0905[1]When Cardiovascular Medications Become Toxins (1)

September 2005Volume 7, Number 9

Authors

Beth Y Ginsburg, MDFellow, Medical Toxicology, Department of Emergency Medicine, New York University School of Medicine—New York, NY.

Ruben Olmedo, MDDirector, Division of Toxicology, Department of Emergency Medicine, Mount Sinai Medical Center—New York, NY.

Peer Reviewers

Frank LoVecchio, DO, MPH, FACEPMedical 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, MDProgram 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, 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; andrecognize 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.

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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 M E R G E N C Y M E D I C I N E

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When Cardiovascular Medications Become Toxins:Managing ß-Blocker, CCB, And Digoxin OverdosesA 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.

CARDIOVASCULAR 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), 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,

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.

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, 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 extended-release 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 frag-ments 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. 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 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, ß-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, ß-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 GlycosidesCardiac 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 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)

ß-blockersAfter the discovery in the 1960s that the effects of cat-echolamines 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 lanataDigitalis purpurea

DigoxinDigitoxin

Lily of the valley Convallaria majalis Convallatoxin

Oleander Nerium oleanderThevetia peruviana

Oleandrin and others

Milkweed Asclepias spp Asclepiadin and others

Red squill Urginea indicaUrginea 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 © 2005September 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 ß-adrenergic receptor antagonist, was first 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 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-ad-renergic receptor antagonist that blocks both ß1 and ß2 receptors. Others include nadolol, sotalol, and timolol. On the other hand, atenolol, metoprolol, and the short-act-ing 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 ß-blockers that also block α1 receptors. CCBsCCBs 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 Raynaud’s 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)

PharmacokineticsDigoxinDigoxin 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 flora 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 patient’s 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 ß-blockers and CCBsPharmacokinetic 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,


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 topi-cally 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 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. PathophysiologyIn 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 in-flux 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 influx 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 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

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. 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 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 influx of Ca++ during each depolariza-tion 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 vascu-lature — 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 bronchodi-lation. Other effects of ß2 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


ß-blockersß-blockers are competitive antagonists of endogenous cat-echolamines for the adrenergic receptor. This effect causes a decrease in heart rate and inotropy.

CCBsCCBs impair Ca++ influx into cardiac and smooth muscle myocytes. Similar to ß-blockers, the effect of CCBs on car-diac 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 block-ade. In smooth muscle, CCBs cause vasodilation and lead to hypotension.

Table 4. Distribution Of ß-Adrenoreceptor Subtypes Within Organs.

ß1 Heart Increase contractility, automaticity, and conduction velocity

Adipose tissue Activate lipolysis

Posterior pituitary ADH secretion

ß2 Vascular and respiratory smooth muscle Relaxation/dilatation

Skeletal muscle RelaxationGlycogenolysisPromote 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 ß-cells.33 (Table 4) DigoxinDigoxin’s primary site of action is cardiac tissue, where it inhibits the Na+-K+-ATPase. It exerts a positive inotro-pic 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 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 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 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 fibers may lead to ventricular tachycardia or fibrillation.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 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 inter-vals 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 pa-tients 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. CCBsThe 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 hyperten-sion. 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

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 EffectsDigoxinThe cardiac toxicity from a digoxin overdose is related to digoxin’s 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, fibrillation or flutter with slow ventricular response, all degrees of AV block, junctional tachycardia, and ventricu-lar tachycardia or fibrillation. 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 first 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) findings include an increased PR interval, AV nodal block, and QT seg-ment 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

ß-blockersß-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


reported, but does not occur frequently and is probably limited to susceptible patients.24,25,58 Insulin release from pancreatic islet ß-cells is regulat-ed by Ca++ influx through a slow Ca++ channel.59 Hypogly-cemia 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.29,62-

64 Intestinal ileus and ischemia, elevated transaminases, acute renal failure, and metabolic acidosis have also been reported following ß-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 AbnormalitiesDigoxinDigoxin 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-specific 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 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 follow-ing 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 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 EffectsDigoxin 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 find-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.

ß-blockers and CCBsSince ß receptors are found throughout the body, ß-blocker toxicity affects many other organ systems. ß-blocker over-dose 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 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, ß-Blocker, And CCB Toxicity.Digoxin ß-Blocker CCB

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 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.

ß-blockersSerum 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 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-fied 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 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 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 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 confirm 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, ß-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 nonspecific gastrointestinal or neurological complaints, or hyperkalemia. Diagnosis of a ß-blocker or CCB overdose should be suspected in the setting of bradycardia with associ-ated 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 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, 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.

DecontaminationDecontamination 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


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 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 decontamina-tion 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 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

AtropinePatients who present with bradycardia and hypotension should be initially managed with atropine and intra-venous fluid 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 AbnormalitiesHyperkalemia 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 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 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. 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 TreatmentDigoxinDigoxin-specific FabThe 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 pa-tients 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 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-cific 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 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-cific Fab.86 Following administration of digoxin-specific 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-specific 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 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 for-mat without written consent of EB Practice, LLC.

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Suspected overdose with bradycardia and hypotension?

ABCDIV line/fluid bolusCardiac monitoringLaboratory

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)

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ECG normalizesDigoxin toxicity likely,continue reassessment

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Clinical Pathway: Treatment Of Possible Digoxin,ß-blocker, Or CCB Overdose

Continue reassessment

SLUDGE(Atropine, until no secretions)

ECGApply pacing pads

Miosis, bradypnea

Atropine: 1-3 mg IVPDigoxin toxicity likely

Digoxin Fab:10 vials if acute OD, 5 vials if chronic

Insulin, 10U IVD50 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 reassessmentExternal/Intravenous Pacing ECG normalizes

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

Glucagon:3-5 mg IV (50-150 µg/kg)

Ca: 1 amp 10% CaCl2 or 2-3 amp 10% Ca Gluconate IV over 5 min10-20 mg/kg CaCl2 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 µg/kg IV, then 0.25-1.0 µg/kg/minor Amrinone: Bolus 0.75 mg/kg IV, then 5-10 µg/kg/min IV infusion







Mechanical BP support: Intra-aortic balloon pump/ECMO

Continuing reassessment, no change in ECG?


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(Invasive cardiac monitoring)

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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 bioavail-ability 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 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-specific Fab. In a patient presenting with symptoms suggesting poisoning by either digoxin, a ß-blocker, or a CCB, treatment with digoxin-specific Fab should be considered early. A diagnosis of digoxin toxicity can be made if symptoms resolve follow-ing antibody administration. Dosing of digoxin-specific 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 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 calcula-tion assumes a volume of distribution of 5 L/kg and that

Ten Pitfalls To Avoid6. “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.

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.

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.

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.

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.”

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.

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 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.”

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-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.

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 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 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 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 ß-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 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 hypo-kalemia.108,109 (Table 8)

Other Treatment Modalitiesß-blockers and CCBsCatecholaminesPatients who are refractory to the preceding treatment op-tions usually require a catecholamine infusion. A ß-agonist would be a logical choice in the setting of ß-blocker toxic-ity. Isoproterenol is a pure ß-agonist and has been dem-onstrated 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

to acute digoxin poisoning. Its use should be considered when digoxin-specific Fab is unavailable and lidocaine has not been successful.

ß-blockers and CCBsCalciumTreatment with intravenous Ca++ should be initiated in patients with refractory hypotension and bradycardia sec-ondary 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 stud-ies 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 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, flushing, constipation, confusion, and angina.95 In addi-tion, repeat dosing or continuous infusions may lead to hypercalcemia and hypophosphatemia.96

GlucagonTreatment with glucagon should be initiated in symp-tomatic patients with refractory bradycardia secondary to ß-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 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 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 InhibitorsPhosphodiesterase 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 in-crease 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-

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, fol-lowed by an infusion of 2-20 µg/kg/min.24 Adverse effects include worsening hypotension secondary to vasodila-tion. 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 TherapiesExternal 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 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 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 hypo-tension might preclude its use. (Table 8)

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.


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)

Disposition

Following an overdose of a non–sustained-release prepa-ration 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 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, ß-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 ß-blocker toxicity. Mild hyperglycemia may be present in CCB toxicity. Regu-lar-release formulations of these medications have an ef-fect within the first 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 specific antidotal treatments — digoxin-specific Fab for digoxin toxicity, glucagon for ß-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 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 follow-ing treatment with intravenous Ca++ chloride.136 Until de-finitive data demonstrating the safety and efficacy of Ca++ administration in the setting of digoxin-induced hyperka-lemia are available, its use should be avoided.

Cutting Edge

High-dose InsulinHigh-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 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 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 contin-ued 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


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 Gilman’s 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 Gilman’s 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 flora: 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. ß-Adrenergic Antagonists. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al, eds. Goldfrank’s 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 Gilman’s 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. Goldfrank’s 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 ß-blocker and CCB toxicity. Patients who have failed standard treat-ments for ß-blocker and CCB overdose may need other therapeutic alternatives: catecholamines, PDIs, and extra-corporeal mechanical support of circulation. ▲

References

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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 1987;287:109-119. (Experimental, animal model)

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-mental, 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 myo-cardial 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. 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. Bronchodilationb. Vasodilationc. Tachycardiad. Glycogenolysis

34. Which beta-blocker is associated with significant CNS depression?a. Metoprololb. Propanololc. Albuterold. Nadolol

35. In which beta-blocker overdose is hemodialysis not a considerable option for treatment?a. Metoprololb. Acebutololc. Atenolold. 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 fluids and atropine?a. High-dose insulin with glucoseb. Amrinonec. Digibindd. 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 propanolol’s blockade of which channel/receptor?a. Na+ channelsb. Ki

+ channelsc. Na+-K+-ATPase channelsd. Beta receptors

38. What rhythm is not consistent with an overdose of verapamil?a. Sinus arrestb. Supraventricular tachycardiac. Sinus bradycardiad. Atrioventricular blocks of various degrees

39. Which group of calcium channel blockers has the least effect on chronotropy?a. Phenylalkylaminesb. Benzothiazepinesc. Dihydropyridinesd. 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. Ipecacb. Orogastric lavagec. Activated charcoald. Whole bowel irrigation

41. Which is not a mechanical treatment for calcium channel blocker overdose?a. Intravenous pacingb. Hemodialysisc. Intra-arterial balloon counterpulsationd. ECMO, cardiopulmonary bypass

42. What is the newest treatment modality for a calcium channel blocker or beta-blocker overdose?a. Norepinephrineb. Milrinonec. Digibindd. 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. Atropineb. Calciumc. Glucagond. Isoproterenol

44. A 3-year-old boy presents to the ED after the inad-vertent 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. Pindololb. Nifedipinec. Digoxind. 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. Nauseab. Altered mental statusc. Headached. Anorexia

47. Which agent does not contain cardiac glycosides?a. Oleanderb. Jimson weedc. Lily of the valleyd. Bufo toad venom

48. Which of the following medical situations may cause digoxin toxicity?a. Hypernatremiab. Hypokalemiac. Dehydrationd. Macrolide antibiotic

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Class IAlways acceptable, safeDefinitely usefulProven in both efficacy and ef-fectiveness

Level of Evidence:One or more large prospective stud-ies are present (with rare exceptions)High-quality meta-analysesStudy results consistently positive and compelling

Class IISafe, acceptableProbably useful

Level of Evidence:Generally higher levels of evidenceNon-randomized or retrospective studies: historic, cohort, or case-control studiesLess robust RCTsResults consistently positive

Class IIIMay be acceptablePossibly usefulConsidered optional or alternative treatments

Level of Evidence:Generally lower or intermediate

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levels of evidenceCase series, animal studies, consen-sus panelsOccasionally positive results

IndeterminateContinuing area of researchNo recommendations until further research

Level of Evidence:Evidence not availableHigher studies in progressResults inconsistent, contradictoryResults not compelling

Significantly modified 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.

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Emergency Medicine Practice is not affiliated with any pharmaceutical firm or medical device manufacturer.

Class Of Evidence Definitions

Each action in the clinical pathways section of Emergency Medicine Practice receives a score based on the following definitions.

Coming in Future Issues:

Deep Venous Thrombosis • Community-Acquired Pneumonia

0905[1]When Cardiovascular Medications Become Toxins (1)

Documents

Transcript of 0905[1]When Cardiovascular Medications Become Toxins (1)