverses the negative inotropy, impaired
conduction, and hypotension.
29,92,93
Ca
++
is most effective in
overcoming mild toxicity and less useful in massive over-
doses, since Ca
++
channel blockade is noncompetitive.
94

The administration of Ca
++
, which is often used in
the treatment of hyperkalemia, is contraindicated in the
setting of digoxin toxicity. Intractable ventricular rhythms,
or even asystolic arrest, referred to as stone heart, could
develop if additional Ca
++
is given.
2
An initial adult dose of 1 g of a 10% solution of Ca
++

chloride may be given via slow intravenous push. This
dose may be repeated up to a maximum of 3 g.
24
In chil-
dren, Ca
++
chloride should be started at 20 mg/kg up to
1 g, and up to 60 mg/kg may be given.
24
Ca
++
chloride is
highly irritating and may induce venous sclerosis, unless
given through a central vein. Ca
++
gluconate can be given
safely through a peripheral vein and may be the preferred
agent via this route. A 10% solution of Ca
++
gluconate con-
tains one-third the amount of elemental calcium compared
to a 10% solution of Ca
++
chloride. Therefore, the equiva-
lent dose of Ca
++
gluconate is 3 times that of Ca
++
chloride.
Adverse effects of Ca
++
therapy include nausea, vomiting,
ushing, constipation, confusion, and angina.
95
In addi-
tion, repeat dosing or continuous infusions may lead to
hypercalcemia and hypophosphatemia.
96
Glucagon
Treatment with glucagon should be initiated in symp-
tomatic patients with refractory bradycardia secondary to
-blockers and CCBs. Glucagon is often able to produce a
increasing heart rate only 11% of the time and blood pres-
sure only 22% of the time, while glucagon was shown to
increase heart rate 67% of the time and blood pressure 50%
of the time. The same review found epinephrine, which
has - and -adrenergic activity, to be more effective
than isoproterenol. When used, the recommended dose
of isoproterenol is 0.1 g/kg/min, with a rapid titration
to effect.
24
High doses are often required and may result
in adverse effects, including vasodilation and worsening
hypotension due to
2
-adrenergic agonism, and induction
of dysrhythmias.
Catecholamines with - and -adrenergic activity,
such as epinephrine and norepinephrine, need be used
with caution.
24
In the setting of -adrenergic antagonism,
overwhelming agonism may increase peripheral
vascular resistance without improving cardiac function
and result in acute cardiac failure.
24
It is preferable to use
invasive hemodynamic monitoring when these agents are
used. Standard dosing is acceptable and catecholamines
should be rapidly titrated to effect. Infusions should be
stopped immediately if congestive heart failure or worsen-
ing hypotension develops.
24
In the setting of digoxin toxicity, treatment with cat-
echolamines is contraindicated. Digoxin raises the thresh-
old for cardiac depolarization by increasing intracellular
Ca
++
, and catecholamine infusion may cause ventricular
dysrhythmias.
Phosphodiesterase Inhibitors
Phosphodiesterase inhibitors (PDIs) might also be helpful
in patients with refractory bradycardia and hypotension
secondary to -blockers and CCBs. PDIs increase cAMP
levels despite -receptor blockade, because they inhibit the
enzyme phosphodiesterase, which is responsible for the
breakdown of cAMP. Drugs in this class include amrinone,
milrinone, and enoximone. PDIs have been shown to in-
crease inotropy and reverse bradycardia and hypotension
in the presence of -blocker and CCB toxicity in animals.
Human data, limited to case reports, demonstrate that
PDIs may be most effective when combined with other
inotropes, such as isoproterenol or glucagon.
112-116
Milri-
none may be given as a 50 g/kg intravenous bolus over 2
minutes, followed by an infusion of 0.25-1.0 g/kg/min.
24

Amrinone may be given as a 0.75 mg/kg intravenous
bolus over 2 minutes and be repeated in 30 minutes, fol-
lowed by an infusion of 2-20 g/kg/min.
24
Adverse effects
include worsening hypotension secondary to vasodila-
tion. In addition, PDIs have long half-lives, making them
difcult to titrate.
24
Therefore, they should only be used in
conjunction with invasive hemodynamic monitoring.
Mechanical Therapies
External pacing pads should be placed in all patients
who present after -blocker and CCB overdose. Internal
pacing should be arranged early for ensuing symptomatic
bradycardia. External and internal cardiac pacing does not
always capture or improve patients hemodynamic status
in this setting.
54,117
In some patients, pacing will increase
the heart rate, but hypotension may worsen secondary to
loss of atrial contraction or impaired ventricular relax-
ation.
118
However, individual patients have been treated
successfully with cardiac pacing.
119,120

In the setting of digoxin toxicity, transvenous pacing
should be avoided, as the myocardium is hyperexcitable.
Transthoracic electrical cardioversion is contraindicated,
as well, for the same reason. It has been associated with
the induction of potentially lethal dysrhythmias similar to
digoxin-toxic rhythms. This effect seems to be related to
the degree of digoxin toxicity and the amount of current
used.
121
Patients who are refractory to pharmaceutical treat-
ment options may require an intra-aortic balloon pump
or extracorporeal circulation.
122,123
Successful use of an
intra-aortic balloon pump and extracorporeal membrane
oxygenation are described in the setting of CCB toxic-
ity.
124,125

Hemodialysis is an ineffective means of removing
digoxin, lipid-soluble -blockers, and CCBs, since all of
these have a large volume of distribution. Hemodialysis
may remove water-soluble -blockers, such as atenolol
and acebutolol.
122
However, severe bradycardia and hypo-
tension might preclude its use. (Table 8)
Table 8. Specic Treatment Modalities In Digoxin, -Blocker, And CCB Toxicity.
Digoxin Fab +
Atropine + + +
Calcium salts + ++
Glucagon ++ +
Catecholamines + +
Phosphodiesterase inhibitors + +
Transvenous pacing + +
Intra-aortic balloon pumps + +
indicates not recommended; + indicates recommended; and ++ indicates strongly recommended.
of insulin become apparent.
24
It is possible that insulin
has its greatest benet if started before patients become
symptomatic, in the setting of a large overdose that is
expected to produce signicant toxicity. Glucose should be
started at a dose of 1 g/kg/h and then titrated to maintain
euglycemia, with frequent monitoring. Since the effects
of insulin will last for several hours after the infusion is
discontinued, further blood glucose administration and
monitoring is necessary.
24
(Table 8)
Disposition
Following an overdose of a nonsustained-release prepa-
ration of a -blocker or CCB, symptoms typically develop
within 6 hours. When symptoms do develop, treatment
should be initiated and the patient should be admitted to
a monitored setting. Those patients who remain asymp-
tomatic during this time period are unlikely to develop
symptoms later on and may be considered medically
stable. Ingestion of sustained-release preparations may
result in a delayed onset of symptoms. Patients who ingest
these products should receive GI decontamination and be
admitted to a monitored setting for 24 hours of observa-
tion.
Following an acute ingestion of digoxin, a digoxin
level will only be meaningful when drawn 6 hours after
ingestion, as this drug follows a 2-compartment distribu-
tion model. Empiric treatment with digoxin Fab should be
initiated if a large overdose is suspected. Following treat-
ment, these patients may be considered medically stable
if they remain asymptomatic. Patients who present with
mild symptoms of digoxin toxicity might also be consid-
ered medically stable if their symptoms resolve following
treatment with digoxin Fab, and no other medical issues
(eg, renal failure) remain unresolved. Otherwise, patients
presenting with digoxin toxicity should be treated with
digoxin Fab and admitted to a monitored setting.
Summary
Digoxin, -blockers, and CCBs are commonly used to treat
hypertension, angina, dysrhythmias, and congestive heart
failure. The hallmark of their toxicity is bradydysrhyth-
mias and hypotension. Other systemic effects encountered
in toxicity are extensions of the pharmacologic effects of
these agents into other organ systems. Acute digoxin toxic-
ity causes hyperkalemia and is a good prognostic marker
of mortality in this setting. Gastrointestinal and CNS
symptoms are common in digoxin toxicity. CNS symp-
toms may also be present in lipophilic -blocker toxicity.
Mild hyperglycemia may be present in CCB toxicity. Regu-
lar-release formulations of these medications have an ef-
fect within the rst 6 hours of ingestion. Extended-release
formulations result in delayed toxicity and require 24-hour
observation and consideration for aggressive decontami-
nation with WBI and MDAC. In the symptomatic patient,
in addition to supportive care and decontamination, there
are specic antidotal treatments digoxin-specic Fab
for digoxin toxicity, glucagon for -blocker toxicity, and
Controversies
Patients with acute digoxin toxicity often present with
hyperkalemia. The administration of Ca
++
, which is often
used in the treatment of hyperkalemia, has long been pre-
sumably contraindicated in the setting of digoxin toxicity.
This is based on a proposed synergistic relationship be-
tween cardiac glycosides, which cause a physiologic rise in
intracellular Ca
++
, as well as extracellular Ca
++
, to explain
the enhanced toxicity seen with concurrent Ca
++
adminis-
tration.
126-130
Studies also demonstrate that high extracel-
lular calcium increased the toxicity of cardiac glycosides
at lower doses.
126,131-133
As a result, it is hypothesized that
intractable ventricular rhythms, or even systolic arrest,
referred to as stone heart, could develop if additional
Ca
++
is given.
2
Individual case reports have not demon-
strated adverse effects from the administration of Ca
++
to
treat hyperkalemia in the setting of digoxin toxicity.
134,135

A recent study examined the effects of the administration
of intravenous Ca
++
chloride in a porcine model of digoxin
toxicity.
126
Although the animals in the treatment group
did not seem to develop increased toxicity, all animals
developed asystole secondary to digoxin toxicity. No clear
benet or detriment related to the administration of Ca
++

chloride was shown. An earlier study, using a guinea-pig
model of digoxin-induced hyperkalemia, reported a trend
toward decreased rates of dysrhythmia and death follow-
ing treatment with intravenous Ca
++
chloride.
136
Until de-
nitive data demonstrating the safety and efcacy of Ca
++

administration in the setting of digoxin-induced hyperka-
lemia are available, its use should be avoided.
Cutting Edge
High-dose Insulin
High-dose insulin should be considered for severe
-blocker and CCB toxicity.
24,29
High-dose insulin with
sufcient 50% dextrose to maintain euglycemia effectively
improved survival, contractility, and blood pressure in
canine models of -blocker and CCB toxicity.
137,138
Insulin
has been shown to increase Ca
++
entry and to have a direct
inotropic effect.
139,140
Verapamil toxicity increases myocar-
dial cell dependence on carbohydrate metabolism.
138,141,142

CCBs impair carbohydrate metabolism by inhibiting the
release of insulin.
143
In addition, it is believed that CCBs
may increase myocardial resistance to insulin.
144
Although
animal studies have demonstrated improved survival with
high-dose insulin and euglycemic therapy in comparison
to calcium, glucagon, and epinephrine, human data are
limited to case series and reports.
99,137,145-149
This therapy is
in its experimental stages, and further study is necessary
to ascertain its efcacy.
Following an intravenous bolus of 10-20 units of
regular insulin along with 25-50 g of dextrose, an insulin
infusion of 0.1 units/kg/h should be started. The infusion
should be increased to 0.2-1.0 units/kg/h and contin-
ued until the patients condition has stabilized. Since the
response to insulin is often delayed for up to an hour, a
catecholamine infusion may be necessary, until the effects
and pharmacokinetic properties. Am Heart J 1979;
97:663-670. (Review)
14. Fleckenstein A. History of calcium antagonists. Circ Res
1983;52:I3-I16. (Review)
15. Doyle AE. Comparison of beta-adrenoceptor blockers
and calcium antagonists in hypertension. Hypertension
1983;5:II103-II108. (Randomized controlled, double-
blind, double-dummy, crossover)
16. Roden DM. Antiarrhythmic drugs. In: Hardman JG,
Limbird LE, Gilman AG, eds. Goodman and Gilmans The
Pharmacological Basis of Therapeutics. 10th ed. New York,
NY: McGraw-Hill; 2001:933-970. (Textbook chapter)
17. Bassan M, Weiler-Raveil D, Shalev O. The additive
antianginal action of oral nifedipine in patients receiv-
ing propranolol: Magnitude and duration of effect.
Circulation 1982; 66:710-716. (Controlled, double-blind,
10 patients)
18. Antman E, Muller J, Goldberg S, et al. Nifedipine
therapy for coronary-artery spasm. Experience in 127
patients. N Engl J Med 1980; 302:1269-1273. (Observa-
tional, 127 patients)
19. Murray C, Haverkamp AD, Orleans M, et al. Nifedip-
ine for treatment of preterm labor: A historic prospec-
tive study. Am J Obstet Gynecol 1992;167:52-56. (Pro-
spective, 102 patients)
20. Ooi H, Colucci WS. Pharamacological treatment of
heart failure. In: Hardman JG, Limbird LE, Gilman AG,
eds. Goodman and Gilmans The Pharmacological Basis
of Therapeutics. 10th ed. New York, NY: McGraw-Hill;
2001:901-932. (Textbook chapter)
21. Lindenbaum J, Rund DG, Butler VP, et al. Inactiva-
tion of digoxin by the gut ora: Reversal by antibiotic
therapy. N Engl J Med 1981;305:789-794. (Experimental,
human model)
22. Haji SA, Movahed A. Update on digoxin therapy in
congestive heart failure. Am Fam Physician 2000;62:409-
416. (Review)
23. Hobson JD, Zettner A. Digoxin serum half-life follow-
ing suicidal digoxin poisoning. JAMA 1973;223:147-149.
24. Brubacher JR. -Adrenergic Antagonists. In: Goldfrank
LR, Flomenbaum NE, Lewin NA, et al, eds. Goldfranks
Toxicologic Emergencies. 7th ed. New York: McGraw-
Hill; 2002:741-757. (Textbook chapter)
25. Love JN. Beta blocker toxicity after overdose: When do
symptoms develop in adults? J Emerg Med 1994;12:799-
802. (Systematic review)
26. Love JN, Howell JM, Litovitz TL, et al. Acute beta
blocker overdose: Factors associated with the develop-
ment of cardiovascular morbidity. J Toxicol Clin Toxicol
2000;38:275-281. (Prospective, cohort study)
27. Reith DM, Dawson AH, Epid D, et al. Relative toxic-
ity of beta blockers in overdose. J Toxicol Clin Toxicol
1996;34:273-278. (Prospective, observational)
28. Kerins DM, Robertson RM, Robertson D. Drugs used
for the treatment of myocardial ischemia. In: Hardman
JG, Limbird LE, Gilman AG, eds. Goodman and Gilmans
The Pharmacological Basis of Therapeutics. 10th ed. New
York, NY: McGraw-Hill; 2001:843-870. (Textbook chap-
ter)
29. De Roos F. Calcium channel blockers. In: Goldfrank LR,
Flomenbaum NE, Lewin NA, et al, eds. Goldfranks Toxi-
cologic Emergencies. 7th ed. New York, NY: McGraw-
Hill; 2002:762-774. (Textbook chapter)
30. Levitzki A, Marbach I, Bar-Sinai A. The signal trans-
duction between beta receptors and adenyl cyclase. Life
Science 1993;52:2093-2100. (Review)
31. Reuter H, Porzig H. Beta-adrenergic actions on cardiac
cell membranes. Adv Myocardiol 1982;3:87-93. (Experi-
mental)
Ca
++
salts for CCBs. Although human data are lacking and
further study is warranted, high-dose insulin with glucose
infusion should be considered in severe cases of -blocker
and CCB toxicity. Patients who have failed standard treat-
ments for -blocker and CCB overdose may need other
therapeutic alternatives: catecholamines, PDIs, and extra-
corporeal mechanical support of circulation.
References
Evidence-based medicine requires a critical appraisal of
the literature based upon study methodology and number
of subjects. Not all references are equally robust. The nd-
ings of a large, prospective, randomized, and blinded trial
should carry more weight than a case report.
To help the reader judge the strength of each refer-
ence, pertinent information about the study, such as the
type of study and the number of patients in the study, will
be included in bold type following the reference, where
available.
1. Watson WA, Litovitz TL, Klein-Schwartz, et al. 2003
Annual report of the American Association of Poison
Control Centers Toxic Exposure Surveillance System.
Am J Emerg Med 2004;22:335-404. (Observational)
2. Hack JB, Lewin NA. Cardiac glycosides. In: Goldfrank
LR, Flomenbaum NE, Lewin NA, et al, eds. Goldfranks
Toxicologic Emergencies. 7th ed. New York, NY: Mc-
Graw-Hill; 2002:724-734. (Textbook chapter)
3. McGufn M, Hobbs C, Upton R, et al, eds. American
Herbal Products Associations Botanical Safety Handbook.
Boca Raton, FL: CRC Press; 1997:138-141. (Textbook)
4. Brubacher JR, Hoffman RS, Bania T, et al. Deaths as-
sociated with a purported aphrodisiac--New York City,
February 1993-May 1995. MMWR Morb Mortal Wkly
Rep 1995;44:853-855, 861. (Case series)
5. Ahlquist RP. A study of the adrenotropic receptors. Am
J Physiol 1948;153:586-600.
6. Black JW, Stephenson JS. Pharmacology of a new
adrenergic beta-receptor blocking compound. Lancet
1962;2:311-314.
7. Lambert DM. Effect of propranolol on mortality in pa-
tients with angina. Postgrad Med 1976;52 Suppl 4:57-60.
(Prospective, 217 patients)
8. Hoffman BB. Catecholamines, sympathomimetic drugs,
and adrenergic receptor antagonists. In: Hardman JG,
Limbird LE, Gilman AG, eds. Goodman and Gilmans The
Pharmacological Basis of Therapeutics. 10th ed. New York,
NY: McGraw-Hill Professional; 2001:215-269. (Text-
book chapter)
9. Geffner DL, Hershman JM. Beta-adrenergic block-
ade for the treatment of hyperthyroidism. Am J Med
1992;93:61-68. (Review)
10. Villanueva C, Balanzo J, Novella MT, et al. Nadolol
plus isosorbide mononitrate compared with sclerother-
apy for the prevention of variceal rebleeding. N Engl J
Med 1996;334:1624-1629. (Prospective, randomized, 86
patients)
11. Tfelt-Hansen P. Efcacy of beta-blockers in migraine. A
critical review. Cephalalgia 1986;6 Suppl 5:15-24. (Sys-
tematic review)
12. Lader M. Beta-adrenoceptor antagonists in neuropsy-
chiatry: An update. J Clin Psychiatry 1988;49:213-223.
(Review)
13. Frishman W. Clinical pharmacology of the new beta-
adrenergic blocking drugs. Part I. Pharmacodynamic
32. Sperlakis N, Xiong Z, Haddad G, et al. Regulation of
slow calcium channels of myocardial cells and vascular
smooth muscle by cyclic nucleotides and phosphoryla-
tion. Mol Cell Biochem 1994;140:103-117. (Review)
33. Hoffman BB, Taylor P. Neurotransmission: The auto-
nomic and somatic motor nervous systems. In: Hard-
man JG, Limbird LE, Gilman AG, et al, eds. Goodman
and Gilmans The Pharmacological Basis of Therapeutics.
10th ed. New York: McGraw-Hill; 2001:115-153. (Text-
book chapter)
34. Smith TW. Digitalis. Mechanisms of action and clini-
cal uses. N Engl J Med 1988;318:358-365. (Systematic
review)
35. Marban E, Tsien RW. Enhancement of calcium current
during digitalis inotropy in mammalian heart: positive
feed-back regulation by intracellular calcium? J Physiol
1982;329:589-614. (Experimental)
36. Eisner DA, Lederer WJ. Does sodium pump inhibition
produce the positive inotropic effects of strophanthidin
in mammalian cardiac muscle? J Physiol 1979;294:279-
301. (Experimental)
37. Kim D, Cragoe EJ, Smith TW. Relations among sodium
pump inhibition, Na-Ca and Na-H exchange activation
and Ca-H interaction in cultured chick heart cells. Circ
Res 1987;60:185-193. (Experimental, animal model)
38. Madan BR, Khanna NK, Soni RK. Effect of some ar-
rhythmogenic agents upon the acetylcholine content of
the rabbit atria. J Pharm Pharmacol 1970;22:621-622.
39. Torsti P. Acetylcholine content and cholinesterase ac-
tivities in the rabbit heart in experimental heart failure
and the effect of g-strophanthin treatment on them.
Ann Med Exp Biol Fenn 1959;37 (Suppl 4):4-9. (Experi-
mental, animal model)
40. Carleton RA, Miller PH, Graettinger JS. Effects of oua-
bain, atropine, and ouabain and atropine on A-V nodal
conduction in man. Circ Res 1967;20:283-288. (Experi-
mental, human model)
41. Kelly RA, Smith TW. Recognition and management
of digitalis toxicity. Am J Cardiol 1992;69:108G-109G.
(Review)
42. Rosen MR, Wit AL, Hoffman BF. Cardiac antiar-
rhythmic and toxic effects of digitalis. Am Heart J
1975;89:391-399. (Review)
43. Love JN, Enlow B, Howell JM, et al. Electrocardio-
graphic changes associated with -blocker toxicity. Ann
Emerg Med 2002;40:603-610. (Prospective, cohort study,
167 patients)
44. Dhalia NS, Lee SL, Anand MB, et al. Effects of acebuto-
lol, practolol and propranolol on the rat heart sarco-
lemma. Biochem Pharmacol 1977;26:2055-2060. (Experi-
45. Hashimoto K, Satoh H, Imai S. Effect of etafenone and
antiarrhythmic drugs on Na and Ca channels of guinea
pig atrial muscle. J Cardiovasc Pharmacol 1979;1:561-570.
(Experimental, animal model)
46. Hohnloser SH, Woosley RL. Sotalol. N Engl J Med
1994;331:31-38. (Review)
47. Newton CR, Delgado JH, Gomez HF. Calcium and beta
receptor antagonist overdose: A review and update of
pharmacological principles and management. Semin
Respir Crit Care Med 2002; 23:19-26. (Review)
48. Taira N. Differences in cardiovascular prole among
calcium antagonists. Am J Cardiol 1987;59:24B-29B.
(Review)
49. Narayan P, Man Int Veld AJ. Clinical pharmacology of
modern antihypertensive agents and their interaction
with -adrenoceptor antagonists. Br J Urol 1998;81
Suppl 1:6-16. (Review)
50. Low R, Takeda P, Mason DT, et al. The effects of cal-
cium channel blocking agents on cardiovascular func-
tion. Am J Cardiol 1982;49:547-553. (Review)
51. Ramoska EA, Spiller HA, Myers A. Calcium channel
blocker toxicity. Ann Emerg Med 1990;19:649-653. (Ret-
rospective, 91 patients)
52. Whitebloom D, Fitzharris J. Nifedipine overdose. Clin
Cardiol 1988;11:505-506. (Case report)
53. Herrington DM, Insley BM, Weinman GG. Nifedipine
overdose. Am J Med 1986;81:344-346. (Case report)
54. Proano L, Chiang WK, Wang RY. Calcium channel
blocker overdose. Am J Emerg Med 1995;13:444-450.
(Case report, review)
55. Beniam ME. Asystole after verapamil. Br Med J
1972;2:169-170. (Case report)
56. Lee TC. Van Goghs vision. JAMA 1981;245:727-729.
57. Montgomery AB, Stager MA, Schoene RB. Marked
suppression of respiration while awake following mas-
sive ingestion of atenolol. Chest 1985;88:920-921. (Case
report)
58. Weinstein RS, Cole S, Knaster HB, et al. Beta-blocker
overdose with propranolol and with atenolol. Ann
Emerg Med 1985;14:161-163. (Case report)
59. Lebrun P, Malaisse WJ, Herchuelz A. Nutrient-induced
intracellular calcium movement in rat pancreatic -cell.
Am J Physiol 1982;(3) 243:E196-E205. (Experimental,
animal model)
60. Abbasi IA, Sorsby S. Prolonged toxicity from atenolol
overdose in an adolescent. Clin Pharmacol 1986;5:836-
837. (Case report)
61. Hesse B, Pedersen JT. Hypoglycemia after propranolol
in children. Acta Med Scand 1973;193:551-552. (Case
series)
62. Shah AR, Passalacqua BR. Case report: Sustained-re-
lease verapamil overdose causing stroke: An unusual
complication. Am J Med Sci 1992;304:357-359. (Case
report)
63. Wells TG, Graham CJ, Moss MM. Nifedipine poisoning
in a child. Pediatrics 1990;86:91-94. (Case report)
64. Passal DB, Crespin FH. Verapamil poisoning in an
infant. Pediatrics 1984;73:543-545. (Case report)
65. Quezado Z, Lippmann M, Wertheimer J. Severe car-
diac, respiratory, and metabolic complications of mas-
sive verapamil overdose. Crit Care Med 1991;19:436-438.
(Case report)
66. Donovan JW, ODonnell S, Burkhart KK. Calcium chan-
nel blocker overdose causing mesenteric ischemia. J
Toxicol Clin Toxicol 1999;37:628. (Case report)
67. Koch AR, Vogelaers DP, Decruyenaere JM, et al. Fatal
intoxication with amlodipine. J Toxicol Clin Toxicol
1995;33:253-256. (Case report)
68. Ori Y, Korzets A, Caneti M, et al. Lymphocytic intracel-
lular calcium in a patient with complicated verapamil
overdose. Am J Med Sci 2000;319:63-67. (Case report)
69. Hofer CA, Smith JK, Tenholder MF. Verapamil intoxica-
tion: A literature review of overdoses and discussion
of therapeutic options. Am J Med 1993;95:431-438.
(Review)
70. Snook CP, Sigvaldason K, Kristinsson J. Severe
atenolol and diltiazem overdose. J Toxicol Clin Toxicol
2000;38:661-665. (Case report)
71. Satchithananda DK, Stone DL, Chauhan A, et al. Les-
son of the week. Unrecognized accidental overdose
with diltiazem. BMJ 2000;321:160-161. (Case report)
72. Harchelroad F. ARDS associated with calcium channel
blocker overdose. Vet Hum Toxicol 1992;34:328. (Case
report)
73. Humbert VH Jr, Munn NJ, Hawkins RF. Noncardiogen-
ic pulmonary edema complicating massive diltiazem
overdose. Chest 1991;99:258-260. (Case report, review)
74. Spurlock BW, Virani NA, Henry CA. Verapamil over-
dose. West J Med 1991;154:208-211. (Case report)
75. Bismuth C, Gaultier M, Conso F, et al. Hyperkalemia
in acute digitalis poisoning: Prognostic signicance
and therapeutic implications. J Toxicol Clin Toxicol
1973;6:153-162. (Prospective, observational, 91 pa-
tients)
76. Rosen MR. Cellular electrophysiology of digitalis
toxicity. J Am Coll Cardiol 1985;(5 suppl A) 2:22A-34A.
(Review)
77. Lundborg P. The effect of adrenergic blockade on
potassium concentrations in different conditions. Acta
Med Scand Suppl 1983;672:121-126. (Review)
78. Tuncok Y, Hazan E, Oto O, et al. Relationship between
high serum digoxin levels and toxicity. Int J Clin
Pharmacol Ther 1997;35:366-368. (Retrospective, 1269
patients)
79. Soni N, Baines D, Pearson IY. Cardiovascular collapse
and propranolol overdose. Med J Aust 1983;2:629-630.
(Case series)
80. Lalonde RL, Deshpande R, Hamilton PP,et al. Accelera-
tion of digoxin clearance by activated charcoal. Clin
Pharmacol Ther 1985;37:367-371. (Randomized con-
trolled trial, crossover, 10 patients)
81. Critchley JA, Critchley LA. Digoxin toxicity in
chronic renal failure: Treatment by multiple dose
activated charcoal intestinal dialysis. Hum Exp Toxicol
1997;16:733-735. (Case report)
82. Kirshenbaum LA, Mathews SC, Sitar DS, et al. Whole-
bowel irrigation versus activated charcoal in sorbitol
for the ingestion of modied-release pharmaceuticals.
Clin Pharmacol Ther 1989;46:264-271. (Randomized
controlled trial, crossover, 10 patients)
83. Smith TW, Willerson JT. Suicidal and accidental
digoxin ingestion. Report of ve cases with serum di-
goxin level correlations. Circulation 1971;44:29-36. (Case
series)
84. Ramoska EA, Spiller HA, Winter M, et al. A one year
evaluation of calcium channel blocker overdoses: Tox-
icity and treatment. Ann Emerg Med 1993;22:196-200.
(Prospective, case series, 139 patients)
85. Antman EM, Wenger TL, Butler VP, et al. Treatment of
150 cases of life-threatening digitalis intoxication with
digoxin specic Fab antibody fragments: Final report
of a multicenter study. Circulation 1990;81:1744-1752.
(Clinical trial, 150 patients)
86. Howland MA. Digoxin-specic antibody fragments. In:
Goldfrank LR, Flomenbaum NE, Lewin NA, et al, eds.
Goldfranks Toxicologic Emergencies. 7th ed. New York:
McGraw-Hill; 2002:735-740. (Textbook chapter)
87. Smith TW, Haber E, Yeatman L, et al. Reversal of
advanced digoxin intoxication with Fab fragments of
digoxin specic antibodies. N Engl J Med 1976;294:797-
800. (Case report)
88. Rumack BH, Wolfe RR, Gilnch H. Diphenylhydan-
toin treatment of massive digoxin overdose. Br Heart J
1974;36:405-408. (Case report)
89. American Heart Association.Guidelines 2000 for
Cardiopulmonary Resuscitation and Emergency Car-
diovascular Care. Circulation 2000;102(8 Suppl):1-383.
(Guidelines)
90. Gay R, Angeo S, Lee R, et al. Treatment of verapamil
toxicity in intact dogs. J Clin Invest 1986;77:1805-1811.
91. Love JN, Haning D, Howell JM. Hemodynamic ef-
fects of calcium chloride in a canine model of acute
propranolol intoxication. Ann Emerg Med 1996;28:1-6.
92. Brimacombe JR, Scully M, Swainston R. Propranolol
overdose a dramatic response to calcium chloride.
Med J Aust 1991;155:267-268. (Case report)
93. Pertoldi F, DOrlando L, Mercant W. Electromechanical
dissociation 48 hours after atenolol overdose. Useful-
ness of calcium chloride. Ann Emerg Med 1998;31:777-
781. (Case report)
94. Krenzelok EP. Acute Calcium Channel Blocker Over-
dosage: More Toxic Than Cyclic Antidepressants? Clin
Tox Forum 1991;3(2):1-6.
95. Kerns W, Kline J, Ford MD. -blocker and calcium
channel blocker toxicity. Emerg Med Clin North Am
1994;12:365-390. (Review)
96. Hantsch C, Seger D, Meredith T. Calcium Channel
Antagonist Toxicity and Hypercalcemia. J Toxicol Clin
Toxicol 1997;35(5):495-496.
97. White CM. A review of potential cardiovascular uses of
intravenous glucagon administration. J Clin Pharmacol
1999;39:442-447. (Review)
98. Bailey B. Glucagon in -blocker and calcium channel
blocker overdoses: A systematic review. J Toxicol Clin
Toxicol 2003;41:595-602. (Systematic review)
99. Kline JA, Tomaszewski CA, Schroeder JD, et al. Insulin
is a superior antidote for cardiovascular toxicity in-
duced by verapamil in the anesthetized canine. J Pharm
Exp Ther 1993;267:744-750. (Experimental, animal
model)
100. Zaloga GP, Malcolm D, Holaday J, et al. Glucagon
reverses the hypotension and bradycardia of verapamil
overdose in rats. Crit Care Med 1985;13:273.
101. Stone CK, May WA, Carroll R. Treatment of verapamil
overdose with glucagon in dogs. Ann Emerg Med
1995;25:369-374. (Experimental, animal model)
102. Tuncok Y, Apaydin S, Kalkan S, et al. The effects of
amrinone and glucagon on verapamil-induced car-
diovascular toxicity in anesthetized rats. Int J Exp Path
103. Stone CK, Thomas SH, Koury SI, et al. Glucagon and
phenylephrine combination vs glucagon alone in
experimental verapamil overdose. Acad Emerg Med
104. Sabatier J, Pouyet T, Shelvey G, et al. Antagonistic ef-
fects of epinephrine, glucagon and methylatropine but
not calcium chloride against atrio-ventricular conduc-
tion disturbances produced by high doses of diltiazem,
in conscious dogs. Fundam Clin Pharmacol 1991;5:93-
106. (Experimental, animal model)
105. Papadopoulos J, ONeil MG. Utilization of glucagon
infusion in the management of a massive nifedipine
overdose. J Emerg Med 2000;18:453-455. (Case report)
106. Doyon S, Roberts JR. The use of glucagon in a case
of calcium channel blocker overdose. Ann Emerg Med
1993;22:1229-1233. (Case report)
107. Mahr NC, Valdes A, Lamas G. Use of glucagon for
acute intravenous diltiazem toxicity. Amer J Cardiol
1997;79:1570-1571. (Case report)
108. Lvoff R, Wilcken DE. Glucagon in heart failure and in
cardiogenic shock Experience in 50 patients. Circula-
tion 1972;45:534-542. (Observational)
109. Peterson CD, Leeder JS, Sterner S. Glucagon therapy
for beta-blocker overdose. Drug Intell Clin Pharm
1984;18:394-398. (Case series)
110. Wei J, Spotnitz H, Spotnitz W, et al. Pharmacologic
antagonism of propranolol in dogs. III. Effects of do-
pamine-isoproterenol and glucagons on hemodynam-
ics and myocardial oxygen consumption in ischemic
hearts during chronic propranolol administration. J
Thorac Cardiovasc Surg 1984;87:732-742. (Experimental,
animal model)
111. Weinstein RS. Recognition and management of poison-
ing with beta-adrenergic blocking agents. Ann Emerg
Med 1984;13:1123-1131. (Review)
112. Whitehurst VE, Vick JA, Alleva FR, et al. Reversal
of propranolol blockade of adrenergic receptors and
related toxicity with drugs that increase cyclic AMP.
Proc Soc Exp Biol Med 1999;221:382-385. (Experimental,
animal model)
113. Travill CM, Pugh S, Noble MIM. The inotropic and
hemodynamic effects of intravenous milrinone when
reex adrenergic stimulation is suppressed by beta-ad-
renergic blockade. Clin Ther 1994;16:783-792. (Clinical
trial, 11 patients)
114. Kollef MH. Labetalol overdose successfully treated
with amrinone (inamrinone) and alpha receptor ago-
nists. Chest 1994;105:626-627. (Case report)
115. Love JN, Leasure JA, Mundt DJ, et al. A comparison
of amrinone and glucagon therapy for cardiovascular
depression associated with propranolol toxicity in a
canine model. J Toxicol Clin Toxicol 1992;30:399-412.
116. Wolf LR, Spadafora MP, Otten EJ. Use of amrinone and
glucagon in a case of calcium channel blocker over-
dose. Ann Emerg Med 1993;22:1225-1228. (Case report)
117. Kenyon CJ, Aldinger GE, Joshipura P, et al. Success-
ful resuscitation using external cardiac pacing in beta
adrenergic antagonist-induced bradyasystolic arrest.
Ann Emerg Med 1988;17:711-713. (Case report)
118. Taboulet P, Cariou A, Berdeaux A, et al. Pathophysiol-
ogy and management of self-poisoning with -block-
ers. J Toxicol Clin Toxicol 1993;31:531-551. (Review)
119. Rodgers GC, Al-Mahasneh QM, White SL. Treatment of
severe sustained release verapamil poisoning with car-
diac pacing: A case report. Vet Hum Toxicol 1989;31:377.
(Case report)
120. Bizovi K, Stork C, Joyce D. Pacemaker use in critically
ill calcium channel blocker overdoses. J Toxicol Clin
Toxicol 1998;36:509.
121. Sarubbi B, Ducceschi V, DAndrea A, et al. Atrial
brillation: What are the effects of drug therapy on the
effectiveness and complications of electrical cardiover-
sion? Can J Cardiol 1998;14:1267-1273. (Review)
122. Rooney M, Massey KL, Jamali F, et al. Acebutolol
overdose treated with hemodialysis and extracorporeal
oxygenation. J Clin Pharmacol 1996;36:760-763. (Case
report)
123. Lane AS, Woodward AC, Goldman MR. Massive pro-
pranolol overdose poorly responsive to pharmacologic
therapy: Use of the intra-aortic balloon pump. Ann
Emerg Med 1987;16:1381-1383. (Case report)
124. Melanson P, Shih RD, De Roos F, et al. Intra-aortic
balloon counterpulsation in calcium channel blocker
overdose. Vet Hum Toxicol 1993;35:345. (Case report)
125. Durward A, Guerguerian A, Lefebvre M, et al. Massive
diltiazem overdose treated with extracorporeal mem-
brane oxygenation. Pediatr Crit Care Med 2003;4:372-
376. (Case report)
126. Hack JB, Woody JH, Lewis DE, et al. The effect of
calcium chloride in treating hyperkalemia due to acute
digoxin toxicity in a porcine model. J Toxicol Clin Toxicol
127. Gold H, Edwards DJ. The effects of ouabain on the
heart in the presence of hypercalcemia. Am Heart J
1927;3:45-50. (Experimental)
128. Lieberman AL. Some inter-relationships of the cardiac
activities of calcium gluconate and scillaren-B. J Phar-
macol Exp Ther 1933;47:183-192. (Experimental)
129. Bower JO, Mengle H. The additive effect of calcium
and digitalis: A warning with a report of two deaths.
JAMA 1936;106:1151-1153. (Case series)
130. Smith PK, Winkler AW, Hoff HE. Calcium and digitalis
synergism: The toxicity of calcium salts injected intra-
venously into digitalized animals. Arch Int Med 1939;
64:322-329. (Experimental, animal model)
131. Nola GT, Pope S, Harrison DC. Assessment of the
syngerstic relationship between serum calcium and
digitalis. Am Heart J 1970;79:499-507.
132. Wagner J, Salzer WW. Calcium-dependent toxic effects
of digoxin in isolated myocardial preparations. Arch Int
Pharmacodyn Ther 1976;223:4-14. (Experimental)
133. Pilati CF, Paradise NF. Ouabain-induced mechanical
toxicity: Aberrations in left ventricular function, cal-
cium concentration and ultrastructure. Proc Soc Exp Biol
Med 1984;175:342-350. (Experimental, animal model)
134. Fenton F, Smally AJ, Laut J. Hyperkalemia and digoxin
toxicity in a patient with kidney failure. Ann Emerg
Med 1996;28:440-441. (Case report)
135. Van Deusen SK, Birkhahn RH, Gaeta TJ. Treatment of
hyperkalemia in a patient with unrecognized digitalis
toxicity. J Toxicol Clin Toxicol 2003;41:373-376. (Case
report)
136. Ghaemmaghami CA, Harchelroad F. Dangers of intra-
venous calcium chloride in the treatment of digoxin-
induced hyperkalemia fact or ction. Acad Emerg Med
1999;6(5):378. (Experimental, animal model)
137. Kerns W II, Schroeder D, Williams C, et al. Insulin
improves survival in a canine model of acute -blocker
toxicity. Ann Emerg Med 1997;29:748-757. (Experimen-
tal, animal model)
138. Kline JA, Tomaszewski CA, Schroeder JD, et al. Insulin
is a superior antidote for cardiovascular toxicity
induced by vaerapamil in the anesthetized canine. J
Pharm Exp Ther 1993;267:744-750. (Experimental, ani-
mal model)
139. Farah AE, Alousi AA. The actions of insulin on cardiac
contractility. Life Sci 1981;29:975-1000. (Review)
140. Korstanje C, Jonkman FA, Van Kemenade JE. Bay k
8644, a calcium entry promoter as an antidote in vera-
pamil intoxication in rabbits. Arch Int Pharmacodyn Ther
141. Kline JA, Leonova E, Williams TC, et al. Myocardial
metabolism during graded intraportal verapamil infu-
sion in awake dogs. J Cardiovasc Pharmacol 1996;27:719-
726. (Experimental, animal model)
142. Kline JA, Raymond RM, Leonova E, et al. Insulin im-
proves heart function and metabolism during non-isch-
emic cardiogenic shock in awake canines. Cardiovasc
Res 1997;34:289-298. (Experimental, animal model)
143. Devis G, Somers G, Van Obberghen E, et al. Calcium
antagonists and islet function I. Inhibition of insulin
release by verapamil. Diabetes 1975;24:247-251. (Experi-
144. Kline JA, Raymond RM, Schroeder JD, et al. The
diabetogenic effects of acute verapamil poisoning.
Toxicol Appl Pharmacol 1997;145:357-362. (Experimental,
animal model)
145. Kline JA, Leonova E, Raymond RM. Benecial myo-
cardial metabolic effects of insulin during verapamil
toxicity in the anesthetized canine. Crit Care Med
146. Yuan TH, Kerns WP, Tomaszewski CA, et al. Insu-
lin-glucose as adjunctive therapy for severe calcium
channel antagonist poisoning. J Toxicol Clin Toxicol
1999;37:463-474. (Case series)
147. Boyer EW, Duic PA, Evans A. Hyperinsulinemia/eug-
lycemia therapy for calcium channel blocker poisoning.
Ped Emerg Care 2002;18:36-37. (Case report)
148. Boyer EW, Quang LS, Woolf A. Severe amlodipine
overdose treated with hyperinsulinemia. J Toxicol Clin
Toxicol 2001;39:297-298. (Case report)
149. Meyer M, Stremski E, Scanlon M. Verapamil-induced
Physician CME questions conclude on back page
hypotension reversed with dextrose-insulin. J Toxicol
Clin Toxicol 2001;39:500. (Case report)
Physician CME Questions
33. Which physiologic effect is not due to beta-2 stimu-
lation?
a. Bronchodilation
b. Vasodilation
c. Tachycardia
d. Glycogenolysis
34. Which beta-blocker is associated with signicant
CNS depression?
a. Metoprolol
b. Propanolol
c. Albuterol
d. Nadolol
35. In which beta-blocker overdose is hemodialysis not
a considerable option for treatment?
a. Metoprolol
b. Acebutolol
c. Atenolol
d. Sotalol
36. A 50-year-old man presents bradycardic and hypo-
tensive after a beta-blocker overdose. What is the
drug of choice, after there has been no response to
intravenous uids and atropine?
a. High-dose insulin with glucose
b. Amrinone
c. Digibind
d. Glucagon
37. A 65-year-old woman has a history of hypertension
that is controlled with propanolol. Her ECG demon-
strates sinus bradycardia and a wide QRS. The later
effect on the ECG is a manifestation of propanolols
blockade of which channel/receptor?
a. Na
+
channels
b. K
i
+
channels
c. Na
+
-K
+
-ATPase channels
d. Beta receptors
38. What rhythm is not consistent with an overdose of
verapamil?
a. Sinus arrest
b. Supraventricular tachycardia
c. Sinus bradycardia
d. Atrioventricular blocks of various degrees
39. Which group of calcium channel blockers has the
least effect on chronotropy?
a. Phenylalkylamines
b. Benzothiazepines
c. Dihydropyridines
d. Cardiac glycosides
40. A 45-year-old man presents 3 hours after an over-
dose of a sustained-release calcium channel blocker.
What is the preferred method of decontamination?
a. Ipecac
b. Orogastric lavage
c. Activated charcoal
d. Whole bowel irrigation
41. Which is not a mechanical treatment for calcium
channel blocker overdose?
a. Intravenous pacing
b. Hemodialysis
c. Intra-arterial balloon counterpulsation
d. ECMO, cardiopulmonary bypass
42. What is the newest treatment modality for a calcium
channel blocker or beta-blocker overdose?
a. Norepinephrine
b. Milrinone
c. Digibind
d. Hyperinsulinemic euglycemia
43. A 55-year-old man presents after an overdose with
digoxin. His ECG demonstrates a high ventricular
block. Which medication is not contraindicated?
a. Atropine
b. Calcium
c. Glucagon
d. Isoproterenol
44. A 3-year-old boy presents to the ED after the inad-
vertent ingestion of 2 of his grandmothers cardiac
pills. His ECG demonstrates sinus tachycardia.
Ingestion of which medication is not consistent with
this nding?
a. Pindolol
b. Nifedipine
c. Digoxin
d. Amlodipine
45. Digoxin increases inotropy, automaticity, cardiac
output, and excitability by its action on the Na
+
-
K
+
-ATPase. Which intracellular ion is ultimately
responsible for this change?
a. Increase in cytosolic Ca
++
b. Increase in plasma K
+
c. Increase in cytosolic K
+
d. Increase in intracellular Na
+
46. Which symptom is not consistent with digoxin toxic-
ity?
a. Nausea
b. Altered mental status
c. Headache
d. Anorexia
47. Which agent does not contain cardiac glycosides?
a. Oleander
b. Jimson weed
c. Lily of the valley
d. Bufo toad venom
48. Which of the following medical situations may
cause digoxin toxicity?
a. Hypernatremia
b. Hypokalemia
c. Dehydration
d. Macrolide antibiotic
Direct all editorial or subscription-related questions to EB Practice, LLC: 1-800-249-5770 Fax: 1-770-500-1316 Non-U.S. subscribers, call: 1-678-366-7933
EB Practice, LLC 305 Windlake Court Alpharetta, GA 30022
E-mail: emp@empractice.net Web Site: EMPractice.net
Emergency Medicine Practice (ISSN 1524-1971) is published monthly (12 times per year) by EB Practice, LLC, 305 Windlake Court, Alpharetta, GA 30022. Opinions expressed are not necessarily those of
this publication. Mention of products or services does not constitute endorsement. This publication is intended as a general guide and is intended to supplement, rather than substitute, professional
judgment. It covers a highly technical and complex subject and should not be used for making specic medical decisions. The materials contained herein are not intended to establish policy,
procedure, or standard of care. Emergency Medicine Practice is a trademark of EB Practice, LLC. Copyright 2005 EB Practice, LLC. All rights reserved. No part of this publication may be reproduced in
any format without written consent of EB Practice, LLC. Subscription price: $299, U.S. funds. (Call for international shipping prices.)
CEO & Publisher: Robert Williford. President & General Manager: Stephanie Williford. Executive Editor: Cheryl Strauss.
Physician CME Information
This CME enduring material is sponsored by Mount Sinai School of Medicine
and has been planned and implemented in accordance with the Essentials
and Standards of the Accreditation Council for Continuing Medical Education.
Credit may be obtained by reading each issue and completing the printed
post-tests administered in December and June or online single-issue post-tests
administered at EMPractice.net.
Target Audience: This enduring material is designed for emergency medicine
physicians.
Needs Assessment: The need for this educational activity was determined by
a survey of medical staff, including the editorial board of this publication;
review of morbidity and mortality data from the CDC, AHA, NCHS, and ACEP;
and evaluation of prior activities for emergency physicians.
Date of Original Release: This issue of Emergency Medicine Practice was
published September 21, 2005. This activity is eligible for CME credit
through September 1, 2008. The latest review of this material was
September 12, 2005.
Discussion of Investigational Information: As part of the newsletter, faculty
may be presenting investigational information about pharmaceutical
products that is outside Food and Drug Administration approved labeling.
Information presented as part of this activity is intended solely as continuing
medical education and is not intended to promote off-label use of any
pharmaceutical product. Disclosure of Off-Label Usage: This issue of Emergency
Medicine Practice discusses no off-label use of any pharmaceutical product.
Faculty Disclosure: In compliance with all ACCME Essentials, Standards, and
Guidelines, all faculty for this CME activity were asked to complete a full
disclosure statement. The information received is as follows: Dr. Ginsburg, Dr.
Olmedo, Dr. LoVecchio, and Dr. Shih report no signicant nancial interest
or other relationship with the manufacturer(s) of any commercial product(s)
discussed in this educational presentation.
Accreditation: Mount Sinai School of Medicine is accredited by the
Accreditation Council for Continuing Medical Education to sponsor
continuing medical education for physicians.
Credit Designation: Mount Sinai School of Medicine designates this
educational activity for up to 4 hours of Category 1 credit toward the AMA
Physicians Recognition Award. Each physician should claim only those hours
of credit actually spent in the educational activity. Emergency Medicine Practice
is approved by the American College of Emergency Physicians for 48 hours of
ACEP Category 1 credit (per annual subscription). Emergency Medicine Practice
has been approved by the American Academy of Family Physicians as having
educational content acceptable for Prescribed credit. Term of approval covers
issues published within one year from the distribution date of July 1, 2005.
This issue has been reviewed and is acceptable for up to 4 Prescribed credits.
Credit may be claimed for one year from the date of this issue. Emergency
Medicine Practice has been approved for 48 Category 2-B credit hours by the
American Osteopathic Association.
Earning Credit: Two Convenient Methods
Print Subscription Semester Program: Paid subscribers with current and
valid licenses in the United States who read all CME articles during each Emer-
gency Medicine Practice six-month testing period, complete the post-test and
the CME Evaluation Form distributed with the December and June issues, and
return it according to the published instructions are eligible for up to 4 hours
of Category 1 credit toward the AMA Physicians Recognition Award (PRA) for
each issue. You must complete both the post-test and CME Evaluation Form
to receive credit. Results will be kept condential. CME certicates will be
delivered to each participant scoring higher than 70%.
Online Single-Issue Program: Paid subscribers with current and valid
licenses in the United States who read this Emergency Medicine Practice CME
article and complete the online post-test and CME Evaluation Form at EM-
Practice.net are eligible for up to 4 hours of Category 1 credit toward the AMA
Physicians Recognition Award (PRA). You must complete both the post-test
and CME Evaluation Form to receive credit. Results will be kept condential.
CME certicates may be printed directly from the Web site to each participant
scoring higher than 70%.
Class I
Always acceptable, safe
Denitely useful
Proven in both efcacy and ef-
fectiveness
Level of Evidence:
One or more large prospective stud-
ies are present (with rare exceptions)
High-quality meta-analyses
Study results consistently positive
and compelling
Class II
Safe, acceptable
Probably useful
Level of Evidence:
Generally higher levels of evidence
Non-randomized or retrospective
studies: historic, cohort, or case-
control studies
Less robust RCTs
Results consistently positive
Class III
May be acceptable
Possibly useful
Considered optional or alternative
treatments
Level of Evidence:
Generally lower or intermediate
levels of evidence
Case series, animal studies, consen-
sus panels
Occasionally positive results
Indeterminate
Continuing area of research
No recommendations until further
research
Level of Evidence:
Evidence not available
Higher studies in progress
Results inconsistent, contradictory
Results not compelling
Signicantly modied from: The
Emergency Cardiovascular Care
Committees of the American Heart As-
sociation and representatives from the
resuscitation councils of ILCOR: How
to Develop Evidence-Based Guidelines
for Emergency Cardiac Care: Quality of
Evidence and Classes of Recommenda-
tions; also: Anonymous. Guidelines for
cardiopulmonary resuscitation and
emergency cardiac care. Emergency
Cardiac Care Committee and Subcom-
mittees, American Heart Association.
Part IX. Ensuring effectiveness of com-
munity-wide emergency cardiac care.
JAMA 1992;268(16):2289-2295.
Emergency Medicine Practice is not afliated with any pharmaceutical rm or medical device manufacturer.
Class Of Evidence Denitions
Each action in the clinical pathways section of Emergency Medicine
Practice receives a score based on the following denitions.
Coming in Future Issues:
Deep Venous Thrombosis Community-Acquired Pneumonia

0905 (1) When Cardiovascular Medications Become Toxins

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

0905 (1) When Cardiovascular Medications Become Toxins

Uploaded by

Copyright:

Available Formats

September 2005

SR. At presentation he has normal vital signs and

was conducted using the key

Suspected overdose with bradycardia and hypotension?

Clinical Pathway: Treatment Of Possible Digoxin,

You might also like