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EMERGENCY MEDICINE
PRACTICE
.
EMPRACTICE NET
AN EVIDENCE-BASED APPROACH TO EMERGENCY MEDICINE
When Cardiovascular
Medications Become Toxins:
Managing ß-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 patient’s 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
patient’s BP and HR drop again, and he is found to be in PEA. He is treated with
IV fluids 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 failure. 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), ß-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, Children’s 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,
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:
1.
2.
3.
4.
discuss the pathophysiology and pharmacokinetics of digoxin, ß-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 specific
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.
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 & Women’s
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.
an ongoing challenge to the emergency physician, when
patients present with symptoms of severe toxicity.
We know that digoxin, ß-blockers, and CCBs cause
hypotension and bradydysrhythmias. Based on the most
recent literature, we find that regular-release formulations
do so within the first 6 hours of ingestion, while extendedrelease formulations result in delayed toxicity and require
24-hour observation. In addition to supportive care and
decontamination, there are specific antidotal treatments
for these medications: digoxin-specific Fab antibody fragments for digoxin toxicity, glucagon for ß-blocker toxicity,
and calcium (Ca++) salts for CCBs. High-dose insulin with
glucose should also be considered for ß-blocker and CCB
toxicity. Other treatments that are useful in this setting
include catecholamines, phosphodiesterase inhibitors, and
mechanical support of circulation.
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, ß-blockers,
and digoxin were the most commonly involved in fatalities, accounting for 60%, 17 %, and 17% of the reported fatalities, 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 first 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 prescribed cardiac glycoside in the US. Other pharmaceutical
preparations — including digitoxin, rarely seen in the US
— are still used worldwide. Although the pharmacokinetics differ among the various cardiac glycoside preparations, 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)
Critical Appraisal Of The Literature
A search of Ovid MEDLINE® was conducted using the key
words digoxin, ß-blocker, CCB, poisoning, overdose, and
toxicity, spanning the period from 1980 to the present. In
addition, current textbooks of toxicology and pharmacology, and classical articles dating from before 1980, were reviewed. 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, ß-blocker, and CCB toxicity, followed
by evidence-based management recommendations.
Etiology, Pharmacokinetics, Pathophysiology
Over the past 100 years, there have been numerous cardiovascular agents developed for the treatment of hypertension, dysrhythmias, and congestive heart failure. Many
of these agents have their effects directly on the cardiovascular 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 Poison Control Centers (AAPCC) reported that, as a class of
medications, cardiovascular agents were the fourth most
ß-blockers
After the discovery in the 1960s that the effects of catecholamines were mediated by the activation of α- and
ß-adrenergic receptors, ß-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
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orally, with a bioavailability of about 70 to 80%.20 Apparent 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 Clarithromycin, erythromycin, and tetracycline alter gut flora and
may lead to elevated serum levels of digoxin.22 Serum digoxin 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, metoclopramide, 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 distribution 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 patient’s creatinine clearance.
Smaller amounts of the drug are excreted in bile, with enterohepatic 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 enhanced 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
Propranolol, the prototypical ß-adrenergic receptor
antagonist, was first synthesized in 1962.6 Its use led to decreased morbidity and mortality in patients with angina,
due to its ability to decrease myocardial oxygen demands.7
Today, at least 15 different ß-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 nonspecific ß-adrenergic receptor antagonist that blocks both ß1 and ß2
receptors. Others include nadolol, sotalol, and timolol. On
the other hand, atenolol, metoprolol, and the short-acting esmolol are selective for ß1 receptors, although this
selectivity is not absolute and is often lost in the setting
of overdose.13 Labetalol and carvedilol are nonspecific ßblockers that also block α1 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 myocytes.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 Noncardiac indications for CCBs include Raynaud’s disease,
migraine headache prophylaxis, cerebral vasospasm following 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 phenylalkylamine class (verapamil), the benzothiazepine class (diltiazem), the diarylaminopropylamine class (bepridil), and
the dihydropyridine class (nicardipine, nifedipine, isradipine, amlodipine, felodipine, nisoldipine, and nimodipine).
There is an additional class of CCB — the diphenylpiperazine; however, there are currently no approved drugs.
(Table 2)
ß-blockers and CCBs
Pharmacokinetic parameters, such as oral bioavailability,
lipid solubility, protein binding, elimination half-life, and
metabolism, vary greatly among the different ß-blockers
and calcium channel blockers.8,24 As a result, onset and
duration of action are dependent upon the individual
ß-blocker or CCB taken. However, following a pure
overdose of a non–sustained-released ß-blocker or CCB,
Pharmacokinetics
Digoxin
Digoxin is typically dosed orally at 0.125 to 0.5 mg/day,
following oral or intravenous loading. It is well absorbed
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
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Emergency Medicine Practice © 2005
symptoms typically occur within 6 hours.25-27 While there
is also large variation in the volume of distribution among
ß-blockers, it is almost uniformly greater than 1 L/kg.24
Most ß-blockers are taken orally, with the exception of
timolol. This agent is a liquid solution that is used topically for the treatment of glaucoma. ß-blocker toxicity can
develop with its use.
Although absorption is nearly complete following
oral administration of CCBs, bioavailability is reduced due
to first-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 preparation 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.
Figure 1. Mechanism Of Myocardial Cell
Muscle Contraction.
A. ß-adrenergic agonists bind to the ß-adrenergic receptors and
activate adenyl cyclase to produce cAMP from ATP. ß-blockers
competitively inhibit agonist binding.
B. cAMP activates slow L Ca++ channels and increase intracellular
Ca++. CCBs act on these channels to impede Ca++ influx.
C. Elevated intracellular Ca++ causes release of Ca++ from the
sarcoplasmic reticulum.
D. And causes muscle contraction.
E. cAMP is metabolized to 5’MP by phosphodiesterase. PDE
inhibitors increase intracellular Ca++ by inhibiting cAMP metabolism.
Pathophysiology
In order to understand the toxicity of digoxin, ß-blockers,
and CCBs, a review of the normal physiology of cardiac
myocyte depolarization and myofibril 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 influx 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 producing muscle contraction. In smooth muscle, the influx
of Ca++ stimulates the phosphorylation of myosin. This
“activated” myosin then binds to actin, causing a contraction. (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++ channel exchanger, which is responsible for moving Ca++ out of
the cell. A portion of Ca++ is also reabsorbed into the sarcoplasmic reticulum via a Ca++-ATPase on the sarcolemma.
Cardiac conduction and contractility, and vasogenic
muscle tone, are under the influence of the sympathetic
and parasympathetic nervous systems via specific cell
membrane receptors. In cardiac myocytes, ß1 receptors are
linked to G proteins that activate adenylate cyclase when
stimulated. This results in the intracellular production of
cyclic AMP (cAMP), which, via protein kinases, phosphorylates several myocyte proteins.30 Ca++ channel phosphorylation increases the influx of Ca++ during each depolarization cycle.31,32 Adrenergic stimulation of the heart via ß1
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 ß1 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
ß2 receptors are predominantly located in the vasculature — particularly in skeletal muscle and the smooth
muscle of bronchioles. ß2 receptors are linked to G proteins
that activate adenylate cyclase and mediate relaxation.33
Receptor stimulation leads to vasodilation and bronchodilation. Other effects of ß2 receptor agonism include ciliary
muscle relaxation, decreased stomach and intestinal motility and tone, gallbladder and gallbladder duct relaxation,
detrusor muscle relaxation in the urinary bladder, uterine
muscle relaxation, increased glycogenolysis in skeletal
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
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EMPractice.net • September 2005
muscle and liver, increased hepatic gluconeogenesis,
stimulation of K+ uptake into cells, and increased insulin
secretion from pancreatic islet ß-cells.33 (Table 4)
Figure 2. Mechanism Of Cardiac Glycosides.
Digoxin
Digoxin’s primary site of action is cardiac tissue, where
it inhibits the Na+-K+-ATPase. It exerts a positive inotropic effect, which is beneficial 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++ efflux 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 response 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
fibers.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 digoxin’s utility as an antidysrhythmic 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 afterdepolarizations, caused by excessive increases in intracellular 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 ventricular muscle fibers may lead to ventricular tachycardia
or fibrillation.20
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.
ß-blockers
ß-blockers are competitive antagonists of endogenous catecholamines for the adrenergic receptor. This effect causes
a decrease in heart rate and inotropy.
CCBs
CCBs impair Ca++ influx into cardiac and smooth muscle
myocytes. Similar to ß-blockers, the effect of CCBs on cardiac myocytes is a decrease in contractility. By impairing
Ca++ influx in the cardiac conduction system, CCBs impair
spontaneous depolarization of the action potential. This
action slows heart rate and causes AV conduction blockade. In smooth muscle, CCBs cause vasodilation and lead
to hypotension.
Table 4. Distribution Of ß-Adrenoreceptor Subtypes Within Organs.
ß1
ß2
Heart
Increase contractility, automaticity, and conduction velocity
Adipose tissue
Activate lipolysis
Posterior pituitary
ADH secretion
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
September 2005 • EMPractice.net
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Emergency Medicine Practice © 2005
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 following 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 ß-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 finding among symptomatic
ß-blocker exposures.43 In addition to sinus bradycardia,
high-degree AV block and prolonged QRS and QTc intervals may be found in some cases.24,43
Lipophilic ß-blockers, particularly propranolol and
acebutolol, have membrane-stabilizing effects on cardiac
myocytes via Na+ channel blockade or altered Ca++ flux.44,45
As a result, ventricular depolarization is prolonged and
manifested on the ECG as a wide QRS interval. These patients are at risk for developing ventricular dysrhythmias
and asystole.24 Sotalol is the only ß-blocker with the ability
to block the delayed rectifier 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.
Differential Diagnosis
All of the agents under consideration here — digoxin,
ß-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 findings
among these agents in overdose amounts, see Table 5.
Noncardiovascular findings are shown in Table 6.)
Cardiovascular Effects
Digoxin
The cardiac toxicity from a digoxin overdose is related to
digoxin’s effects on both the sympathetic and parasympathetic innervation of the heart. Consequently, digoxin
poisoning may result in almost any type of cardiac dysrhythmia, including sinus bradycardia, atrial tachycardia,
fibrillation or flutter with slow ventricular response, all
degrees of AV block, junctional tachycardia, and ventricular tachycardia or fibrillation. However, rapidly conducted
supraventricular tachydysrhythmias cannot occur, due to
inhibition of AV nodal conduction. Bidirectional ventricular tachycardia is considered to be pathognomonic for
digoxin toxicity and is caused by alterations of intraventricular conduction, junctional tachycardia with aberrant
intraventricular conduction, or alternating ventricular
pacemakers.2 However, the most commonly seen cardiac
conduction abnormalities are premature ventricular contractions,42 often the first indication of digoxin poisoning.
Electrocardiographic manifestations of digoxin
toxicity are due to decreased conduction accompanied
by increased automaticity and a shortened repolarization interval. Electrocardiogram (ECG) findings include
an increased PR interval, AV nodal block, and QT segment shortening. Scooping of the ST segment, commonly
referred to as “Salvador Dali’s 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
CCBs
The clinical effect of a CCB depends on its relative affinity
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 significant vasodilation.48
These agents are often used for the treatment of hypertension. They do not typically affect cardiac conduction and
cause little or no decrease in myocardial contractility.49
Verapamil has a significant inhibitory effect on cardiac
ß-blockers
ß-blockers prevent the normal physiologic responses
to adrenergic stimulation of ß receptors. In overdose,
cardiovascular toxicity is of primary concern. ß-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, ß-blocker, And
CCB Toxicity.
Digoxin
ß-Blocker
CCB
Atrial tachycardia
+
–
–
Wide QRS
+
+/–
–
High-degree AV block
+
+
+
Biventricular tachycardia
+
–
–
– indicates absent; and + indicates present
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EMPractice.net • September 2005
pacemaker cells and myocytes.49 It produces a negative
chronotropic and inotropic effect. Diltiazem has greater
affinity 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 finding following a CCB overdose.51 In the setting of a dihydropyridine
overdose, hypotension may be accompanied by a reflex
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 blockade, and lead to the development of junctional or ventricular 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
reported, but does not occur frequently and is probably
limited to susceptible patients.24,25,58
Insulin release from pancreatic islet ß-cells is regulated by Ca++ influx through a slow Ca++ channel.59 Hypoglycemia may occur in children following an overdose from
ß-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 ß 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 deficit, seizure, and coma.29,6264
Intestinal ileus and ischemia, elevated transaminases,
acute renal failure, and metabolic acidosis have also been
reported following ß-blocker and CCB overdose.65-69 Rhabdomyolysis 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
Noncardiovascular Effects
Digoxin
Digoxin toxicity is also manifested by noncardiac symptoms. Gastrointestinal effects are common and include
nausea, vomiting, and anorexia. Central nervous system
(CNS) symptoms include confusion and delirium, particularly 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 findings 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.
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 digoxinspecific 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 binding resins, or diarrhea. Hypomagnesemia may occur for
ß-blockers and CCBs
Since ß receptors are found throughout the body, ß-blocker
toxicity affects many other organ systems. ß-blocker overdose may lead to significant 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 following overdose typically occurs in patients who are hypotensive 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, ß-Blocker, And CCB Toxicity.
Mental status changes
Digoxin
ß-Blocker
CCB
–
+
–
++
–
–
Normal
Decreased
Decreased
Heart rate
Decreased
Decreased
Decreased
Potassium
Increased
Mildly increased
No effect
Glucose
No effect
Decreased
Increased
GI symptoms
Blood pressure
– indicates absent; and + indicates present.
September 2005 • EMPractice.net
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Emergency Medicine Practice © 2005
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
digoxin’s volume of distribution.2 Hypokalemia is also
known to increase cardiac automaticity. The combined
effects of digoxin poisoning and hypokalemia predispose
patients to more significant dysrhythmias at lower digoxin
levels.
associated with toxicity. In a study of 1269 patients on digoxin, 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, ß-blockers, and CCBs all cause bradycardia,
which may be accompanied by conduction delays. However, there are some subtle differences among these agents.
Diagnosis of digoxin toxicity should be suspected in any
patient presenting with signs of increased cardiac automaticity, such as atrial or ventricular tachycardias, particularly when accompanied by conduction delays. The diagnosis 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 nonspecific gastrointestinal or
neurological complaints, or hyperkalemia.
Diagnosis of a ß-blocker or CCB overdose should
be suspected in the setting of bradycardia with associated hypotension. Reflex tachycardia may be seen in an
overdose of a dihydropyridine CCB. CNS depression,
mild hypoglycemia, and mild hyperkalemia may make
the diagnosis of ß-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 neurological 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 asymptomatic 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.
ß-blockers
Serum K+ levels have been shown to increase slightly with
ß-blocker use.77 However, significant hyperkalemia rarely
complicates an acute overdose.24
Prehospital Care
Prehospital care of patients with an overdose of cardiovascular 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 household medications. Patients are often asymptomatic and
have normal vital signs on initial medical contact. Nevertheless, 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 symptomatic patient, ACLS guidelines should be followed, with
adequate airway management and prompt use of calcium
salts. In these cases, the admitting hospital should be notified of the patient’s status and expected time of arrival.
ED Evaluation And Management
In the initial evaluation of those who have possibly taken
a digoxin, ß-blocker, or CCB overdose, patients should
be attached to a cardiac monitor, and an ECG should be
obtained emergently to determine if conduction abnormalities 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 ß-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 confirm exposure 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 confirm a diagnosis. Conversely, an elevated digoxin level is not always
Emergency Medicine Practice © 2005
Treatment
In the setting of digoxin, ß-blocker, and CCB overdoses,
general supportive care is immediately aimed at the
patient’s cardiovascular status. Attention should then be
turned to gastrointestinal and neurologic symptoms, with
equal consideration given to any electrolyte abnormalities.
Specific 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
patient’s level of consciousness, resulting in a significant
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
8
EMPractice.net • September 2005
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 orally 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 enteroenteric 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 ß-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 decontamination for sustained-release products.82 In adults, 1 to 2 L/h
of polyethylene glycol should be administered until the
rectal effluent is clear. It is important to consider decontamination 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
in the setting of digoxin toxicity has not been shown to
improve survival.75 Definitive treatment of digoxin toxicity
with digoxin-specific 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 first. The administration
of Ca++, which is often used in the treatment of hyperkalemia, is contraindicated in the setting of digoxin toxicity. A
change in the ECG with this treatment will assure the diagnosis 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.
ß-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-specific Fab
The mainstay of treatment for digoxin toxicity is the
administration of digoxin-specific Fab. These antibodies
have a high affinity for digoxin, but they have sufficient
cross-reactivity to be useful for the treatment of toxicity
secondary to other cardiac glycosides.4 A study of 125 patients with digoxin toxicity found that 90% had a response
to digoxin-specific Fab within minutes to several hours of
administration.85 In addition, complete resolution of symptoms 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-specific Fab to be very safe, and no significant adverse effects
related to its administration were noted.
Digoxin-specific Fab works by binding intravascular
free digoxin immediately following intravenous administration. 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 intravascular compartment, where it is then bound to digoxin-specific Fab.86 Following administration of digoxin-specific
Fab, free digoxin has been shown to drop to an undetectable 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-specific
Fab, unless the assay measures free digoxin.
Treatment should be initiated in any patient manifesting clinical signs of digoxin toxicity. This includes patients
Atropine
Patients who present with bradycardia and hypotension
should be initially managed with atropine and intravenous fluid boluses. Atropine has been useful in the
management of severe supraventricular bradydysrhythmias 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
September 2005 • EMPractice.net
Continued on page 11
9
Emergency Medicine Practice © 2005
Clinical Pathway: Treatment Of Possible Digoxin,
ß-blocker, Or CCB Overdose
Suspected overdose with bradycardia and hypotension?
➤
ABCD
IV line/fluid bolus
Cardiac monitoring
Laboratory
➤
BP normalizes?
Continue reassessment
➤
➤
Bradycardia and hypotension?
Physical Exam
➤
➤
SLUDGE
(Atropine, until no secretions)
Miosis, bradypnea
➤
➤
Signs of hyperkalemia
(No P waves, peaked T waves,
wide-sinusoidal QRS)
ECG
Apply pacing pads
Atrial tachycardia with AVB
or biventricular tachycardia
➤
➤
➤
➤
➤
➤
➤
Hyperkalemia likely,
continue reassessment
Digoxin toxicity likely
Atropine: 1-3 mg IVP
➤
ECG normalizes
➤
➤
Insulin, 10U IV
D50 glucose, 1 amp IV
Sodium bicarbonate, 1 amp IV
Digoxin Fab:
10 vials if acute OD, 5
vials if chronic
➤
ECG normalizes
Digoxin toxicity likely,
continue reassessment
Continuing reassessment, no change in ECG?
➤
External/Intravenous Pacing
Glucagon:
3-5 mg IV (50-150 µg/kg)
➤
Hemodialysis: Hx of acebutolol
or atenolol ingestion
➤
➤
➤
(Invasive cardiac
monitoring)
(Start
infusion at
dose that
produced
response)
Continue reassessment
➤
➤
Ca: 1 amp 10% CaCl2 or
2-3 amp 10% Ca Gluconate IV over 5 min
10-20 mg/kg CaCl2 IV
➤
ECG normalizes
Insulin: 10-20 U IVP, followed by 0.2-1.0 IU/kg/hrGlucose: 1 amp D50, then 0.5 g/kg/h (euglycemia)
Hypotension resolves
➤
Continue reassessment
➤
Hypotension resolves
➤
Continue reassessment
➤
Hypotension resolves
➤
Continue reassessment
➤
Mechanical BP support: Intra-aortic
balloon pump/ECMO
➤
➤
Catecholamines: Isoproterenol (to correct HR in beta-blocker OD):
0.1 µg/kg/min, titrate to effect, or norepinephrine (for BP): 8-12
µg/min IV, then titrate to BP
➤
Phosphodiesterase inhibitor (PDI):
Milrinone: Bolus 50 µg/kg IV, then 0.25-1.0 µg/kg/min
or Amrinone: Bolus 0.75 mg/kg IV, then 5-10 µg/kg/min IV infusion
➤
➤
Hypotension resolves
Continue reassessment
The evidence for recommendations is graded using the following scale. For complete definitions, see back page. Class I: Definitely
recommended. Definitive, 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 patient’s 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 format without written consent of EB Practice, LLC.
Emergency Medicine Practice © 2005
10
EMPractice.net • September 2005
each vial contains 0.5 mg of digoxin-specific 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 bioavailability of digoxin. For patients who display significant
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-specific Fab is unavailable,
lidocaine may be helpful in the management of ventricular
dysrhythmias. Lidocaine combats enhanced cardiac automaticity 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 refractory 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, phenytoin was used for refractory cardiotoxicity secondary
Continued from page 9
presenting with life-threatening dysrhythmias. In the setting 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-specific Fab. In a patient
presenting with symptoms suggesting poisoning by either
digoxin, a ß-blocker, or a CCB, treatment with digoxinspecific Fab should be considered early. A diagnosis of
digoxin toxicity can be made if symptoms resolve following antibody administration.
Dosing of digoxin-specific Fab depends on the total
body load of digoxin, which can be calculated by multiplying the serum digoxin concentration, in ng/mL, by the
volume of distribution of digoxin and the patient’s 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-specific 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 patient’s weight (in kg) divided by 100.86 This calculation assumes a volume of distribution of 5 L/kg and that
Ten Pitfalls To Avoid
6. “We didn’t 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.
1. “I wanted to wait for a digoxin level before treating the
patient with digoxin Fab.”
Don’t wait. A patient’s 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.
7. “I thought that reversing the patient’s digoxin level would
put him into acute pulmonary edema or atrial fibrillation.”
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 fibrillation may be managed with CCBs or ß-blockers.
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.
8. “I didn’t 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.
4. “We administered calcium chloride because we were
following ACLS guidelines for hyperkalemia. We didn’t
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.”
9. “I didn’t think that calcium chloride was going to
damage the baby’s 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.
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.
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. ▲
September 2005 • EMPractice.net
11
Emergency Medicine Practice © 2005
to acute digoxin poisoning. Its use should be considered
when digoxin-specific Fab is unavailable and lidocaine has
not been successful.
positive chronotropic and inotropic cardiac effect despite
ß-blockade.97 Evidence supporting the use of glucagon in
the management of patients with ß-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 vitro 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 efficacy of
glucagon in ß-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 pressure 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 calcium, it may have a deleterious effect in this setting.
Appropriate dosing of glucagon for ß-blocker toxicity
includes both an intravenous bolus dose and a maintenance infusion.24 The initial adult dose is 3-5 mg over 1-2
minutes. If there is no response to the initial dose, additional 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
µg/kg, followed by an infusion of 50 µg/kg/h, up to the
maximum adult dose. Side effects may be dose-dependent
and include nausea, vomiting, hyperglycemia, and hypokalemia.108,109 (Table 8)
ß-blockers and CCBs
Calcium
Treatment with intravenous Ca++ should be initiated in
patients with refractory hypotension and bradycardia secondary to ß-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 studies have demonstrated the efficacy of Ca++ in improving
blood pressure and inotropy in the setting of ß-blocker or
CCB toxicity.90,91 In reports of human ß-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 overdoses, 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 children, 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 contains one-third the amount of elemental calcium compared
to a 10% solution of Ca++ chloride. Therefore, the equivalent dose of Ca++ gluconate is 3 times that of Ca++ chloride.
Adverse effects of Ca++ therapy include nausea, vomiting,
flushing, constipation, confusion, and angina.95 In addition, repeat dosing or continuous infusions may lead to
hypercalcemia and hypophosphatemia.96
Other Treatment Modalities
ß-blockers and CCBs
Catecholamines
Patients who are refractory to the preceding treatment options usually require a catecholamine infusion. A ß-agonist
would be a logical choice in the setting of ß-blocker toxicity. Isoproterenol is a pure ß-agonist and has been demonstrated to be more effective than glucagon in reversing
ß-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
Glucagon
Treatment with glucagon should be initiated in symptomatic patients with refractory bradycardia secondary to
ß-blockers and CCBs. Glucagon is often able to produce a
Table 7. Calculation Of Dose Of Digoxin-Specific 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 patient’s 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-specific antibody fragments. In: Goldfrank’s Toxicologic Emergencies. 7th ed. 2002;735-740. See Reference 86.
Emergency Medicine Practice © 2005
12
EMPractice.net • September 2005
increasing heart rate only 11% of the time and blood pressure 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 α- and ß-adrenergic activity, to be more effective
than isoproterenol. When used, the recommended dose
of isoproterenol is 0.1 µg/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 ß2-adrenergic agonism, and induction
of dysrhythmias.
Catecholamines with α- and ß-adrenergic activity,
such as epinephrine and norepinephrine, need be used
with caution.24 In the setting of ß-adrenergic antagonism,
overwhelming α 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 worsening hypotension develops.24
In the setting of digoxin toxicity, treatment with catecholamines is contraindicated. Digoxin raises the threshold for cardiac depolarization by increasing intracellular
Ca++, and catecholamine infusion may cause ventricular
dysrhythmias.
none may be given as a 50 µg/kg intravenous bolus over 2
minutes, followed by an infusion of 0.25-1.0 µg/kg/min.24
Amrinone may be given as a 0.75 mg/kg intravenous
bolus over 2 minutes and be repeated in 30 minutes, followed by an infusion of 2-20 µg/kg/min.24 Adverse effects
include worsening hypotension secondary to vasodilation. In addition, PDIs have long half-lives, making them
difficult 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 ß-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 relaxation.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 treatment 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 toxicity.124,125
Hemodialysis is an ineffective means of removing
digoxin, lipid-soluble ß-blockers, and CCBs, since all of
these have a large volume of distribution. Hemodialysis
may remove water-soluble ß-blockers, such as atenolol
and acebutolol.122 However, severe bradycardia and hypotension might preclude its use. (Table 8)
Phosphodiesterase Inhibitors
Phosphodiesterase inhibitors (PDIs) might also be helpful
in patients with refractory bradycardia and hypotension
secondary to ß-blockers and CCBs. PDIs increase cAMP
levels despite ß-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 increase inotropy and reverse bradycardia and hypotension
in the presence of ß-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-
Table 8. Specific Treatment Modalities In Digoxin, ß-Blocker, And CCB Toxicity.
Digoxin
ß-Blocker
CCB
Digoxin Fab
+
–
–
Atropine
+
+
+
Calcium salts
–
+
++
Glucagon
–
++
+
Catecholamines
–
+
+
Phosphodiesterase inhibitors
–
+
+
Transvenous pacing
–
+
+
Intra-aortic balloon pumps
–
+
+
– indicates not recommended; + indicates recommended; and ++ indicates strongly recommended.
September 2005 • EMPractice.net
13
Emergency Medicine Practice © 2005
of insulin become apparent.24 It is possible that insulin
has its greatest benefit if started before patients become
symptomatic, in the setting of a large overdose that is
expected to produce significant 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)
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 presumably contraindicated in the setting of digoxin toxicity.
This is based on a proposed synergistic relationship between cardiac glycosides, which cause a physiologic rise in
intracellular Ca++, as well as extracellular Ca++, to explain
the enhanced toxicity seen with concurrent Ca++ administration.126-130 Studies also demonstrate that high extracellular 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 demonstrated 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
benefit 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 following treatment with intravenous Ca++ chloride.136 Until definitive data demonstrating the safety and efficacy of Ca++
administration in the setting of digoxin-induced hyperkalemia are available, its use should be avoided.
Disposition
Following an overdose of a non–sustained-release preparation of a ß-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 asymptomatic 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 observation.
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 distribution model. Empiric treatment with digoxin Fab should be
initiated if a large overdose is suspected. Following treatment, these patients may be considered medically stable
if they remain asymptomatic. Patients who present with
mild symptoms of digoxin toxicity might also be considered 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.
Cutting Edge
High-dose Insulin
High-dose insulin should be considered for severe
ß-blocker and CCB toxicity.24,29 High-dose insulin with
sufficient 50% dextrose to maintain euglycemia effectively
improved survival, contractility, and blood pressure in
canine models of ß-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 myocardial 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 efficacy.
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 continued until the patient’s 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
Emergency Medicine Practice © 2005
Summary
Digoxin, ß-blockers, and CCBs are commonly used to treat
hypertension, angina, dysrhythmias, and congestive heart
failure. The hallmark of their toxicity is bradydysrhythmias and hypotension. Other systemic effects encountered
in toxicity are extensions of the pharmacologic effects of
these agents into other organ systems. Acute digoxin toxicity causes hyperkalemia and is a good prognostic marker
of mortality in this setting. Gastrointestinal and CNS
symptoms are common in digoxin toxicity. CNS symptoms may also be present in lipophilic ß-blocker toxicity.
Mild hyperglycemia may be present in CCB toxicity. Regular-release formulations of these medications have an effect within the first 6 hours of ingestion. Extended-release
formulations result in delayed toxicity and require 24-hour
observation and consideration for aggressive decontamination with WBI and MDAC. In the symptomatic patient,
in addition to supportive care and decontamination, there
are specific antidotal treatments — digoxin-specific Fab
for digoxin toxicity, glucagon for ß-blocker toxicity, and
14
EMPractice.net • September 2005
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 ß-blocker
and CCB toxicity. Patients who have failed standard treatments for ß-blocker and CCB overdose may need other
therapeutic alternatives: catecholamines, PDIs, and extracorporeal mechanical support of circulation. ▲
14.
15.
16.
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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 cardiovascular toxicity in anesthetized rats. Int J Exp Path
1996;77:207-212. (Experimental, animal model)
103. Stone CK, Thomas SH, Koury SI, et al. Glucagon and
phenylephrine combination vs glucagon alone in
experimental verapamil overdose. Acad Emerg Med
1996;3:120-125. (Experimental, animal model)
104. Sabatier J, Pouyet T, Shelvey G, et al. Antagonistic effects of epinephrine, glucagon and methylatropine but
not calcium chloride against atrio-ventricular conduction disturbances produced by high doses of diltiazem,
in conscious dogs. Fundam Clin Pharmacol 1991;5:93106. (Experimental, animal model)
105. Papadopoulos J, O’Neil 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. Circulation 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 dopamine-isoproterenol and glucagons on hemodynamics 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 poisoning with beta-adrenergic blocking agents. Ann Emerg
Med 1984;13:1123-1131. (Review)
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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
reflex adrenergic stimulation is suppressed by beta-adrenergic blockade. Clin Ther 1994;16:783-792. (Clinical
trial, 11 patients)
114. Kollef MH. Labetalol overdose successfully treated
with amrinone (inamrinone) and alpha receptor agonists. 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.
(Experimental, animal model)
116. Wolf LR, Spadafora MP, Otten EJ. Use of amrinone and
glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993;22:1225-1228. (Case report)
117. Kenyon CJ, Aldinger GE, Joshipura P, et al. Successful 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. Pathophysiology and management of self-poisoning with ß-blockers. 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 cardiac 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, D’Andrea A, et al. Atrial
fibrillation: What are the effects of drug therapy on the
effectiveness and complications of electrical cardioversion? 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 propranolol 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 membrane oxygenation. Pediatr Crit Care Med 2003;4:372376. (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
2004;42:337-342. (Experimental, animal model)
127. Gold H, Edwards DJ. The effects of ouabain on the
heart in the presence of hypercalcemia. Am Heart J
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128. Lieberman AL. Some inter-relationships of the cardiac
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129. Bower JO, Mengle H. The additive effect of calcium
and digitalis: A warning with a report of two deaths.
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130. Smith PK, Winkler AW, Hoff HE. Calcium and digitalis
synergism: The toxicity of calcium salts injected intra-
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64:322-329. (Experimental, animal model)
131. Nola GT, Pope S, Harrison DC. Assessment of the
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132. Wagner J, Salzer WW. Calcium-dependent toxic effects
of digoxin in isolated myocardial preparations. Arch Int
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133. Pilati CF, Paradise NF. Ouabain-induced mechanical
toxicity: Aberrations in left ventricular function, calcium concentration and ultrastructure. Proc Soc Exp Biol
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134. Fenton F, Smally AJ, Laut J. Hyperkalemia and digoxin
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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 intravenous calcium chloride in the treatment of digoxininduced hyperkalemia – fact or fiction. 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 ß-blocker
toxicity. Ann Emerg Med 1997;29:748-757. (Experimental, 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, animal 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 verapamil intoxication in rabbits. Arch Int Pharmacodyn Ther
1987;287:109-119. (Experimental, animal model)
141. Kline JA, Leonova E, Williams TC, et al. Myocardial
metabolism during graded intraportal verapamil infusion in awake dogs. J Cardiovasc Pharmacol 1996;27:719726. (Experimental, animal model)
142. Kline JA, Raymond RM, Leonova E, et al. Insulin improves heart function and metabolism during non-ischemic 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. (Experimental, animal model)
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. Beneficial myocardial metabolic effects of insulin during verapamil
toxicity in the anesthetized canine. Crit Care Med
1995;23:1251-1263. (Experimental, animal model)
146. Yuan TH, Kerns WP, Tomaszewski CA, et al. Insulin-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/euglycemia 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)
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hypotension reversed with dextrose-insulin. J Toxicol
Clin Toxicol 2001;39:500. (Case report)
39. Which group of calcium channel blockers has the
least effect on chronotropy?
a. Phenylalkylamines
b. Benzothiazepines
c. Dihydropyridines
d. Cardiac glycosides
Physician CME Questions
33. Which physiologic effect is not due to beta-2 stimulation?
a. Bronchodilation
b. Vasodilation
c. Tachycardia
d. Glycogenolysis
40. A 45-year-old man presents 3 hours after an overdose 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
34. Which beta-blocker is associated with significant
CNS depression?
a. Metoprolol
b. Propanolol
c. Albuterol
d. Nadolol
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
35. In which beta-blocker overdose is hemodialysis not
a considerable option for treatment?
a. Metoprolol
b. Acebutolol
c. Atenolol
d. Sotalol
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
36. A 50-year-old man presents bradycardic and hypotensive after a beta-blocker overdose. What is the
drug of choice, after there has been no response to
intravenous fluids and atropine?
a. High-dose insulin with glucose
b. Amrinone
c. Digibind
d. Glucagon
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
37. A 65-year-old woman has a history of hypertension
that is controlled with propanolol. Her ECG demonstrates sinus bradycardia and a wide QRS. The later
effect on the ECG is a manifestation of propanolol’s
blockade of which channel/receptor?
a. Na+ channels
b. Ki+ channels
c. Na+-K+-ATPase channels
d. Beta receptors
44. A 3-year-old boy presents to the ED after the inadvertent ingestion of 2 of his grandmother’s cardiac
pills. His ECG demonstrates sinus tachycardia.
Ingestion of which medication is not consistent with
this finding?
a. Pindolol
b. Nifedipine
c. Digoxin
d. Amlodipine
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
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+
Physician CME questions conclude on back page
September 2005 • EMPractice.net
19
Emergency Medicine Practice © 2005
46. Which symptom is not consistent with digoxin toxicity?
a. Nausea
b. Altered mental status
c. Headache
d. Anorexia
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.
47. Which agent does not contain cardiac glycosides?
a. Oleander
b. Jimson weed
c. Lily of the valley
d. Bufo toad venom
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.
48. Which of the following medical situations may
cause digoxin toxicity?
a. Hypernatremia
b. Hypokalemia
c. Dehydration
d. Macrolide antibiotic
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 significant financial interest
or other relationship with the manufacturer(s) of any commercial product(s)
discussed in this educational presentation.
Coming in Future Issues:
Deep Venous Thrombosis • Community-Acquired Pneumonia
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• Definitely useful
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• One or more large prospective studies 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, consensus panels
• Occasionally positive results
Credit Designation: Mount Sinai School of Medicine designates this
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of credit actually spent in the educational activity. Emergency Medicine Practice
is approved by the American College of Emergency Physicians for 48 hours of
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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
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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
Earning Credit: Two Convenient Methods
• Print Subscription Semester Program: Paid subscribers with current and
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the CME Evaluation Form distributed with the December and June issues, and
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delivered to each participant scoring higher than 70%.
Significantly modified from: The
Emergency Cardiovascular Care
Committees of the American Heart Association and representatives from the
resuscitation councils of ILCOR: How
to Develop Evidence-Based Guidelines
for Emergency Cardiac Care: Quality of
Evidence and Classes of Recommendations; also: Anonymous. Guidelines for
cardiopulmonary resuscitation and
emergency cardiac care. Emergency
Cardiac Care Committee and Subcommittees, American Heart Association.
Part IX. Ensuring effectiveness of community-wide emergency cardiac care.
JAMA 1992;268(16):2289-2295.
• 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 EMPractice.net are eligible for up to 4 hours of Category 1 credit toward the AMA
Physician’s Recognition Award (PRA). You must complete both the post-test
and CME Evaluation Form to receive credit. Results will be kept confidential.
CME certificates may be printed directly from the Web site to each participant
scoring higher than 70%.
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