Hoffman R, et al. Go!dfronk's Toxicologic Emergencies . 8th ed.

New York: McG raw-Hill, 2006.

cardiotoxicity, coma, and death (Table 60- 1). Antimuscarinic findings are commonly appreciated in poisoned patients, including dry skin and mucous membranes,

diminished or absent bowel sounds, urinary retention, and

sinus tachycardia. Acute cardiovascular toxicity must be

recognized and treated expediently. Sinus tachycardia is a

very common early finding, but typically does not result in

hemodynamic compromise. That said, severe poisonings

frequently progress to induce wide complex tachycardias

and refractory hypotension. CNS toxicity can range from

disorientation and agitation to outright lethargy. Early

subtle alterations in levels of consciousness can quickly

progress to obtundation and coma. Generalized tonicclonic seizures occur in -4o/o of all patients who present

with CA poisoning and in 13o/o of those who subsequently

experience cardiopulmonary arrest.

DIAGNOSTIC STUDIES

� Laboratory

Although quantitative assays for serum CA concentrations

do exist, their limited availability and prolonged turnaround times preclude any clinical utility. Furthermore,

serum levels correlate poorly with clinical significance.

There are no additional laboratory studies useful for the

diagnosis or management of patients with CA poisoning.

� Electrocardiogram

The electrocardiogram (ECG) is the most useful and r eadily available modality for the evaluation of patients with

potential CA poisoning. It not only provides rapid, distinctive, and diagnostic findings suggestive of toxicity, but also

facilitates the provision of targeted therapy. ECG abnor ­

malities develop within the first 6 hours of ingestion and

typically resolve by 36-48 hours.

The classic ECG pattern in moderate to severely poisoned patients is sinus tachycardia with right axis devia ­

tion of the terminal 40 msec of the QRS complex (terminal

R-wave in lead aVR) associated with prolongation of the

PR, QRS, and QT intervals (Figure 60-1). Life-threatening

complications are far more likely when the QRS c omplex is

prolonged beyond 100 msec. Thirty percent of patients will

experience seizures with a QRS > 100 msec, and the risk of

ventricular tachycardia increases drastically when the QRS

complex exceeds 160 msec.

MEDICAL DECISION MAKING

A high index of suspicion combined with a thorough history, physical examination, and ECG analysis is required to

establish the diagnosis of CA toxicity. Keep in mind that

patients with intentional overdoses may neither be reliable

nor forthcoming regarding their ingestions. Every effort

must be made to ascertain the exact time of ingestion,

specific agent and amount consumed, and the presence of

CYCLIC ANTIDEPRESSANTS

Cook County Hospital-ER

Vent. rate

PR interval

QRS duration

QT/QTc

P-R-T axes

1 1 6 BPM

1 58 ms

••• Age and gender specific ECG analysis •••

Sinus tachycardia

1 08 ms Biatrial enlargement

336/467 ms

85 259 71

Right superior axis deviation

No previous ECGs available

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Figure 60-1 . ECG findings in a patient with chronic pain who mistook his Elavil for Tylenol #3 and ingested

approximately 500 mg. Note sinus tachycardia, the prolonged QRS interva ls, and the terminal R-wave in aVR .

any co-ingestants. Once identified, the treatment for CA

toxicity should be initiated without delay (Figure 60-2).

TREATMENT

All patients require large-bore intravenous (IV) access and

continuous cardiac monitoring. Early intubation is recommended for patients with CNS depression and/or hemodynamic instability, as they have the potential for rapid

deterioration. Furthermore, respiratory acidosis secondary

to ventilatory insufficiency can exacerbate the cardiotoxicity of CA poisoning.

...... Gastrointestinal Decontamination

The induction of emesis with syrup of ipecac is no longer

recommended given the potential for sudden decompensation and secondary aspiration.

 

mia in the standard fashion with sodium bicarbonate,

albuterol nebulizers, glucose with insulin, and sodium

polystyrene sulfonate (Kayexalate), but avoid empiric

treatment with intravenous (IV) calcium due to the

theoretical risk of "stone heart" and fatal dysrhythmias.

That said, N calcium can be given to patients with severe

Check serum

digoxin level and

electrolytes

Consider digibind therapy if:

1) Hyperkalemia

2} Elevated digoxin level

3} Borderline BP or HR

Figure 59-2. Digoxin diag nostic algorithm. BP, blood pressure; ECG,

electroca rd iogram; H R, heart rate.

CHAPTER 59

hyperkalemic cardiotoxicity (sinus arrest, sinusoidal

rhythm) refractive to alternative treatments. In patients

with chronic toxicity, carefully supplement serum hypokalemia and hypomagnesemia to prevent overcorrection.

Treat significant bradycardias and/or AV nodal conduction

disturbances with IV atropine (0.5-2 mg).

Digoxin-specific antibodies (Digibind, Digoxin Fab

fragments) provide an eloquent and effective method for

treating digoxin toxicity. Indications for use include significant dysrhythmias, hypotension, and hyperkalemia secondary to cardiac glycoside ingestion. Although no absolute

contraindications exist, exercise caution in patients with a

known hypersensitivity to ovine (sheep) derived products.

The appropriate dose of Fab fragments can be determined

by 1 of 3 ways and is based on the total body burden of

digoxin. After an acute ingestion, digoxin has a roughly

80% bioavailability and each vial of Fab fragments can bind

0.5 mg of circulating digoxin. Based on this, the proper dose

of Fab fragments can be calculated as follows:

1. Known quantity of ingested digoxin:

Number of Fab vials = [ (Amount of digoxin ingested (mg)

X 0.8)/0.5]

Rounded-up to the nearest whole number

2. Measured serum digoxin concentrations:

Number of Fab vials = [Serum digoxin level (ng!mL)

X patient weight (kg) ] /100

Rounded-up to the nearest whole number

3. Patients demonstrating significant toxicity (lifethreatening dysrhythmias, profound hypotension, and/

or severe hyperkalemia):

Empirically treat acute ingestions with 10-20 vials of

Fab fragments and chronic exposures with 5 vials.

Repeated dosing may be required.

Of note, most lab assays do not distinguish between free

and bound digoxin, and serum levels lose their c linical utility after the administration of Fab fragments. Furthermore,

treatment with Fab fragments may lead to the secondary

decompensation of underlying cardiac conditions such as

CHF or atrial fibrillation, which had been previously controlled with digoxin therapy.

DISPOSITION

� Admission

Admit all patients after a potentially significant ingestion

who either have a history of significant comorbid

conditions or exhibit signs or symptoms of clinical toxicity

including cardiovascular instability, dysrhythmias, GI

distress, and mental status changes. Any patient with

toxicity significant enough to warrant digoxin Fab

fragments requires admission to an intensive care unit

setting. Patients who ingest digoxin as part of a suicide

attempt warrant psychiatric evaluation once they are

medically stabile.

� Discharge

Patients with accidental ingestions and no significant

comorbidities who remain symptom free after an 8- to

12-hour observation period may be safely discharged home.

SUGGESTED READING

Boyle JS, Kirk MA. Digitalis glycosides. In: Tintinalli JE,

Stapczynski JS, Ma OJ, Cline DM, Cydulka RK, Meckler GD.

Tintinalli's Emergency Medicine: A Comprehensive Study Guide.

7th ed. New York, NY: McGraw-Hill, 201 1, pp. 1260-1264.

Hack JB. Cardioactive steroids. In: Nelson LS, Lewin NA,

Howland MA, et al. Go/drank's Toxicologic Emergencies. 9th ed.

New York, NY: McGraw-Hill, 20 1 1, pp. 936-945.

Ma G, Brady WJ, Pollack M, Chan TC. Electrocardiographic

manifestations: digitalis toxicity. ] Emerg Med. 200 1;20: 145-152.

Manini AF, Nelson LS, Hoffman RS. Prognostic utility of serum

potassium in chronic digoxin toxicity. Am J Cardiovasc Drugs.

20 1 1; 1 1:173-178.

Cyclic Antidepressants

Harry C. Karydes, DO

Key Points

• Cyclic antidepressants remain a leading cause of

poisoning-related fatalities among psychoactive

medications.

• Patients will frequently present with minimal signs

and symptoms only to abruptly decompensate from

l ife-threatening card iovascular and central nervous

system toxicity.

INTRODUCTION

Cyclic antidepressants (CA) consist of a group of pharmacologically related medications that were initially developed

in the late 1950s for the treatment of patients with severe

depression. Although used less frequently for this purpose,

their role has expanded to include the management of

various alternative conditions including neuralgic pain,

migraine headaches, enuresis, and attention deficit hyperactivity disorder. Traditional cyclic antidepressants have a

chemical structure built on a 3-ring nucleus and include

such medications such as amitriptyline, nortriptyline, doxepin, imipramine, and clomipramine. Antidepressants have

historically remained a leading cause of pharmacologic

self-poisoning owing to their near ubiquitous availability to

a depressed patient population inherently at risk for selfharming behavior. Although the introduction of selective

serotonin reuptake inhibitors (SSRls) has decreased the

overall incidence of CA poisonings, CA overdoses c ontinue

to account for a greater morbidity and mortality given their

increased potential for significant toxicologic complications, especially in pediatric patients.

Cyclic antidepressants are nonselective agents that

exhibit a wide array of pharmacologic effects with consid ­

 

erable variations in potency. The majority of clinical

• Cardiovascular toxicity (specifica lly refractory hypotension) is the leading cause of morbidity and morta lity in

cycl ic antidepressant overdose.

• Hypertonic sodium bicarbonate should be given in

1 -2 mEq/kg boluses to reverse the wide-complex

dysrhythmias commonly encountered with cyclic

antidepressant poison ing.

findings associated with CA poisoning can be attributed to

;:::1 of the following pharmacologic actions:

• Competitive inhibition of acetylcholine at central and

peripheral muscarinic (but not nicotinic) receptors

• Inhibition of a-adrenergic receptors

• Inhibition of norepinephrine and serotonin uptake

• Sodium channel blockade

• Antagonism of GABA-A receptors

Although it is the inhibition of norepinephrine and

serotonin uptake that is believed to account for the antidepressant effects of these agents, the alternative actions just

listed account for the significant toxicity associated with

CA overdose, with sodium channel blockade being the

most important factor contributing to patient mortality.

CLINICAL PRESENTATION

� History

Patients commonly present to the emergency department

with minimal clinical findings only to develop life-threatening cardiovascular and central nervous system (CNS)

manifestations within the timespan of a few hours.

255

CHAPTER 60

Co-ingestants are not uncommon in patients with CA

overdoses, and this possibility must always be investigated.

Attempt to determine the exact amount of drug

ingested, as the cyclic antidepressants have a rather narrow

therapeutic window, and small excursions beyond the

usual therapeutic range (2-4 mg/kg) may result in significant toxicity. Acute ingestions of more than 1 0-20 mg/kg

will cause significant cardiovascular and CNS disturbances

owing to the blockade of cardiac sodium channels and

inhibition of CNS GABA-A receptors, respectively. Toxicity

in children has been reported with ingestions as low as

5 mg/kg.

� Physical Examination

The clinical presentation of CA toxicity varies widely from

mild anti-muscarinic signs and symptoms to severe

Table 60-1 Clinical manifestations of toxicity

resulting from cyclic antidepressants.

Cardiovascular Toxicity

Conduction Delays

PR interval, QTc interval, and QRS complex prolongation

Terminal right access deviation (S in lead I and R in aVR)

Atrioventricular block

Dysrhythmias

Sinus tachycardia

Supraventricular tachycardia

Wide·complex tachycardia

Sinus tachycardia with rate·dependent aberrancy

Ventricular tachycardia

Torsades de pointes

Bradycardia

Ventricular fibril lation

Asystole

Hypotension

Central Nervous System Toxicity

Altered mental status

Delirium

Psychosis

Lethargy

Coma

Myoclonus

Seizures

Anticholinergic Toxicity

Altered mental status

Hyperthermia

Urinary retention

Paralytic ileus

Pulmonary Toxicity

Acute lung·injury aspiration

Repri nted with permission from Flomenbaum N, Goldfrank L,

 

 Although normal therapeutic concentrations

generally range between 0.5 and 2 ng/mL, given the

significant toxicity and narrow therapeutic window, the

safest suggested concentration with maximal therapeutic

benefit is between 0.5 and 1 ng!mL.

At the cellular level, digoxin inhibits the membranebased sodium-potassium pumps, causing an increase in

intracellular sodium concentrations. This rise in

intracellular sodium inhibits the membrane-based

sodium-calcium exchanger, causing a secondary elevation

in intracellular calcium levels. The increased intracellular

calcium concentration augments myocardial contractility

and increases cardiac inotropy. It is this increase in cardiac

inotropy that makes digoxin an attractive agent for the

CHAPTER 59

management of congestive heart failure. Additionally,

digoxin increases the overall vagal tone of the heart and

thereby decreases the electrical conduction velocity

through both the SA and AV nodes. This property allows

digoxin to be used as a rate-controlling agent in patients

with supraventricular tachydysrhythmias ( eg, atrial

fibrillation). That said, this global slowing of myocardial

signal conduction combined with a secondary shortening

of the myocyte refractory period can potentially increase

overall cardiac automaticity and excitability. Given these

phenomena, toxic exposures typically present with a

multitude of cardiovascular manifestations.

CLINICAL PRESENTATION

� History

Ascertaining the time of exposure is extremely important

with potential digoxin toxicity. As with all potential

poisonings, it is extremely important to determine the total

amount ingested. Elucidate the number and frequency of

exposures to distinguish between acute versus chronic

versus acute on chronic toxicity. Carefully clarify the

circumstances of the overdose to differentiate between

accidental versus more insidious etiologies. Inquire about

the presence of any gastrointestinal symptoms, such as

nausea, vomiting, and abdominal pain, which typically

accompany most acute overdoses. Central nervous

system (CNS) effects include mood changes, headache,

altered mental status, lethargy, and hallucinations. Visual

disturbances are common and include blurry vision,

photophobia, and chromatopsia (a change of color vision),

in which visualized objects are classically surrounded by

yellowish-green halos.

� Physical Examination

Obtain a complete set of vital signs and carefully monitor

for any evidence of hemodynamic instability. Although

bradydysrhythrnias and systemic hypotension are most

common, patients may present with any number of cardiac manifestations, including life-threatening tachycardias. Additional physical exam findings are variable and

nonspecific and typically lag up to several hours after

ingestion. CNS effects including confusion, generalized

weakness, altered mental status, and lethargy may be

present, and generalized seizures may accompany severe

overdoses.

DIAGNOSTIC STUDIES

� Laboratory

Obtain a STAT metabolic panel as serum electrolytes play

an extremely important role in digoxin toxicity. Serum

hyperkalemia (K+ >5.5 mEq/L) indicates significant toxicity with acute overdoses and is associated with increased

fatality. Serum hypokalemia (K+ <3.5 mEq/L) is far more

common with chronic toxicity and inhibits the function of

the cellular sodium-potassium pumps, thereby increasing

myocardial susceptibility to digoxin-related dysrhythrnias.

Serum hypomagnesemia may further predispose to this

increased cardiac toxicity. Finally, any decline in renal

function will intensify toxicity, as digoxin is primarily

eliminated via the kidneys.

Obtain a serum digoxin level, as this will guide the

dosing of digoxin Fab fragments. Therapeutic digoxin

levels range from 0.5 to 2.0 ng/mL. Interpret the digoxin

level carefully within the clinical context. The distributive

phase of digoxin lasts for -6 hours after an ingestion, and

serum levels obtained within this period may be falsely

elevated.

� Electrocardiogram

Obtain an emergent electrocardiogram (ECG) in all

patients with potential digoxin toxicity. Prolongation of

the PR interval and shortening of the QT segment are not

uncommon with therapeutic digoxin concentrations.

Upward "scooping" of the ST segment is also fairly

common. These changes taken as a whole are referred to as

the digitalis effect. In addition, excesses in intracellular

calcium may produce frequent premature ventricular

complexes (PVCs) and occasional U waves.

Digoxin poisoning can induce nearly every form of

dysrhythmia or conduction disturbance. Classic ECG

fmdings include supraventricular tachydysrhythmias

(atrial flutter or fibrillation) combined with variable AV

nodal blockade resulting in slow ventricular rates

(Figure 59- 1). Bidirectional ventricular tachycardia is

nearly pathognomonic for serious digoxin toxicity.

Additional ECG findings include sinus bradycardia,

ventricular bigeminy, and ventricular fibrillation.

PROCEDURES

Cardioversion or defibrillation may be performed following Advanced Cardiovascular Life Support protocols in

digoxin-poisoned patients exhibiting significant toxicity

and unstable rhythms (ventricular tachycardia or

.A Figure 59·1 . Digitalis toxicity: Atrial fibril lation with

slow ventricular rate and "scooped" ST-segment

depression. Reproduced with permission from Ritchie JV,

Juliano ML, Thurman RJ. Chapter 23. ECG Abnormal ities.

In: Knoop KJ, Stack LB, Storrow AB, Thurman RJ, eds. The

Atlas of Emergency Medicine. 3rd ed. New York:

McGraw-Hill, 201 0. Photo contributor: JV Ritchie, MD.

fibrillation). Transcutaneous or transvenous pacing often

fails to correct digoxin-associated bradydysrhythmias and

may actually lower the threshold for life-threatening ventricular dysrhythmias.

MEDICAL DECISION MAKING

The differential diagnosis of digoxin toxicity includes any

disease process or toxin capable of inducing cardiac

dysrhythmias. Specific toxins include calcium channel

blockers, beta-blockers, clonidine, organophosphate

insecticides, class lA antidysrhythmics, and cardiotoxic

plants (eg, rhododendron, monkshood). Medical conditions

include underlying cardiac pathologies such as sick sinus syndrome and AV nodal blocks as well as systemic conditions

such as sepsis, myxedema coma, and adrenal crisis.

The toxicologic differential of any hypotensive and/or

bradycardic patient includes beta-blockers, calcium

channel blockers, digoxin, and clonidine. Obtaining a

thorough history frequently aids in establishing the

appropriate diagnosis. The most common current presen ­

tation of digoxin toxicity is an elderly patient with an

underlying cardiac history on multiple medications who

experiences either significant drug-drug interactions or

dehydration with secondary renal insufficiency and

decreased digoxin clearance despite therapeutic usage.

DIGOXIN

The physical exam combined with appropriate

ancillary testing is invaluable for identifying the correct

toxidrome. Clonidine poisoning typically presents similar

to an opioid toxidrome. A significantly elevated capillary

blood glucose in a nondiabetic patient may indicate serious calcium channel blocker toxicity. Taken in context of

the history and physical exam, classic ECG findings and

abnormal serum digoxin levels may be used to direct further treatment (Figure 59-2).

TREATMENT

After addressing and stabilizing the patient's airway,

breathing, and circulation status, pursue gastrointestinal

(GI) decontamination with activated charcoal (AC) for

cases of acute overdose. Do not give AC to patients with

depressed levels of consciousness without first securing the

airway to prevent aspiration. Initiate volume resuscitation

in dehydrated patients but be wary of those with a history

of congestive heart failure (CHF). Treat severe hyperkale ­

 

especially in those with risk for CO exposure.

Inquire about the location of presumed exposure and

whether or not anyone else in the vicinity has developed

symptoms. Ask about the presence of regularly maintained

CO detectors in the house. High-risk scenarios for CO exposure include fire victims, patients in older houses with faulty

furnaces during the winter time and/or those using alternative forms of combustion to heat their homes, and patients

in enclosed spaces with running automobiles. Finally, ask

about the recent use of any paint stripper or solvents, as

these compounds may contain methylene chloride.

� Physical Examination

As with other poisonings, rapidly assess the patient's airway,

breathing, and circulation. Take careful note of a full set of

vital signs, keeping in mind that standard pulse oximetry is

of minimal utility in this setting. Tachypneic patients may

be attempting to compensate for an underlying metabolic

acidosis. Although patients with acute CO poisoning are

classically described as having a "cherry red" appearance to

their skin due to the bright red color of carboxyhemoglo ­

bin, this finding is absent far more often than present.

Perform a detailed neurologic exam, looking for signs

of altered mental status and loss of coordination, as neurologic findings often dictate final care. Perform an ocular

exam, looking for signs of retinal flame hemorrhages. The

cardiovascular exam should focus on signs of hemodynamic instability and dysrhythmia, which might indicate

underlying myocardial ischemia.

Carefully auscultate the lungs, noting any inspiratory

crackles, which may be indicative of chemical injury to the

lung parenchyma with secondary acute respiratory distress

syndrome. Finally, check the skin for any signs of thermal

injury in fire victims. Rarely, CO poisoning has been

known to cause diffuse bullous lesion in the absence of

thermal burns.

DIAGNOSTIC STUDIES

� Laboratory

Order an immediate COHb level on all patients to help

confirm the diagnosis and estimate the severity of the

exposure. COHb analysis requires co-oximetry of the

blood sample and can be done on either a venous or arte ­

rial specimen. Of note, COHb levels correlate poorly with

patient symptoms and should not be used in isolation to

guide management. Check a metabolic panel looking for

electrolyte abnormalities and to calculate the anion gap, as

significant CO poisoning will result in an anion gap metabolic acidosis. Use the anion gap calculation along with a

blood gas analysis to determine the severity of the acidbase derangement.

Obtain a urine pregnancy on all females of childbearing

age, as a positive pregnancy test will markedly impact management. Check a serum lactate level. Significantly high

levels (> 10 mmol!L) indicate severe cellular toxicity or

concurrent cyanide poisoning. Order serum cardiac

markers in all patients complaining of chest pain or with

electrocardiogram (ECG) abnormalities, as myocardial

ischemia has been reported, especially in patients with

underlying coronary artery disease (CAD). Finally, check a

creatine phosphokinase level in patients with unknown

downtimes, as rhabdomyolysis is a serious concern.

� Electrocardiogram

Obtain an ECG looking for signs of ischemia in patients

complaining of chest pain, shortness of breath, and those

with underlying CAD.

� Imaging

Check a chest x-ray in patients with shortness of breath

or a history of smoke inhalation, as chemical injury to the

lungs with secondary pulmonary edema is common.

Order a computed tomography ( CT) of the brain in

patients with altered mental status or focal neurologic

deficits to rule out alternative etiologies. Low-density

lesions of the bilateral globus pallidi have been reported

CARBON MONOXIDE POISONING

with CO poisoning, and patients with abnormalities on

CT imaging are more likely to exhibit chronic neurologic

sequelae.