Concepts in Emergency and Critical Care Carlotta M. Rinke, MD, Section Editor

Tricyclic Antidepressant Overdose A Review David A. Frommer, MD; Kenneth W. Kulig, MD; John A. Marx. MD: Barry Rumack, MD

Significant advances in diagnosis and management of tricyclic antidepressant overdose have occurred in recent years. This article reviews epidemiologic, pharmacologic, and therapeutic information to provide a systematic approach to these potentially life-threatening overdoses. The tricyclics are discussed as a group, with individual drugs specified when established differences exist.

(JAMA 1987;257:521-526)

0 true apothecary Thy drugs are quick.

Shakespeare W: Romeo and Juliet, act V, scene 3, line 119

SYNTHESIS of the forerunner of the first tricyclic antidepressant (TCA), iminodibenzyl, occurred in the late 19th century, with investigation of its deriva-tives beginning in the late 1940s.' Imipraznine hydrochloride, which is chemically similar to the phenothia-zines, was selected for further trials in psychotic patients as a result of its

.sedative-hypnotic effects. Although in-effective in treating psychoses, it was fortuitously discovered in 1957 to be quite effective in treating endogenous depression. In 1958, initial reports in the American literature demonstrated that 83% of depressed patients taking TCAs significantly improved.' By 1959, lethal overdoses were first reported.

CHEMICAL STRUCTURE The term tricyclics is derived from

the three-ring chemical structure of the central portion of the molecule. Ami-triptyline hydrochloride and imipra-mine are prototypes (Fig). Three carbon substituents are found on the terminal

From the Department of Emergency Medicine, Boston City Hospital (Dr Frommer); the Clinical Tox-icology Fellowship Program (Dr Kulig) and the Depart-ment of Pediatrics (Dr Rumack), University of Colorado Medical School, Denver; and the Rocky Mountain Poison and Drug Center (Drs Kulig and Rumack) and the Department of Emergency Medicine (Dr Marx), Denver General Hospital.

Reprint requests to Department of Emergency Medi-cine, Boston City Hospital, 818 Harrison Ave, Boston, MA 02118 (Dr Frommer).

nitrogen of their side chains, thus classi-fying them as tertiary amines within the tricyclic class. The pharmacologi-cally active demethylated metabolites, nortriptyline hydrochloride and desip-ramine hydrochloride, retain two car-bon substituents on the terminal nitro-gen of the side chain, and are therefore secondary amines. Doxepin hydrochlo-ride, trimipramine maleate, and pro-triptyline hydrochloride have minor al-terations of the basic tricyclic structure, but are similar in their efficacy and toxicity. Amoxapine is unique in having a fourth ring as a side structure, but retains the classic three-ring nucleus of the tricyclics. Maprotiline hydrochlo-ride, the only tetracyclic currently available in the United States, has a similar toxicity profile to the TCAs and will therefore be included in this dis-cussion.

EPIDEMIOLOGY The annual incidence of TCA over-

dose in the United States has been estimated at 500 OW.' Tricyclics are re-sponsible for a disproportionate share of both intensive care unit (ICU) admis-sions and mortality when compared with other drug ingestions, and proba-bly represent the most common life- threatening drug ingestion worldwide. In one series, over 50% of serious over-doses resulting in admission to an adult ICU involved TCAs. 4

A typical patient profile has been described for those TCA ingestions re-sulting in fatal outcomes. These pa-tients are likely to be female, between 20 and 29 years old, single, employed,

living alone, and without prior suicide attempts or history of drug abuse.'

Data on TCA mortality are difficult to interpret because published series fre-quently select very different types of patients, ranging from asymptomatic children at home to critically ill adults in an ICU setting. Thus, mortality figures have ranged from 0% to 15% (Table 1). In both the 1983 and 1984 annual reports of the American Association of Poison Control Centers, TCAs were the num-ber one cause of death from drug inges-tion.'• A retrospective review of coro-ner's records determined that over 70% of successful TCA suicides are pro-nounced dead without ever reaching a health care facility.' The magnitude of this problem is thus fax greater than series from poison centers or hospitals suggest.

PREVENTION AND DEVELOPMENT OF NEWER CYCLIC ANTIDEPRESSANTS

Tricyclic antidepressants are effec-tive therapy for endogenous depression and are widely prescribed. Therefore, they are frequently available to suicide- prone patients. Since TCAs are also widely prescribed as treatment for childhood enuresis, accidental as well as intentional overdoses occur.'

A typical therapeutic dosage of a TCA is 2 to 4 mg/kg/d, while 15 to 20 mg/kg is thought to be potentially lethal.' To place this into pediatric per-spective, for a child weighing 10 kg, as few as four 50-mg tablets may be fatal. Thus, preventive measures must in-clude limiting amounts of nonrefillable prescriptions, safe packaging, and lim-iting access to medication by "poison- proofing" the home. Each of these mea-sures may lessen the number of serious

Advisory Panel: Mickey Stewart Eisenberg, MD, Seattle; Joseph E. Parrillo, Jr, MD, Bethesda. Md; and Donald D. Trunkey, MD. San Francisco.

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Tricyclic Antidepressants—Frommer et al 521

Tertiary Amines

O N 0 CH2CH,CH 2N(CH)2 CHCH2CH2N(CH)2

Imipramine Hydrochloride (Tofranil, SK-Pramine,

Janimine)

Desipramine Nortriotyline Hydrochloride Hydrochloride (Norpramin, (Aventyl Hydrochloride,

Pertofrane) Pamelor)

ingestions, but ultimate prevention may depend on the development of safer therapeutic alternatives.

Amoxapine, a tricyclic introduced in 1980, has shown a remarkable lack of cardiotoxicity even in cases of ex-tremely large overdose. However, sig-nificant central nervous system (CNS) toxicity' with development of status epilepticus" has offset this advantage. Maprotiline, a tetracyclic antidepres-sant, was initially advertised as being less cardiotoxic than the TCAs, but has shown similar CNS and cardiac toxicity after overdose.' Trazodone hydro-chloride has been marketed since 1982, having a structure distinct from that of both TCAs and maprotiline. Trazodone appears to be much less toxic than TCAs after acute overdose," but its efficacy and safety remain to be proved.

PHARMACOLOGY Absorption and Distribution

Tricyclic antidepressants in thera-peutic doses are readily absorbed from the gastrointestinal tract, circulate in the plasma, and rapidly bind to tissue. Their high lipid solubility results in a very large volume of distribution, esti-mated at 10 to 50 L/kg.' Large inges-tions may be absorbed more slowly due to anticholinergic effects on gastric emptying and peristalsis. The finding of large amounts of TCA in autopsied stomachs, including intact pill frag-ments, supports this theory.' Never-theless, precipitous clinical deteriora-tion within a few hours after an acute overdose provides convincing evidence that rapid absorption occurs.

When TCAs enter the circulation, a large but variable portion quickly binds

522 JAMA, Jan 23/30, 1987—Vol 257, No 4

CHCH2C1-12N(0-1,)2

Doxepin Hydrochloride (Adapin, Sinequan)

/–"N

lU N=C a

to plasma proteins. More than a ninefold difference in percentage of unbound drug has been reported among patients receiving the same drug dosage." This wide range is affected by such variables as hepatic function and acid-base sta-tus." Hypoalbuminemia and acidemia increase free TCA, whereas diseases associated with elevated "acute-phase reactant? (eg, malignancy, inflamma-tion, and hepatorenal disease) will de-crease free TCA by up to one third." Having potentially great therapeutic relevance, increasing serum pH from 7.38 to 7.50 in an in vitro study resulted in a 21% reduction in free TCA." When unbound drug circulates, tissue uptake occurs in a preferential fashion. Levels have been found to be roughly five times greater in myocardial cells, 30 times greater in liver cells, and 40 times greater in brain tissue than in plasma."

Metabolism and Elimination Metabolism of TCAs occurs primarily

in the liver via demethylation or hy-droxylation, followed by glucuronide conjugation.' Both parent and demethy-lated compounds retain pharmacologic activity until terminated by hydroxyla-tion. Microsomal enzymes in the liver control hydroxylation and are stimu-lated by barbiturates, oral contra-ceptives, alcohol, trihexyphenidyl hydrochloride, methylphenidate hydro-chloride, or smoking." Some drugs, such as haloperidol, disulfiram, and morphine, may prolong TCA toxicity by interfering with hydroxylation." Mean elimination half-lives in both therapeu-tic doses and overdose are extremely variable, ranging from ten to 81

Table 1.—Incidence of Significant Clinical Fincings After Tricyclic Antidepressant Overdose in Pub-lished Case Series'

Finding

Incidence, %

Sinus tachycardia (heart

51 rate, X100 beats , minit

35

21

Hypotension (systolic

14 blood pressure. <90 mm Hg)§

Seizures

8.4

Arrhythmias (ventricular

6.2 and supraventricular)

Cardiorespiratory arrest

3.6 (survivors and fatalities)

Death 2.2

'Summation of reported findings from 16 studies tabulated by Callaham 39 plus ten additional stud-ies29 . 3, . 4,,,,,6671 totaling 2536 patients. Information for each finding was not always available in each series, and each series selected patients with variable severity. Incidence of other significant findings such as myo-clonus was unavailable.

tlncidence may be underestimated since eight stud-ies variably defined sinus tachycardia as heart rates of either more than 110, 120, or 130 beats per minute.

tIncidence may be underestimated since five studies variably defined conduction delay as ORS of 0.12 s or more, or electrocardiograms were not always per-formed.

§Incidence may be underestimated since three stud-ies variably defined hypotension as systolic blood pres-sure below 80 mm Hg.

hours.'•" Variable but extensive first- pass elimination through the liver con-tributes to these wide ranges. Binding to plasma proteins and high lipid solubility allow minimal renal clear-ance, with less than 3% to 10% excreted unchanged daily. Other, less important, routes of elimination include biliary and gastric secretion.

Mechanism of Action The probable mechanism of action of

TCAs in treating depression is central inhibition of biogenic amine reuptake. By blocking reuptake of norepinephrine and serotonin, the deficiency thought present in endogenous depression is corrected.

In addition to central effects, TCAs are also competitive antagonists of his-tamine H1 and H2 receptors.' These receptor effects, including the anti-cholinergic side effects seen with TCAs, are probably unrelated to their action in treating depression.

SYMPTOMS AND SIGNS OF OVERDOSE General Comments

Overdose of TCA primarily affects the parasympathetic nervous system, CNS, and cardiovascular system. With few exceptions, patients having signifi-cant ingestions develop symptoms within the first few hours after over-dose.

Mild early symptoms and signs of toxic reactions to TCAs are predomi-

Tricyclic Antidepressants—Frommer

Amitriptyline Hydrochloride Endep,

SK-Amitriptyline Hydrochloride)

Secondary Amines

ONO OHO o•0 #01 CH2CH2CH2NHCH3 CHCH 2CH2NHCH3 CH,CH 2CH,NHCH 3 CH2CH(CH3)CH 2N(CH3)2

Protriptyline Hydrochloride

Trimipramine

Amoxapine (Vivactil)

(Surmontil)

(Asendin)

Chemical structure of tricyclics.

Coma

ORS =0.10 st

nantly anticholinergic, which may in-clude mydriasis, blurred vision, dry mouth, tachycardia, hyperpyrexia, uri-nary retention, decreased intestinal peristalsis, and CNS excitation pro-gressing to an acute organic brain syn-drome (Table 2). More serious features are probably unrelated to anticholin-ergic effects and may include convul-sions, coma, hypotension, arrhythmias, and cardiorespiratory arrest. The pro-gression from being alert with mild symptoms to life-threatening toxic ef-fects may be extremely rapid.' As previ-ously mentioned, accurate incidence of symptoms and signs after overdose is difficult to ascertain, since selection cri-teria have been variable among studies. Table 1 summarizes data from the liter-ature to provide estimates of reported significant findings after TCA overdose.

Before discussing toxicity, it is help-ful to examine TCA effects at therapeu-tic doses, especially those involving the cardiovascular system. Even at thera-peutic doses, anticholinergic, adrener-gic, and direct "quinidine-like" mem-brane effects interplay on the heart.' Increased heart rate is believed to be due largely to an anticholinergic effect, whereas other electrocardiographic (ECG) changes result from the drug's quinidine-like effect. This quinidine-like property is thought to be caused by slowing of sodium flux into cells, result-ing in altered repolarization and conduc-tion. This altered conduction notably occurs at the His-ventricular portion of the atrioventricular (AV) node.' The ECG changes can be seen within weeks of beginning therapy. These may in-clude increased heart rate, increased PR interval, and flattened T waves." Occasionally, slight QRS or QT-interval prolongation may be seen during thera-peutic dosing. Little clinical significance can be ascribed to these isolated ECG changes," and each is reversible with discontinuation of TCA therapy.

Both antiarrhythmic and arrhyth-mogenic properties of TCAs at thera-peutic doses have been described. Pa-tients with known ventricular irri-tability have shown marked improve-ment after beginning TCA therapy.' But, analogous to quinidine, TCAs can also precipitate arrhythmias as levels increase."

Myocardial dysfunction, infarctions. and cardiomyopathies have been anec-dotally attributed to tricyclic use in the past. However, more advanced cardiac scan techniques have shown no decline in ejection fraction even in patients with preexisting heart disease,"•" and epi-demiologic studies have demonstrated no difference in mortality in those using TCAs." Orthostatic hypotension has

been a significant side effect of TCA therapy that is unrelated to age or dura-tion of use. Orthostasis is caused pre-dominantly by peripheral a-receptor blockade.' Collectively, these results suggest that therapeutic use of TCAs is unassociated with serious cardiac events, except perhaps for complica-tions resulting from orthostatic hypo-tension.

Cardiovascular Toxicity After Overdose

Most patients brought to the emer-gency department after TCA overdose who subsequently die do so within the first few hours.''" Cardiovascular tox-icity with intractable myocardial de-pression, ventricular tachycardia, or ventricular fibrillation are the most common mechanisms of death. Al-though a systematic progression of toxic effects—from increased heart rate to axis deviation, to conduction distur-bance, to ventricular arrhythmia, to bradycardia, and finally to asystole-has been described in an animal model"—this has not been substanti-ated in humans. Malignant ventricular arrhythmias have occurred without prior sinus tachycardia."'" The most accurate predictor of subsequent life- threatening complications may be the QRS duration on ECG, with limb-lead QRS of 0.10 s or more being predictive of both seizures and arrhythmias.'"." Conduction delays commonly assume a rightward axis" or a right bundle- branch block pattern, 2 2' and may evolve into varying degrees of AV block. Other ECG changes may include PR- and QT- interval prolongation, and ST-T–wave abnormalities. Torsade de pointes has been reported after QT-interval prolongation resulting from a maprotiline overdose."

Hypotension is a serious manifesta-tion of TCA overdose and may be the harbinger of cardiac arrests." Several mechanisms may be involved in the de-velopment of TCA-induced hypoten-sion: vasodilation, central or peripheral a-receptor blockade, and cardiac de-pression."'"

Sinus tachycardia, defined as a heart rate of 100 beats per minute or more, is a sensitive indicator of TCA anticho-linergic effect, but an insensitive marker for development of serious tox-icity. It was seen initially in 71 of 100 consecutive overdoses in one uncon-trolled series in which only three con-duction abnormalities and no mortality were seen." Also, sinus tachycardia was present in a retrospective study in only 20 of 113 fatalities who were alive at the time of hospital presentation." The relatively poor correlation of tachycar-

Table 2.—Symptoms and Signs of Toxic Reactions to Tricyclic Antidepressants

Symptoms Blurred vision Dry mouth Dizziness Urinary retention Constipation

Signs Seizure Myoclonus Respiratory depression Coma Hypotension/hypertension Conduction delay Heart block Arrhythmias Cardiac arrest Sinus tachycardia Mydriasis Agitation Drowsiness Absent bowel sounds Acute organic brain syndrome Extrapyramidal/cerebellar Hypothermiaihyperthermia

dia with more serious cardiac abnormal-ities may be because of different mecha-nisms for each. Sinus tachycardia is primarily an anticholinergic effect, whereas conduction disturbances and arrhythmias are primarily related to the quinidinelike action of TCAs."•"

Isolated premature ventricular con-tractions, atrial premature contrac-tions, supraventricular tachycardia, atrial fibrillation, or nodal rhythms oc-cur infrequently with TCA overdoses. Since ventricular tachycardia and fibril-lation can be unusually difficult to con-trol, any ventricular irritability should be viewed as significant in this set-ting.'"

Rare cases of myocardial infarction and congestive heart failure have been anecdotally reported after TCA over-dose." Whether this was from preexist-ing heart disease, systemic hypotension resulting in coronary hypoperfusion, or direct myocardial cell toxicity is open to conjecture.

CNS Toxicity Confusion, agitation, hallucinations,

coma, myoclonus, and seizures are com-mon after serious TCA overdose."•" Lethargy may rapidly progress to coma and respiratory arrest. Depression of the CNS usually resolves quickly if hy-poxic encephalopathy has not occurred. In a large review, nearly one third of comatose patients were awake within 12 hours, and two thirds by 24 hours.' Full recovery is the rule, but subtle mental status changes may persist.'

Generalized seizures have been asso-ciated with increased mortality in TCA overdose cases and have been noted immediately before cardiorespiratory arrest. 32.' Seizures may cause signifi-cant metabolic acidemia, thereby increasing unbound TCA in the circula-

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Tricyckc Antidepressants—Frommer et a, 523

tion and contributing to the develop-ment of malignant dysrhythmias.

Coarse myoclonic jerking may pre-cede or mimic seizure activity.' Sei-zures and generalized myoclonus may be difficult to differentiate, but patients having myoclonus usually remain awake. Cerebellar and extrapyramidal signs, such as nystagmus, choreoathe-tosis, dysarthria, and ataxia, may also occur after a toxic reaction to TCA ingestion.

LABORATORY FINDINGS The utility of quantitative serum lev-

els in TCA overdose has been controver-sial. Although some investigators have reported a high correlation of limb-lead ECG QRS duration of 0.10 s or more with serum TCA levels of 3700 nmol/L (1000 ng/mL) or more, 36 "42 others have stressed the lack of correlation.' QRS widening has been reported with much lower levels,' and cases have been de-scribed with normal QRS complexes and TCA levels above 9200 nmol/L (2500 ng/mL). 34 '33 Since QRS duration more accurately and rapidly predicts serious toxicity such as seizures and arrhythmias,""" quantitative drug levels are rarely justified.

Explanations for the generally poor correlation of TCA levels with the clini-cal course include the fact that plasma levels represent only a minute fraction of the TCA body burden, metabolites are produced rapidly and may have similar pharmacologic actions, and plasma protein binding is rapidly af-fected by many factors including pH.

Quantitative levels may be helpful in selected patients who take TCAs therapeutically and then present with findings consistent with, but not diagnostic of, TCA overdose. Levels may also be helpful in determining the cause of death in suspected over-dose. Forensic studies have found lethal TCA levels ranging from 4000 nmol/L (1100 ng/mL'6) to 80 000 nmol/L (21 800 ng/mL). 8

TREATMENT General Management

General emergency department management of suspected TCA over-dose includes securing an airway if needed, establishing intravenous ac-cess, cardiac monitoring, and stabiliz-ing vital signs. Patients with depressed consciousness should receive oxygen, dextrose, naloxone hydrochloride, and thiamine hydrochloride, and have ar-terial blood gas values determined. A 12-lead ECG and chest roentgenogram should be obtained, the stomach la-vaged with a large-bore (36 to 40 F) orogastric tube, and charcoal, 50 to

100 g, plus cathartic administered. These measures should be instituted for every patient with a history of signifi-cant TCA ingestion or having symp-toms, signs, or ECG changes consistent with TCA poisoning. Syrup of ipecac should be avoided since decreased men-tal status or seizures may occur ab-ruptly, increasing the aspiration haz-ard. In addition, the prolonged emetic effect of ipecac may cause an unaccept-able delay in charcoal instillation.

Activated charcoal significantly ad-sorbs TCA, estimates being that 100 g binds 4 g of TCA." Repeated charcoal administration may well hasten TCA elimination from the vascular compart-ment." Continuous adsorption by char-coal throughout the gut by "intestinal dialysis" may best explain the efficacy of repeated charcoal dosing. Charcoal he-moperfusion and other extracorporeal maneuvers have been anecdotally re-ported to result in clinical improve-ment." However, since only a small amount of total TCA body burden is in serum, enhancing elimination from the vascular compartment may not be clini-cally significant.

Rapid reversal of coma, myoclonus, and extrapyramidal effects led to initial enthusiasm for physostigmine salicy-late being "the antidote" for TCA poi-soning." It readily enters the CNS and blocks cholinesterase, thereby inhibit-ing degradation of acetylcholine at the receptor site. Since TCA-induced car-diotoxicity is largely unrelated to the drug's anticholinergic effect, it is not surprising that physostigmine has not proved effective as treatment for life- threatening cardiotoxicity." Reports of serious complications from physostig-mine, including bradycardia, vomiting, seizures, asystole, and death," have decreased its popularity.

Treatment of CNS Toxicity Seizures and coma represent the

most significant CNS toxicity from TCA overdose. Coma usually resolves within 24 hours,' but is frequently se-vere enough to require active airway support. Extrapyramidal effects and organic brain syndrome usually require supportive care only, although judicious use of physostigmine for obvious anti-cholinergic psychosis in severe cases may be warranted.

Generalized seizures have been asso-ciated with increased mortality in TCA overdose and have been noted imme-diately before cardiac arrest."' The resultant acidemia from seizures may abruptly increase unbound TCA in the circulation and predispose to arrhyth-mias. Aggressive treatment is, there-fore, indicated to prevent or minimize

seizure activity. Due to availability, rapid onset of action, and reported suc-cess in treating TCA-induced sei-zures, diazepam should be consid-ered the first-line agent to halt seizure activity. Diazepam's antiseizure effects diminish within 20 minutes as the drug redistributes; thus, longer-acting anti-convulsants should be administered concurrently. Phenytoin has been rec-ommended as the long-acting anticon-vulsant of choice in this setting because of its coincident antiarrhythmic and anticonvulsant properties.' At con-trolled infusion rates of less than 40 to 50 mg/min, phenytoin has proved to be quite safe," with a rapid onset and a 12- to 24-hour duration of action. Prophy-lactic use of phenytoin for seizures re-mains controversial, although recent controlled animal studies support its efficacy."

Treatment of Conduction Disturbances and Arrhythmias

Conduction disturbances or ventricu-lar arrhythmias should prompt ag-gressive therapy (Table 3). Should cardiac arrest occur, it must be empha-sized that asystole, refractory ventricu-lar fibrillation, and electrical-mechani-cal dissociation do not carry the same prognosis after drug overdose as in acute myocardial infarction. A case of full recovery with five hours of external cardiac massage following TCA poison-ing has been reported.' This suggests that a previously healthy myocardium can recover from a major TCA insult.

Substantial evidence exists that alkalinization of the plasma, either by intravenous sodium bicarbonate or hy-perventilation (if the patient is artifi-cially ventilated), can temporarily reverse TCA cardiotoxicity. Alkalinize-tion has been effective in narrowing widened QRS complexes, correcting hypotension, and controlling arrhyth-mias." The optimal serum pH is not known, but ventricular arrhythmias have occurred at physiologic pH (7.35 to 7.45) in experimental animals, and have been reversed by alkalinizing above this range." A case report in which recur-rent ventricular tachycardia was halted by alkalinizing above 7.47" also sup-ports maintaining serum pH above 7.45.

Phenytoin therapy for conduction delay and ventricular arrhythmias in acute TCA overdose is controversial. Unlike most other antiarrhythmics, phenytoin improves conduction through specialized conduction tissues of the heart, and therefore has been consid-ered by some as the drug of choice in this setting.' While phenytoin can cause a variety of problems if given too rapidly, it is safe when infused slowly as

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Tricyclic Antidepressants—Frommer et a

previously described. A recent study of TCA overdose in patients with conduc-tion delays (QRS duration, a.0.10 s) suggested that phenytoin corrected conduction delays and helped control ventricular arrhythmias." Since 20 to 30 minutes is required to deliver a 15-mg/kg loading dose of phenytoin, bi-carbonate and lidocaine should be used as initial therapy to control ventricular arrhythmias.

Lidocaine is effective and safe in sup-pressing ventricular arrhythmias in various acute settings such as myocar-dial infarction. Unlike other class I anti-arrhythmics, such as quinidine sulfate, procainamide hydrochloride, and diso-pyramide, which are contraindicated after TCA overdose, lidocaine does not significantly depress conduction or con-tractility. Since it can be delivered rapidly, lidocaine should be considered an initial therapy for immediate control of ventricular arrhythmias due to TCA overdose.

13-Blockers have been used to treat TCA cardiotoxicity, with variable suc-cess. Theorizing that the initial adre-nergic action of TCAs might adversely affect the cardiovascular system, 13-blockers have been reported to nar-row widened QRS complexes and con-vert ventricular tachycardia to sinus rhythm." Since some patients with TCA overdose have developed severe hypotension or had a cardiac arrest shortly after receiving a 13-blocker," these drugs should be used with cau-tion. Further depression of myocardial contractility in patients with depressed cardiac output from TCA toxicity could be hazardous.

Bretylium tosylate is a unique antiar-rhythmic with prominent antifibrilla-tory properties. Although it does not in-terfere with conduction velocity nor does it possess quinidine-like membrane effects, it does cause a sympathetic ganglionic blockade. This blockade fre-quently results in transient hypoten-sion. Since TCAs block norepinephrine reuptake, the combined effects of these drugs could be detrimental. Further research is needed to help define the role of bretylium in TCA overdose.

Since AV conduction disturbances in TCA overdoses are largely distal to the AV node,' attempts to improve conduc-tion through the node with atropine sulfate have been largely ineffective. Mobitz II heart block and complete heart block are indications for tempo-rary pacemaker insertion and over-drive. Isoproterenol may be helpful in controlling bradyarrhythmias and tor-sade de pointes ventricular tachycardia while overdrive pacing is being estab-lished."'

Treatment of Hypotension Hypotension may be the result of

direct TCA-induced vasodilation, a-blockade, or myocardial depression. If hypotension does not respond to crys-talloid infusion alone, alkalinization guided by arterial pH may be corrective (Table 3). Benefit from alkalinization in humans appears to result largely from serum pH changes rather than sodium loading, since hyperventilation has af-forded similar improvements."•" Ani-mal experimentation suggests that sodium loading may have an effect inde-pendent of pH,' but this remains to be shown in humans. Since cell membranes are more permeable to carbon dioxide than bicarbonate, the alkalemia of hy-perventilation theoretically may pro-vide more rapid benefit in the artificially ventilated patient.

Patients remaining significantly hy-potensive after volume expansion and alkalinization may require vasopressor support and right-sided heart Swan- Ganz catheterization to guide hemo-dynamic interventions. Since TCAs block reuptake of norepinephrine at both central and peripheral adrenergic neurons, pressors such as dopamine that partially rely on norepinephrine release from storage vesicles may have diminished effect. Phenylephrine or norepinephrine, with their predomi-nant a-stimulating effects, are pre-ferred.

If volume repletion, alkalinization, and vasopressors are inadequate in re-versing hypotension, inotropic agents such as dobutamine hydrochloride may help correct any existing myocardial depression. Isoproterenol may also be used selectively for its inotropic effects, with the caution that increased ventric-ular irritability and more pronounced peripheral vasodilation could occur.

PATIENT DISPOSITION After stabilization and gastric decon-

tamination, patients with serious toxic reactions should be expeditiously ad-mitted to an ICU. Patients with no symptoms or signs of toxic reactions to TCAs should be closely monitored in the emergency department for a mini-mum of six hours." After six hours, if no symptoms or signs are present and the ECG is normal, psychiatric disposition may be made. Patients demonstrating an isolated sinus tachycardia with a heart rate of 100 beats per minute or more are perhaps the most frequent and difficult disposition problem. Tachycar-dia may be secondary to other common occurrences, such as simultaneously in-gested drugs (including alcohol), anx-iety, dehydration, or the emergency treatment itself. If the tachycardia re-

Table 3.—Tricyclic Antidepressant Overdose: Sum-

mary of Pharmacologic Treatment Recommenda-

tions*

Symptom Sign Treatment

Convulsions

Diazepam, 0.1 mg/kg intravenously (IV) per dose as needed

Alkalinization Phenytoin, 15 mg/kg

IV over 30 min

Coma

Airway support

Hypotension

Crystalloid infusion Alkalinization Vasopressors: norepinephrine

preferred Inotropic agents:

dobutamine preferred

Ventricular Alkalinization arrhythmiast Lidocaine

Phenytoin, 15 mg/kg IV over 30 min

Prolonged QRS Alkalinization

s) Phenytoin, 15 mg/kg IV over 30 min

Bradyarrhythmia/ Isoproterenol heart block Pacemaker

*Basic and advanced cardiac life support measures are initiated first, including administration of dextrose, naloxone, and thiamine when warranted. Pharma-cologic recommendations are listed in order of prefer-ence.

tCardioversion should be considered for any hemo-dynamically compromising arrhythmia. Torsade de pointes ventricular tachycardia may respond only to overdrive pacing or isoproterenol infusion. Quinidine, procainamide, and disopyramide are contraindicated for any tricyclic overdose.

Mobitz II second-degree or third-degree heart block.

solves with volume repletion or time, and no further signs of toxicity develop, then the patient can be medically cleared for psychiatric disposition. This approach is based on data showing sinus tachycardia to be a sensitive indicator of TCA anticholinergic effect, but rela-tively nonpredictive of serious tox-icity."'" If additional symptoms or signs of toxic reactions to TCAs develop during observation, or if an isolated tachycardia fails to resolve, ICU admis-sion is indicated. Persistent tachycardia might represent continued TCA ab-sorption with potential for delayed com-plications."

Case reports of delayed in-hospital TCA overdose deaths have generated much discussion in the literature.'" Most of these deaths occurred in previ-ously symptomatic patients who had recently been sent from an ICU to an unmonitored ward. Refractory hypo-tension, ventricular fibrillation, or asystole occurred. Continued evidence of tachycardia, conduction abnormali-ties, or other symptoms of toxicity were present shortly before each patient's death. Therefore, those at risk for de-layed complications should be readily identifiable, and aggressive manage-ment continued until all manifestations of toxicity have resolved for at least 24 hours. s.""

We thank Lisa Wolfe for her excellent and per-severing secretarial assistance.

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526 JAMA, Jan 23/30, 1987-Vol 257, No. 4

Tricyclic Antidepressants-Frommer et a