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Clinical Toxicology (2007) 45, 203–233
Copyright © Informa Healthcare
ISSN: 1556-3650 print / 1556-9519 online
DOI: 10.1080/15563650701226192
LCLT
PRACTICE GUIDELINE
Tricyclic antidepressant poisoning: an evidence-based
consensus guideline for out-of-hospital management*
Tricyclic antid epressant poisoning
ALAN D. WOOLF, M.D., M.P.H., ANDREW R. ERDMAN, M.D., LEWIS S. NELSON, M.D.,
E. MARTIN CARAVATI, M.D., M.P.H., DANIEL J. COBAUGH, P
HARM.D., LISA L. BOOZE, PHARM.D., PAUL M. WAX, M.D.,
ANTHONY S. MANOGUERRA, P
HARM.D., ELIZABETH J. SCHARMAN, PHARM.D., KENT R. OLSON, M.D.,
PETER A. CHYKA, P
HARM.D., GWENN CHRISTIANSON, M.S.N., and WILLIAM G. TROUTMAN, PHARM.D.
American Association of Poison Control Centers, Washington, District of Columbia, USA
A review of U.S. poison center data for 2004 showed over 12,000 exposures to tricyclic antidepressants (TCAs). A guideline that
determines the conditions for emergency department referral and prehospital care could potentially optimize patient outcome, avoid
unnecessary emergency department visits, reduce healthcare costs, and reduce life disruption for patients and caregivers. An evidence-
based expert consensus process was used to create the guideline. Relevant articles were abstracted by a trained physician researcher. The
first draft of the guideline was created by the lead author. The entire panel discussed and refined the guideline before distribution to
secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline
is to assist poison center personnel in the appropriate prehospital triage and management of patients with suspected ingestions of TCAs by
1) describing the manner in which an ingestion of a TCA might be managed, 2) identifying the key decision elements in managing cases of
TCA ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for
research. This guideline applies to ingestion of TCAs alone. Co-ingestion of additional substances could require different referral and
management recommendations depending on their combined toxicities. This guideline is based on the assessment of current scientific and
clinical information. The panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative
of the patient and the health professionals providing care, considering all the circumstances involved. This guideline does not substitute for
clinical judgment. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses. 1)
Patients with suspected self-harm or who are the victims of malicious administration of a TCA should be referred to an emergency
department immediately (Grade D). 2) Patients with acute TCA ingestions who are less than 6 years of age and other patients without
evidence of self-harm should have further evaluation including standard history taking and determination of the presence of co-ingestants
(especially other psychopharmaceutical agents) and underlying exacerbating conditions, such as convulsions or cardiac arrhythmias.
Ingestion of a TCA in combination with other drugs might warrant referral to an emergency department. The ingestion of a TCA by a
patient with significant underlying cardiovascular or neurological disease should cause referral to an emergency department at a lower dose
than for other individuals. Because of the potential severity of TCA poisoning, transportation by EMS, with close monitoring of clinical
status and vital signs en route, should be considered (Grade D). 3) Patients who are symptomatic (e.g., weak, drowsy, dizzy, tremulous,
palpitations) after a TCA ingestion should be referred to an emergency department (Grade B). 4) Ingestion of either of the following
amounts (whichever is lower) would warrant consideration of referral to an emergency department: an amount that exceeds the usual
maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose. For all TCAs except desipramine,
nortriptyline, trimipramine, and protriptyline, this dose is >5 mg/kg. For despiramine it is >2.5 mg/kg; for nortriptyline it is >2.5 mg/kg; for
trimipramine it is >2.5 mg/kg; and for protriptyline it is >1 mg/kg. This recommendation applies to both patients who are naïve to the
specific TCA and to patients currently taking cyclic antidepressants who take extra doses, in which case the extra doses should be added to
the daily dose taken and then compared to the threshold dose for referral to an emergency department (Grades B/C). 5) Do not induce
emesis (Grade D). 6) The risk-to-benefit ratio of prehospital activated charcoal for gastrointestinal decontamination in TCA poisoning is
unknown. Prehospital activated charcoal administration, if available, should only be carried out by health professionals and only if no
contraindications are present. Do not delay transportation in order to administer activated charcoal (Grades B/D). 7) For unintentional
poisonings, asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the initial call to a poison
center is greater than 6 hours. These patients do not need referral to an emergency department facility (Grade C). 8) Follow-up calls to
determine the outcome for a TCA ingestions ideally should be made within 4 hours of the initial call to a poison center and then at
Received 20 July 2006; accepted 20 July 2006.
*Guidelines for the Management of Poisoning, supported in full by Cooperative Agreement 8 U4BHS00084 between the American
Association of Poison Control Centers and the Health Resources and Services Administration, Department of Health and Human Services.
Address correspondence to American Association of Poison Control Centers, 3201 New Mexico Avenue NW, Suite 330, Washington,
DC 20016, USA. E-mail: info@aapcc.org
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204 A.D. Woolf et al.
appropriate intervals thereafter based on the clinical judgment of the poison center staff (Grade D). 9) An ECG or rhythm strip, if available,
should be checked during the prehospital assessment of a TCA overdose patient. A wide-complex arrhythmia with a QRS duration longer
than 100 msec is an indicator that the patient should be immediately stabilized, given sodium bicarbonate if there is a protocol for its use,
and transported to an emergency department (Grade B). 10) Symptomatic patients with TCA poisoning might require prehospital
interventions, such as intravenous fluids, cardiovascular agents, and respiratory support, in accordance with standard ACLS guidelines
(Grade D). 11) Administration of sodium bicarbonate might be beneficial for patients with severe or life-threatening TCA toxicity if there is
a prehospital protocol for its use (Grades B/D). 12) For TCA-associated convulsions, benzodiazepines are recommended (Grade D). 13)
Flumazenil is not recommended for patients with TCA poisoning (Grade D).
Keywords Antidepressive agents, tricyclic/poisoning; Poison control centers/standards; Practice guidelines
Introduction
Statement of the scope of the problem and importance of
the guideline
Tricyclic antidepressant (TCA) poisoning is common in the
United States. In 2004, the Toxic Exposure Surveillance System
(TESS) national database of poison center calls maintained by
the American Association of Poison Control Centers (AAPCC)
recorded 7,430 exposures to amitriptyline, 185 to desipramine,
1,288 to doxepin, 819 to imipramine, 1,152 to nortriptyline, and
26 to protriptyline, as well as 1,152 exposures to “other” or
unknown cyclic antidepressants and 182 exposures to a cyclic
antidepressant formulated with a benzodiazepine or phenothiaz-
ine. Within the 12,234 exposures in these categories, there were
1,351 (9%) exposures in children less than 6 years of age and
3,881 (32%) exposures described as unintentional. A total of
9,324 (76%) exposures were treated in healthcare facilities (1).
The high referral rate reflects the potential toxicity of this class
of pharmaceuticals.
The toxicity of TCAs was apparent relatively soon after
their introduction. One case series reported two deaths in 10
adults hospitalized in 1968 for TCA poisoning (2). A review
of 111 TCA deaths reported to a coroner’s office over 8 years
in the 1970s and early 1980s found that 71% had died in the
field and another 13% were dead on arrival at a hospital (3).
In a 5-year cohort study of 172,598 patients on antidepres-
sants reported in 1995, eight of the 50 patients who commit-
ted suicide did so by antidepressant poisoning (4). Table 1
shows the deaths attributed solely to unintentional exposures
to TCA (no apparent co-ingestants) culled from the TESS
database for 1985–2003. In 2004, there were 85 TCA-related
poisoning deaths reported in the TESS database, all of which
were intentional and/or involved co-ingestants (1). Fifty-one
(60%) of these intentional deaths were associated with
amitriptyline.
TCA poisoning is also a cause of important morbidity. One
poison center-based study reported in 1993 that, over a 2-year
period, TCAs alone accounted for 25% of all overdose-
induced convulsions (5). In a 1995 retrospective study of 388
consecutive patients with TCA poisoning admitted to the
Fernand Widal Hospital in Paris over a 4-year period, 6.2%
developed grand mal seizures, although this figure could
underestimate the risk since some patients had also ingested
benzodiazepines, which have anticonvulsant properties (6).
Appropriate referral to healthcare facilities is critically
important as TCA ingestion can result in convulsions, coma,
life-threatening arrhythmias and cardiac conduction distur-
bances, and death. Despite the frequency and severity of TCA
poisoning, there is little consensus among poison centers on
how patients should be managed in the prehospital setting.
Toxicity of different cyclic antidepressants
A prospective study of 489 patients with TCA overdoses per-
formed in the 1970s (including 203 amitriptyline, 68 imi-
pramine, 27 nortriptyline, 27 trimipramine, 22 clomipramine,
and 21 doxepin cases), found no significant differences in
clinical course between individual antidepressants (7). How-
ever, a cohort study comparing death rates per million pre-
scriptions written in Great Britain showed TCAs such as
amitriptyline and imipramine to be more toxic than other
antidepressants (8). A 6-year review of annual mortality rates
per million prescriptions written for antidepressants in Great
Britain during 1987–92 showed TCAs generally had the
highest mortality rates, with desipramine, amitriptyline, and
imipramine contributing disproportionately to deaths,
whereas there were no protriptyline-related deaths (9).
Another British study of 3,185 fatalities due to antidepres-
sants found doxepin to have a disproportionately higher case
fatality rate (CFR) among the elderly. High mortality rates
were also associated with amitriptyline, trimipramine, imi-
pramine, and clomipramine (10). A 3-year, poison center-
based review of 1,313 patients with TCA poisoning reported
by Wedin et al. in 1986 (11) found that 18% of patients
ingesting imipramine suffered convulsions, which was higher
than other TCAs and similar to convulsion rates found with
overdoses of antidepressants such as amoxapine and mapro-
tiline. A secondary analysis of comparative CFRs of five
TCAs using the TESS database for 1983–2002 found that the
CFR of desipramine was 4–12-fold higher than the CFRs of
amitriptyline, doxepin, imipramine, and nortriptyline (12,13).
Thus, there may be some differences between individual
TCA agents in terms of their potential for producing toxicity.
Pharmacology and pharmacokinetics
The neuropharmacology of TCA action is incompletely
understood. Some of the therapeutic effects of TCAs on
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Tricyclic antidepressant poisoning 205
clinical depression have been attributed to their ability to
deplete norepinephrine (NE) from neuronal presynaptic vesi-
cles, selectively inhibit NE transport, and block NE reuptake.
There are variable inhibitory effects on serotonin uptake-
inactivation as well. TCAs have both central and peripheral
anticholinergic properties. Delayed gastric emptying time
and slowed intestinal peristalsis associated with such effects
could account in part for the variable absorption rates and
delayed clinical toxicity seen in TCA poisoning. TCAs also
affect cardiac conduction by blocking fast inward Na
+
chan-
nels on myocardial cells, analogous to type Ia antiarrhyth-
mic drugs. Such actions can lead to arrhythmias and cardiac
conduction disturbances. Blockade of postsynaptic periph-
eral α-adrenergic receptors decreases preload and vascular
resistance and contributes to the hypotension associated
with TCA use (14).
TCAs have narrow dosage ranges for therapeutic effi-
cacy; higher doses are anticipated to produce adverse
effects. A trial in 173 children and adolescents found that
single doses of 3.75 mg/kg of desipramine produced serum
concentrations of 45 ng/mL and clearance rates of 0.74 L/
kg/hour with no significant age- or gender-related variation
in pharmacokinetics (15). The prolonged clinical effects of
TCAs could be related to slow absorption, their large vol-
umes of distribution (10–50 L/kg), and the enterohepatic
recirculation of both parent compound and metabolites. In
overdose, the half-life for amitriptyline elimination (without
decontamination or enhanced elimination therapies) aver-
ages almost 37 hours and is commonly greater than 60
hours (16).
Therapeutic dosages and uses
Table 2 presents the recommended therapeutic dosage ranges
for the medications covered in this guideline. TCAs are fre-
quently prescribed for depression, panic attacks, severe anxi-
ety, phobic disorders, obsessive-compulsive disorders, eating
Table 1. 1985–2003 TESS TCA deaths (single drug, unintentional)
Age/sex TCA
Dose/serum
concentration Circumstances
13 mo/F I Empty bottle/unk time Coma at home, cardiac arrest in ED, cerebral anoxia. Died 36 hr after admission.
18 mo/M I Whole bottle 30 mins to ED. Seizures, arrest, lavage, lorazepam, dopamine, NaHCO
3
. Hypotension,
widened QRS 5 hr later, seizure, arrhythmias, died 27.5 hr after admission.
30 yr/F I Empty bottle No pulse. DOA.
10 mo/F De 600 mg Coma at home; To ED 90 mins after ingestion. Lavaged, ventricular fibrillation, pH 6.9,
CPR, dead within 1 hr.
11 mo/M De Possibly 1 tablet ED by 1 hr. Ataxic, lavage, activated charcoal, seizure, arrest.
15 mo/M De 500 mg
2556 ng/mL
Coma, hypotension. Intubated, ventilated, dopamine, NE, died 2nd d after admission.
19 mo/F De Unk dose/time
1377 ng/mL
Seizure, cardiac arrest at home; pH 6.9; cerebral edema, ileus, diabetes insipidus, brain dead
4 d after admission. Multiple-dose activated charcoal, NaHCO
3
, epinephrine,
isoproterenol, atropine, Fab, mannitol, furosemide, hyperventilated.
20 mo/M De 800 mg
1600 ng/mL
Seizure, hypotension, widened QRS. Within 2 hr of ED admission, 2 cardiac arrests and died.
Phenytoin, NaHCO
3
, pacer, physostigmine.
20 mo/F De Unk dose Seizure at home, skin grey, intubated, p = 60, DOA.
2 yr/F De 1250 mg
3900 ng/mL
Vomited at home, apnea, cardiac arrest in car, DOA.
2 yr/M De 1250 mg
8000 ng/mL
ED by 45 min. Seizure, bradycardia, arrest. ACLS, intubation/atropine, NE, pacing. Dead at 1 hr.
3 yr/M Do Unk dose/time Coma, cardiac arrest at home. DOA.
5 yr/? Do 900 mg Therapeutic error? Vomited; found dead at home.
84 yr/M Do AOC: 200 mg Coma, respiratory depression.
17 mo/M A Unk dose/time Seizure, pneumothorax. NaHCO
3
, intubated, ventilation, dopamine, NE,
diazepam. Died on 12
th
d.
3 yr/M A 100–125 mg Cyanosis, coma, DOA
5 yr/M A Unk dose/time
A 1150 ng/mL
N 790 ng/mL
DOA. Necrotizing pneumonia & pulmonary edema at autopsy.
5 yr/M N
Unk dose
851 ng/mL
Coma, hyperthermic, hypotensive, aspiration pneumonia, arrhythmias. Intubated, ventilated,
lidocaine, NE, bretylium, NaHCO
3
, dopamine, antibiotics. Multisystem failure over 5 d.
ED: emergency department; Fab: Digoxin Fab anti-digoxin antibodies; CPR: cardiopulmonary resuscitation; AOC: acute on chronic; ACLS: advanced car-
diac life support; DOA: dead on arrival at emergency department; NaHCO
3
: sodium bicarbonate; NE: norepinephrine; Unk: unknown; TCA: I = imi-
p
ramine, De = desipramine, A = amitriptyline, Do = doxepin, N = nortriptyline.
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206 A.D. Woolf et al.
disorders, and attention deficit hyperactivity disorders
(14,17). They have also been used for a variety of other con-
ditions including pain syndromes, insomnia, cataplexy,
migraines, fibromyalgia, chronic fatigue, irritable bowel syn-
drome, and peptic ulcer disease (14,18). Doxepin cream is
used for relief of localized pain and for itching.
Clinical toxicity
Typical side effects seen in patients given therapeutic
doses of TCAs include anticholinergic symptoms, such as
tachycardia, mydriasis, dry mouth, warm flushed dry
skin, delayed gastric emptying, slowed intestinal peristal-
sis or even ileus, urinary retention, and confusion or agi-
tation. Headache, fatigue, anxiety, increased intraocular
pressure, blurred vision, drowsiness, weakness, dizziness,
and restlessness are also common, as are gastrointestinal
complaints including constipation, anorexia, nausea, and
epigastric distress (19). Other adverse effects include
ophthalmoplegia or paralysis of gaze (20,21) and acute
pancreatitis (22).
The cardinal features of severe poisoning include life-
threatening cardiac arrhythmias and conduction disturbances,
Table 2. Current formulations and dosing recommendations for tricyclic antidepressants (309–311)
*†
Amitriptyline HCl tablets (Elavil
‡
, Endep): 10, 25, 50, 75, 100, 150 mg
Adults: 40–100 mg initially and daily maintenance (max 150–300 mg daily)
Adolescents & elderly: 10 mg TID and 20 mg q HS (maximum: 200 mg daily)
Clomipramine HCl capsules (Anafranil): 25, 50, 75 mg
Adults: 25 mg initially to 100 mg maintenance (max 300 mg daily)
Children (10–18 years old): 25 mg initially to 100 mg (or 3mg/kg) maintenance (max 200 mg daily)
Desipramine HCl tablets (Norpramin): 10, 25, 50, 75, 100, 150 mg
Adults: 100–200 mg (max 300 mg daily in hospitalized patients)
Adolescents & elderly: 25–100 mg (max 150 mg daily)
Child (6–12 years old): 1–3 mg/kg/day (max 5 mg/kg/day)
Doxepin HCl capsules (Sinequan): 10, 25, 50, 75, 100, 150 mg; oral concentrate 10 mg (base)/ mL
Adults: 25–75 mg (max 300 mg daily – max single dose: 150 mg)
Child: 1–3 mg/kg/day
Doxepin cream (Prudoxin, Zonalon): 5%; each g = 50 mg doxepin HCl
As directed QID.
Imipramine HCl tablets (Norfranil, Tipramine, Impril, Janimine, Novopramine, Tofranil): 10, 25, 50 mg
Impiramine pamoate capsules (Tofranil-PM): 75, 100, 125, 150 mg
Adults: 75–100 mg daily (max 200 mg daily; 300 mg daily for hospitalized patients only)
Adolescents & elderly: 30–40 mg daily (max 100 mg daily)
Children: >5 yr of age 1.5–2.5 mg/kg/day (max 5 mg/kg/d)
Child (enuresis, in 6–12 years old): 25–50 mg at bedtime
Child (enuresis, in ≥12 year olds) 25–75 mg (max 2.5 mg/kg)
Nortriptyline HCl capsules (Aventyl, Pamelor): 10, 25, 50, 75 mg; oral concentrate 10 mg/5 mL
Adults: 25 mg TID or QID (max 150 mg daily)
Adolescents & elderly: 30–50 mg daily (max 50 mg daily)
Children 6–12 years old: 1–3 mg/kg/day or 10–20 mg/day
Protriptyline HCl tablets (Vivactil): 5, 10 mg
Adults: 15–40 mg daily in divided doses (max 60 mg daily)
Adolescents & elderly: 15 mg daily initially (max 20 mg daily)
Trimipramine maleate capsules (Surmontil): 25, 50, 100 mg
Adults: 75–100 mg in divided doses (max 150 mg outpatients; 200 mg hospitalized patients)
Adolescents & elderly: 50 mg daily (max 100 mg daily)
Tricyclic Antidepressants in Combination
Perphenazine & amitriptyline HCl tablets (Etrafon, Triavil): 2/10, 2/25, 4/10, 4/25, 4 mg/50 mg
Amitriptyline dosing same as above
Chlordiazepoxide & amitriptyline HCl tablets (Limbitrol): 5/12.5, 10 mg/ 25 mg
Amitriptyline dosing same as above
*Manufacturers specify to use their lower maximum doses in outpatient, unmonitored settings.
†
Manufacturers do not recommend most tricyclic antidepressants for use in children.
‡
Elavil is no longer marketed in the U.S.
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Tricyclic antidepressant poisoning 207
abrupt changes in level of consciousness, coma, convul-
sions, hypotension, and sudden death. Pulmonary complica-
tions (e.g., respiratory depression, sudden apnea, aspiration
pneumonia, adult-type respiratory distress syndrome, and
pulmonary edema) can be life threatening. Other signs of
TCA poisoning include palpitations, tachycardia, hyperten-
sion, ileus, tremors, myoclonus, confusion, delirium, and
lethargy.
Definition of terms used in this guideline
Toxicity from TCAs can occur as a result of a single acute
ingestion, which could be unintentional or intentional, or
with repeated or therapeutic use. An acute exposure might
involve unintentional ingestion of a second therapeutic dose in
a patient already on the drug, unintentional ingestion of some-
one else’s therapeutic dose in a patient not taking a TCA, unin-
tentional ingestion by a child, or intentional ingestion.
This guideline focuses on the ingestion of more than a sin-
gle therapeutic dose. It is known that even therapeutic doses
of TCAs can sometimes cause adverse effects in both adults
and children—some idiosyncratic and some dose-dependent.
However, the focus of this guideline is on the effects of TCAs
in overdose. Articles that were reviewed and found to report
adverse effects related to usual therapeutic doses were
included if they provided useful information on the dose-
response relationship.
For the purpose of this guideline, age groups are defined as
1) children less than 6 years of age and 2) older children and
adults. The older age group is much more likely to attempt
self-harm and to conceal the ingestion. Acute exposures are
defined as those occurring over a period of no more than 8
hours, and chronic exposures are those that occur over a
period of more than 8 hours. The terms “out-of-hospital” or
“prehospital” are defined as the period before a patient
reaches a healthcare facility.
Intended users of this guideline
The intended users of this guideline are personnel in U.S.
poison centers. It has been developed for the conditions prev-
alent in the U.S. While the toxicity of tricyclic antidepres-
sants is not expected to vary in a clinically significant manner
in other nations, the out-of-hospital conditions could be much
different. This guideline should not be extrapolated to other
settings unless it has been determined that the conditions
assumed in this guideline are present.
Exclusions
This guideline does not provide guidance on exposures to some
antidepressants such as maprotiline, amoxapine, and loxapine,
which are heterocyclic compounds with somewhat different
adverse effect profiles. Dothiepin, dibenzipine, melipramine,
prothiaden (dosulepin), and other antidepressants not currently
available in the U.S. are not included in this guideline.
This guideline applies to unintentional ingestions or inges-
tions resulting from medication errors. Poisonings resulting
from intentional abuse or self-harm will all require referral to
an emergency department for evaluation. The likelihood of
self-harm is greatest in adolescent and adult patients, who
might also seek to conceal an overdosed. TCAs have been
implicated in cases of Munchausen syndrome by proxy when
parents purposefully overdose their children chronically to
garner attention from healthcare providers (23,24). Likewise,
TCAs have also been administered with homicidal intent or
in instances of child abuse (25,26). If there is suspicion
concerning the circumstances of poisoning, referral to an
emergency department is of paramount importance.
Objective of the guideline
The objective of this guideline is to assist poison center person-
nel in the appropriate prehospital triage and management of
patients with suspected ingestions of tricyclic antidepressants
by 1) describing the manner in which an ingestion of a tricyclic
antidepressant might be managed, 2) identifying the key deci-
sion elements in managing cases of tricyclic antidepressant
ingestion, 3) providing clear and practical recommendations
that reflect the current state of knowledge, and 4) identifying
needs for research. This guideline applies to ingestion of tricy-
clic antidepressants alone. Co-ingestion of additional sub-
stances could require different referral and management
recommendations depending on their combined toxicities.
This guideline is based on the assessment of current scientific
and clinical information. The panel recognizes that specific
patient care decisions may be at variance with this guideline and
are the prerogative of the patient and the health professionals
providing care, considering all the circumstances involved. This
guideline does not substitute for clinical judgment.
Methodology
The methodology used for the preparation of this guideline was
developed after reviewing the key elements of practice guide-
lines (27,28). An expert consensus panel was established to
develop the guideline (Appendix 1). The American Association
of Poison Control Centers (AAPCC), the American Academy of
Clinical Toxicology (AACT), and the American College of
Medical Toxicology (ACMT) appointed members of their orga-
nizations to serve as panel members. To serve on the expert con-
sensus panel, an individual had to have an exceptional record of
accomplishment in clinical care and scientific research in toxi-
cology, board certification as a clinical or medical toxicologist,
significant U.S. poison center experience, and be an opinion
leader with broad esteem. Two specialists in poison information
were included as full panel members to provide the viewpoint of
the end-users of the guideline.
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208 A.D. Woolf et al.
Search strategy
The National Library of Medicine’s MEDLINE database was
searched (1966 to September 2003) using antidepressive agents,
tricyclic as a MeSH term with the subheadings poisoning (po) or
toxicity (to), limited to humans. MEDLINE and PreMEDLINE
(1966 to September 2003) were searched using amitriptyline,
nortriptyline, imipramine, desipramine, protriptyline, clomi-
pramine, and doxepin as textwords (title, abstract, MeSH term,
CAS registry) plus either poison* or overdose* or toxic*, limited
to humans. This process was repeated in International Pharma-
ceutical Abstracts (1970 to September 2003, excluding meeting
abstracts), Science Citation Index (1977 to September 2003),
Database of Abstracts of Reviews of Effects (accessed Septem-
ber 2003), Cochrane Database of Systematic Reviews (accessed
September 2003), and Cochrane Central Register of Controlled
Trials (accessed September 2003).
The bibliography of the tricyclic antidepressant management
in Poisindex (19) was examined and the abstracts of suitable arti-
cles not previously discovered by the search were reviewed. The
bibliographies of recovered articles were reviewed to identify
previously undiscovered articles. In addition, the chapter bibliog-
raphies in six current major pharmacology and toxicology text-
books (14,29–33) were reviewed for additional articles with
original human data. Published abstracts on TCA overdose pre-
sented at the North American Congress of Clinical Toxicology
between the years 1995–2004 were also reviewed.
Criteria used to identify applicable studies
Published studies that provided original information on the epi-
demiology, pharmacology, toxicology, toxic dose, decision-
making, or management of TCA poisoning were included. Ani-
mal studies were not systematically reviewed for the guideline.
Reviews, letters to the editor, commentaries, and published
information that did not contribute original data were excluded.
Article selection
The recovered citations were entered into an EndNote library
and duplicate entries were eliminated. The abstracts of these
articles were reviewed, looking specifically for those that
dealt with 1) estimations of ingested doses with or without
subsequent signs or symptoms, and 2) management tech-
niques that might be suitable for out-of-hospital use (e.g.,
gastrointestinal decontamination). Articles excluded were
those that did not meet either of the preceding criteria, did not
add new data (e.g., reviews with few references, editorials),
or clearly described only inpatient procedures (e.g., hemodi-
alysis) and forensic analyses without exposure details.
Data extraction
All articles retrieved from the original search were reviewed by
a single, trained, physician abstractor. Each article was
assigned a level-of-evidence score from 1 to 6 using the rating
scheme developed by the Centre for Evidence-based Medicine
at Oxford University (Appendix 2). Single case reports were
classified along with case series as level 4. The complete paper
was then reviewed for original human data regarding the toxic
effects of cyclic antidepressants, or original human data
directly relevant to the out-of-hospital management of patients
with cyclic antidepressant-related toxicity or overdose. Rele-
vant data (e.g., dose, resultant effects, time of onset of effects,
therapeutic interventions or decontamination measures given,
efficacy or results of any interventions, and overall patient
outcome) were compiled into a table and a brief summary
description of each article was written. This full evidence table
is available at http://www.aapcc.org/DiscGuidelines/Guide-
lines%20Tables/TCA%20Evidence%20Table.pdf. The com-
pleted table of all abstracted articles was then forwarded to the
guideline primary author and panel members for review and
consideration in developing the guideline. A list of foreign arti-
cles for which English translations were not available and a list
of articles that could not be located were also forwarded to the
guideline primary author for a decision on whether the article
merited translation and inclusion in the guideline. Every
attempt was made to locate such articles and have their crucial
information extracted, translated, and tabulated. Copies of all
of the articles were made available for reading by the panel
members on a secure AAPCC website. In addition to the com-
plete evidence table of all the abstracted articles, several brief
summary tables were generated to highlight the available data
for various relevant subpopulations (e.g., acute pediatric inges-
tions). These summary tables were also forwarded to the
author and guideline panel members. Finally, a written sum-
mary of the available data was also created and distributed by
the abstractor.
Estimation of doses
In many published case reports of childhood poisonings, only a
total dose of the drug and age of the child are given, without the
child’s weight. In order to compare case reports, a dose per kilo-
gram body weight was estimated by using the child’s age, sex,
and the 95
th
percentile weight using standardized growth charts
(34). If the dose and patient age were given but the patient’s sex
was not reported, the 95
th
percentile for boys at that age was
used. Such calculated doses are shown in italics where appropri-
ate throughout the guideline. Table 4 utilizes this method of dose
calculation to compare case report outcomes.
Guideline writing and review
A guideline draft was prepared by the primary author (listed
first). The draft was submitted to the expert consensus panel
for comment. Using a modified Delphi process, comments
from the expert consensus panel members were collected,
copied into a table of comments, and submitted to the pri-
mary author for response. The primary author responded to
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Tricyclic antidepressant poisoning 209
each comment in the table and, when appropriate, the guide-
line draft was modified to incorporate changes suggested by
the panel. The revised guideline draft was again reviewed by
the panel and, if there was no strong objection by any panelist
to any of the changes made by the primary author, the draft
was prepared for the external review process. External review
of the second draft was conducted by distributing it electroni-
cally to AAPCC, AACT, and ACMT members and the sec-
ondary review panel. The secondary review panel consisted
of representatives from the federal government, public health,
emergency services, pediatrics, pharmacy practice, and con-
sumer organizations (Appendix 3). Comments were submitted
via a discussion thread on the AAPCC web site or privately
through email communication to AAPCC staff. All submitted
comments were stripped of any information that would identify
their sources, copied into a table of comments, and reviewed by
the expert consensus panel and the primary author. The primary
author responded to each comment in the table and his
responses and subsequent changes in the guideline were
reviewed and accepted by the panel. Following a meeting of the
panel, the final revision of the guideline was prepared.
Review of the Evidence
Current poison control center practices
Because the toxic doses overlap with the upper therapeutic
range for many of these drugs, some poison control centers
recommend hospital evaluation after any potentially toxic
TCA exposure. One survey of 44 poison centers (30 respon-
dents or 68%) in 1999 reported that 26 of 30 poison centers
(87%) sent all TCA-poisoned children to healthcare facilities
regardless of dose (the other four poison centers varied in
their thresholds: more than 1.5–5 mg/kg) (35). McFee et al.
(36) reported a second survey of 30 poison centers (22
replies, a 73% return rate) the following year. Of 14 poison
centers setting a threshold dose, six referred all children
ingesting more than 5 mg/kg.
To gather additional evidence for this guideline, a request
was sent out in 2004 to all U.S. poison centers for their cur-
rent TCA poisoning triage guidelines. Table 3 presents a
comparison of current practice of the nine poison centers that
provided guidelines (seven other centers indicated that they
did not have guidelines for TCA management). The range of
doses for hospital referral in acute poisoning was from 3 mg/
kg or “one pill” to as much as the TCA therapeutic dose (5
mg/kg). These results give evidence of the need for consensus
building among poison centers nationally for uniformity in
the approach to the triage of prehospital TCA exposures.
Review of textbooks
Several textbooks noted that TCA ingestions greater than
1000 mg in adults are associated with life-threatening toxicity
Table 3. Comparison of poison center guidance: tricyclic antidepressants, May, 2004
Poison center A B C D E F G H I
Stay-home dose
(child)
≤5 mg/kg <5 mg/kg — one pill <3 mg/kg <5 mg/kg — Rx dose (≤6 yr),
double dose (7–64 yr)
<3.5 mg/kg
Protriptyline <1 mg/kg
Follow-up calls 1–2, 6 hr 1–2, 4–6 hr, prn — — 2, 6 hr — — 2, 4, 6 hr 2 hr
AC Yes Yes Yes Yes, remove
pill fragments
Yes Yes Yes Yes Yes
Multi-dose AC — No No Yes Yes — No Yes —
Lavage Yes Yes Yes Yes Yes Yes Yes Yes Yes
Ipecac — No — No — Not preferred No — No
NaHCO
3
bolus — Yes Yes Yes Yes Yes Yes Yes Yes
NaHCO
3
drip — Yes Yes Yes Yes Yes Yes Yes Yes
Target blood pH 7.45–7.50 7.45–7.55 7.45–7.55 7.45–7.55 7.45–7.50 7.45–7.55 <7.55
Symptoms
monitored at home
Minor
drowsiness
No — No
Minor
drowsiness
——
Minor drowsiness,
urinary retention
No
Legend: prn = as needed, AC = activated charcoal, NaHCO
3
= sodium bicarbonate, Rx = therapeutic.
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210 A.D. Woolf et al.
(31–33). Some also defined a dose of 10 mg/kg or more as
causing significant toxicity in children (19,29–32). None
made any distinctions between individual TCA drugs in
terms of potentially toxic doses. Several texts specified 6
hours after the ingestion as the period during which the
onset of symptoms is likely (19,30,31,33). Some recom-
mended 6 hours as the observation period for symptoms
(assuming the patient had received oral decontamination)
before a patient with TCA poisoning could be medically
cleared (32,33).
Toxic dose considerations
A precise toxic threshold dose was difficult to determine
from the literature for several reasons: 1) a paucity of good
quality studies (no articles specifically investigated a toxic
dose threshold, and only a small number of articles con-
tained dose-effect information), 2) questions about the
accuracy of the dose estimate, because the TCA was not
prospectively administered and dose information relied on
historical data from a witness or parent, 3) presence of co-
ingestants (e.g., barbiturates, antipsychotics, ethanol) that
could alter the clinical presentation, 4) interindividual dif-
ferences in weight or TCA pharmacokinetics, and 5) a num-
ber of articles involved many patients (some of whom
remaining asymptomatic) in which doses and/or effects
were only reported as ranges, percentages, or means. The
task was made more difficult by the fact that therapeutic
doses are associated with adverse effects (e.g., sedation,
heart rate and ECG interval changes). Despite these limita-
tions, some dose-toxicity information could be gleaned
from the cumulative evidence.
Minimum acute toxic dose in children less
than 6 years of age
In 1967, Steel et al. (37) published a level 4 review of 31
cases of childhood amitriptyline and imipramine poison-
ing and cited a report of a TCA dose at 8 mg/kg as a
threshold associated with severe toxicity. The lowest dose
associated with a fatality in that series was 32 mg/kg,
whereas one child survived despite ingesting a dose esti-
mated at 112 mg/kg. A 1974 level 4 report of 60 children
hospitalized for a one-time TCA poisoning estimated the
minimum lethal dose of amitriptyline or imipramine to be
30 mg/kg, although the authors included the case of a 2½-
year-old child who died within 4 hours of ingesting 15 mg/
kg. While the authors listed 15 mg/kg as the dose associ-
ated with severe symptoms in their case series, they stated
“…children who ingest tricyclics in whatever dosage
should always be admitted…” (38).
Additionally, there was a level 2b article (39), a level 3b
investigation (40), and a number of level 4 or 6 case series
(41–48) in which the exact TCA ingested was not reported
but in which some dose-effect information was available. The
lowest dose of an unidentified TCA associated with any tox-
icity (described as “minor”—probably drowsiness) in a child
was an ingestion of 0.5 mg/kg (47); the lowest specified dose
associated with severe toxicity was up to three times the daily
dose (43); and the lowest quantified dose associated with
severe toxicity was 15–25 mg/kg (44). A level 6 abstract of a
retrospective case series of 48 children less than 6 years of
age with acute TCA poisoning found that only three of 43
children at TCA doses of 5 mg/kg or less developed any tox-
icity at all (described as “minimal”) and that only one of the
remaining five children (doses 5–9.4 mg/kg) became
“sleepy” (45). Two level 4 reports (both retrospective and
with few cases) investigating a toxic threshold for uninten-
tional childhood TCA ingestion found that, while children
ingesting doses of less than 5 mg/kg sometimes developed
mild toxicity such as drowsiness, none developed severe
poisoning (46,47).
From more than 60 published case reports of pediatric
TCA poisoning reviewed (see Table 4), symptoms were
reported at doses as low as 3 mg/kg. The lowest amitriptyline
ingestion associated with mild toxicity was 50 mg and the
lowest dose associated with death was 15 mg/kg (38). The
lowest dose of desipramine associated with severe toxicity
was 100 mg [6 mg/kg] in a 3-year-old (49). The lowest dose
of imipramine associated with coma was up to 75 mg [3 mg/
kg] by a 5-year-old, and the lowest dose associated with con-
vulsions was an ingestion of up to 100 mg [7.5 mg/kg] by a
15-month-old (50). A single case involved the ingestion of
325 mg [16 mg/kg] nortriptyline by a 4-year-old, which
resulted in severe toxicity (48).
Minimum acute toxic dose in patients 6 years
of age and older
Life-threatening symptoms in adults are often seen with TCA
doses in excess of 1000 mg. However, cardiac arrest has been
noted with imipramine doses as low as 200 mg (51). A 22-
year-old woman suffered a myocardial infarction 26 hours
after ingesting 300 mg amitriptyline and 80 mg diazepam.
However, in that case report there was no laboratory verifica-
tion of the exposure and there was no blood or urine screen-
ing to rule out other substance abuse that might have
contributed to a myocardial infarction (52). Bramble et al.
(53) studied 27 acute TCA-poisoned patients prospectively
(level 2b) and found that imipramine doses of 1000 mg were
associated with life-threatening symptoms or death in two
patients, while a patient who ingested 600 mg clomipramine
suffered only mild toxicity. Three patients in that series who
ingested 500–750 mg amitriptyline suffered moderate to
severe symptoms. Of four patients ingesting 500–1200 mg
trimipramine, the lowest dose associated with moderate tox-
icity was 1000 mg. There were several articles in which the
exact TCA ingested was not reported but in which some
dose-effect information was available. There was a single
level 2b article (39), two level 3b investigations (40,51), and
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Tricyclic antidepressant poisoning 211
Table 4. One-time overdoses of tricyclic antidepressants in children less than 6 years of age
Drug
Dose*
(mg/kg) Age sex
Onset of
symptoms
Duration of
toxicity
Arrhythmia
Cardiac arrest
Coma
Hypotension
Pneumonia
Pulmonary
edema
Respiratory
arrest
Respiratory
depression
Seizure
Fatal Ref.
A 81 15 mo F 45 min – X X X X Yes 228
A
‡
68 24 mo F – – X No 42
A 36 23 mo M – – X X X X X X X No 197
A
‡
31 24 mo F <60 min – X No 229
A
‡
19 17 mo F – – X No 230
A 4 48 mo M 3.5 hr 24 hr N 231
A – 42 mo F <180 min 24 hr X No 232
A – 36 mo M 240 min – X X X No 151
A SR
§
– 60 mo M – – No 233
N
16 48 mo – – No 48
N
– 30 mo M <120 min – X X X X No 232
I 213 24 mo M – – X X X Yes 163
I 188 30 mo M 60 min Several d X X X X No 173
I 155 30 mo M 10 min
–
X X X X Yes 234
I 116 35 mo M 30 min 2–3 d X X X X X X No 235
I 100 20 mo M 40 min – X X X X No 236
I 90 19 mo M <45 min 48 hr X X X No 237
I 86 36 mo M – – X X X X X Yes 238
I 70 ? M 105 min – X X X X No 42
I 68 30 mo M <14 hr – X X X X No 236
I 62 30 mo M 3.5 hr Several d X X X X X No 239
I 61 48 mo F – – No 240
I 57 24 mo F 30 min – X X X X X Yes 241
I 60 30 mo F – 5 d X X X X No 232
I 47 36 mo F – 2 d X X X X No 242
I 47 30 mo – – Yes 243
I 44 18 mo F – – X X X Yes 244
I 40 23 mo M <90 min 2 d X X X X X No 245
I 36 44 mo M – 2–3 d X X X X X No 246
I 50 20 mo M <180 min – X No 232
I 34 22 mo M <120 min 24 hr X X X No 247
I 32 48 mo M 240 min – X X X Yes 150
I 31 30 mo M 30 min Several d X X X X X No 248
I 31 30 mo M 15 min – X X X X X X Yes 249
I 30 18 mo F 75 min – X X X X No 44
I 26 36 mo F <60 min 4 d X X X X X No 221
I 26 20 mo – – X X X No 250
I 25 30 mo M 120 min >13 hr X No 251
I 25 18 mo M 90 min – X X X X Yes 50
I 25 14 mo F – – X X X X X X Yes 196
I 25 11 mo M 30 min – X X X X X Yes 198
I 23 26 mo F 30 min – X X X X X X No 252
I 23 18 mo F 90 min 7 d X X X X X No 253
I 21 21 mo F – – X No 254
I 20 15 mo F – – X X X Yes 62
I 15 30 mo 240 min – X X X X X X 38
I 12 36 mo F – – X X No 42
I 8 30 mo – – X X No 254
I 7.5 15 mo M 120 min – X X X No 50
I 5 19 mo M 75 min 24 hr X No 50
(Continued)
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212 A.D. Woolf et al.
eight level 4 case series (41–44,48,54–56). Among all of these
retrospective investigations, the lowest dose of an unidentified
type of TCA associated with mild toxicity was 200 mg (48), the
lowest semi-quantified dose associated with severe toxicity was
up to three times the daily dose (43), and the lowest quantified
dose associated with severe toxicity was 15–25 mg/kg (44).
Amitriptyline
There were two prospective, randomized, controlled trials
(level 1b) in which a dose of 12.5 mg amitriptyline, given to
healthy adults, was associated with sedation (57,58). In a
level 1b, double-blind study of 12 adults, “auditory vigi-
lance” was impaired within 1½ hours of administration of
6.25 mg amitriptyline and lasted 5 hours (57). There were a
number of articles in which the recognition of the amitrip-
tyline ingestion was retrospective, so there was uncertainty
about the actual amount ingested. Among these were five
level 2b articles (16,53,59–61), a single level 3b article
(62), and five level 4 articles (6,48,63–65). Also, there were
over 50 level 4 or 6 articles in which detailed information
was presented concerning 65 cases (see Table 5). Among
these, the lowest dose of amitriptyline associated with mild
toxicity was 50 mg (38) and the lowest dose associated with
severe toxicity was 300 mg (52).
Clomipramine
There was a single level 2b study (53) and four level 4 case
series or case reports (6,22,48,66) that provided information on
dose-effect relationships for clomipramine. The lowest dose
associated with mild toxicity was 600 mg (53), and the lowest
associated with severe toxicity was 750–1500 mg (22).
Desipramine
There were 10 level 4 articles with individual case informa-
tion on dose-effect relationships for desipramine (54,67–75).
The lowest dose of desipramine associated with severe toxic-
ity was 1000–1200 mg (70).
Doxepin
Some subjects in a self-controlled, level 2b trial of eight adult
volunteers taking doxepin 50 mg after an overnight fast experi-
enced pronounced sedation between 30 minutes and 3 hours
after ingestion (76). There were two level 4 retrospective case
series containing dose-effect information for doxepin (48,65),
and there were eight individual cases reported in seven level 4
articles (71,77–82). Among these, the lowest doxepin dose asso-
ciated with toxicity was in a 23-year-old man who died after tak-
ing nine tablets (tablet strength not reported; total dose could
have been as low as 1.3 mg/kg [90 mg total dose] or as high as
19 mg/kg [1350 mg total dose]) (82). A 24-year-old woman
developed severe toxicity (AV block, hypotension and respira-
tory failure) with eventual recovery after ingesting 425 mg dox-
epin but she had concomitantly taken 2500 mg amitriptyline and
1125 mg desipramine (71). Death was reported after an inges-
tion of up to 1500 mg of doxepin (80). Vohra et al. (65) reported
a 42-year-old woman who became unconscious after ingesting
750 mg doxepin and a 19-year-old who experienced only drows-
iness after ingesting 575 mg doxepin; both survived.
Table 4. (Continued)
Drug
Dose
*
(mg/kg) Age sex
Onset of
symptoms
Duration of
toxicity
Arrhythmia
Cardiac arrest
Coma
Hypotension
Pneumonia
Pulmonary
edema
Respiratory
arrest
Respiratory
depression
Seizure
Fatal Ref.
I
†
3 60 mo M <60 min 48 hr X No 50
I
–
24 mo M 6 hr Several d X X No 50
I
–
24 mo F 180 min 12 hr X X X No 255
I
–
16 mo F ? – X Yes 256
I
–
15 mo M – – X X X No 205
De 171 24 mo F <60 min – X X X X X Yes 257
De 65 19 mo M 90 min 28 hr X X X X X No 214
De 30 19 mo F – – X X X Yes 44
De 6 15 mo – – 49
*Italics indicate estimated dose from the child’s weight at 95
th
percentile for age.
†
Co-ingestant thioridazine.
A = amitriptyline.
A-SR = amitriptyline, sustained release.
‡
Co-ingestant perphenazine.
N
= nortriptyline.
De = desipramine.
§
Co-ingestant orphenadrine.
I = imipramine.
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Tricyclic antidepressant poisoning 213
Table 5.
O
ne-t
i
me over
d
oses o
f
tr
i
cyc
li
c ant
id
epressants
i
n pat
i
ents
6
years o
f
age an
d
o
ld
er
Drug Dose (mg) Age (yr) sex Onset (hr) Duration Survived Ref.
A 10,000 32 F – – Yes 251
A 9000 46 F 1 Several d Yes 258
A 8000 45 M – – Yes 219
A
*
6300 30 F – – No 259
A
*
6000 38 M – 7 d Yes 260
A
†
6000 35 F – – Yes 204
A 6000 29 M 1 – Yes 261
A 5000 30 F – 5 d Yes 260
A 3750 23 M 2.5 – Yes 262
A
*
3750 25 F 3 3 d Yes 263
A 3000 36 M – 2 d Yes 264
A
*
2750 31 F – – Yes 265
A 2500 42 F 2 36 hr Yes 266
A 2500 70 F 3 – Yes 267
A 2200 57 M – 16 mo Yes 268
A
*
2000 26 F – – No 269
A
†
2000 39 F – 4 d Yes 202
A 2000 47 M – 2 d Yes 270
A 1875 23 F – – Yes 86
A 1750 19 F – – Yes 271
A 1500 30 F – – Yes 272
A
*
1500 38 M – – Yes 86
A
*
1300 41 F 1 Several d Yes 273
A
*
1250 – F – – Yes 265
A
†
1250 25 M – – No 274
A
*
1250 56 M – – No 159
A 1200 42 M – – Yes 275
A 1050 14 F – Several d Yes 276
A
*
1050 17 M – – Yes 93
A 1000 24 M 2 24 hr Yes 277
A
*
1000 35 F – – Yes 117
A 1000 61 M 9 – Yes 278
A
†
1000 65 M 2 Several d Yes 279
A 1000 67 M 4.5 48 hr Yes 280
A 950 70 F 4.5 – No 280
A 800 53 F – – Yes 281
A
*
850 67 F 1 3.5 hr No 3
A
*
750 14 M – – Yes 230
A
†
750 44 M 16 Several d Yes 155
A 750 45 F – 13 d No 259
A 525 8 M – – Yes 229
A 500 45 F 3 Yes 262
A 350 33 F – – Yes 117
A
*
300 22 F – 36 hr Yes 52
A
*
200 46 F 1 – Yes 196
A 150 52 F – – Yes 21
A
*
– 13 M – – Yes 230
A
*
– 18 M – – Yes 149
A – 22 F – – Yes 151
A
*
– 22 F – – Yes 151
A – 24 F – – Yes 265
A
*
– 24 F 2 – Yes 152
A – 25 F – – Yes 282
A
*
– 27 F – – No 182
A – 28 F – 4 d Yes 260
A – 28 F 2 – Yes 93
(Continued)
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214 A.D. Woolf et al.
Table 5. (Continued)
Drug Dose (mg) Age (yr) sex Onset (hr) Duration Survived Ref.
A
–
31 F – 3 d Yes 152
A – 33 M – – No 283
A
*
– 34 F – 7 d No 284
A
*
– 35 F – – Yes 149
A
*
– 38 F 1 – No 219
A
*
– 39 F – Several d Yes 190
A
*
– 39 F – Several d Yes 285
A – 44 F – – Yes 286
A – 44 M 12 – Yes 287
A
*†
– 44 M – 50 hr No 92
A
*
– 46 F 2 56 hr No 154
A – 47 F – – No 269
A
*
– 55 F – 8 d Yes 288
A
*
– 56 F 0.25 – Yes 222
A – 16 F – 3 d Yes 226
A – 63 M – 3 d Yes 213
A/I 1000 9 F – 2 wk Yes 289
A/I
*
– 47 F 2 – Yes 222
A/I
*
– 50 F 6 4 hr Yes 290
A/N
*
– 34 F 3 40 hr No 2
C
*
15,000 27 M 5 >4 d Yes 66
C 750 48 F 6 2 weeks Yes 22
De 9000 15 F – – No 73
De 2700 14 F – – Yes 75
De 2500 40 F – – Yes 54
De 2000 24 F 4 – Yes 69
De 1800 22M 7 19 hr Yes 72
De
*
1500 38 F 2 – No 68
De 1500 19 F 4 – Yes 67
De
*
1200 18 F 12 – Yes 70
De 1150 58 F 1.5 Several hr Yes 74
De – 19 F – – Yes 189
De – 31M – – Yes 218
De
*
–27 F – – No2
Do
*
3000 55 M – – Yes 77
Do
*
2500 24 M 1 – No 78
Do 1500 35 F 3 – No 80
Do 1500 54 F 1 24 hr Yes 81
Do
*
600 34 M 4 – Yes 79
Do – 18 F 2 – No 152
Do – 23 M 1 13 hr No 82
Do
*
– 49 F – Yes 291
Do
*
– 53 F – – Yes 117
I
*
10,000 34 F – – No 54
I
*
5375 21 F 3.5 Several d Yes 292
I 5350 23 F 1.5 – Yes 171
I 4700 41M – Several d Yes 293
I 4500 25 F – – Yes 188
I 2500 30 F – – Yes 294
I 2500 14 F 2 – Yes 211
I 2250 19 F 0.66 Several d Yes 295
I 1875 38 F – – No 296
I
*
1500 14 F – – Yes 199
I 1500 29 F 8 3 d Yes 297
I
1250
19 F 0.75 – Yes 209
(Continued)
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Tricyclic antidepressant poisoning 215
Imipramine
There was one level 1b, prospective, randomized trial in which a
single 12.5 mg dose of imipramine given to healthy adults
resulted in sedation and dry mouth (83). There were a number of
articles in which the recognition of imipramine ingestion was
retrospective. There was a single level 2b article (53), a single
level 3b article (51), two level 4 case series (38,84), and 30 cases
in 28 level 4 or 6 case reports, case series, or their abstracts. The
lowest dose of imipramine associated with toxicity was 100 mg
(38); the lowest fatal dose was 200 mg (51).
Table 5. (Continued)
Drug Dose (mg) Age (yr) sex Onset (hr) Duration Survived Ref.
I 1250 24 F – – Yes 136
I
*
1150 38 F 2 – Yes 298
I
†
1000 6 M 4 – Yes 299
I
†
1000 8.5 M – – No 300
I
*
1000 47 F – – No 159
I
†
800 32 M – – Yes 133
I 750 7 M 4 – Yes 300
I 750 36 F – – No 301
I
†
625 28 F 2 – No 302
I 475 7 F – – Yes 303
I – 10 M – – No 210
I – 18 M – – No 54
I – 24 F – – No 304
I – 25 F – – Yes 305
I – 27 F 1.5 – Yes 306
I – 27 F – – Yes 212
I – 28 M 1 – No 209
I – 29 F – – Yes 54
I – 34 F 10 – Yes 307
I – 36 F – – No 137
I – 37 F – – No 137
I
*
– 40 M – – Yes 308
I – 49 F – 5 d No 153
I – 54 F – – Yes 200
N
8000 29 F 0.25 – Yes 90
N
5000 52 F – – Yes 89
N
2350 69 F 2 10 hr No 82
N
2000 30 F – 17 hr No 91
N
*†
1250 21 F – – No 92
N
1250 59 M – – Yes 86
N
950 19 F 0.75 – Yes 87
N
*
600 25 F 4 24 hr Yes 85
N
–16 F – – No88
N
– 34 F – – No 151
P – 28 M – – No 201
T
*
3500 21 F – – Yes 93
T
*
–59 F – – Yes93
Unk
*
– 39 F – – Yes 207
Unk – 45 M – – Yes 208
*Co-ingestant confirmed.
†
Acute-on-chronic poisoning.
A = amitriptyline.
C = clomipramine.
De = desipramine.
Do = doxepin.
I = imipramine.
N
= nortriptyline.
P = protriptyline.
T = trimipramine.
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216 A.D. Woolf et al.
Nortriptyline
There was a single level 1b, prospective, randomized trial in
which single nortriptyline doses of 12.5 mg given to healthy
adults were associated with sedation, impairment in reaction,
and poor performance of complex tasks (57). There were
several articles in which the recognition of nortriptyline inges-
tion was retrospective. There was a single level 2b article (85),
two level 4 case series (63,84), and nine individually reported
cases (82,85–92). Among these, the lowest dose of nortrip-
tyline associated with severe toxicity was 600 mg (85).
Trimipramine
There was a single level 2b study (53), a single level 4 case
series (6), and a single case report (93) of trimipramine
ingestion. Among these, the lowest dose of trimipramine
associated with moderate toxicity was 1000 mg (53) and the
lowest dose resulting in severe toxicity was 1200 mg (6).
Protriptyline
There are few studies of protriptyline toxicity. In one level 1b
adult study, some functions (tapping rate, arithmetic function,
and reaction time) were perturbed with 25 mg doses of ami-
triptyline and nortriptyline, whereas a therapeutic dose of
protriptyline (10 mg) produced no functional disturbances.
Both nortriptyline and protriptyline (secondary amines) were
associated with much less sedation than amitriptyline (ter-
tiary amine) at such doses (57).
Chronic therapeutic TCA dosing in children less
than 6 years of age
Therapeutic doses of TCAs produce severe symptoms of toxicity
in some children. One child in a prospective trial (level 1b) of imi-
pramine developed listlessness and constipation on 50 mg/day
(94). In a level 3b study, children treated with desipramine (mean
dosage 3 mg/kg/day) had increases in the PR intervals on their
ECGs (95). A 3-year-old boy with autism was treated with
amphetamines and imipramine (25 mg three times daily, increased
to 50 mg three times daily after several weeks). One week after the
upward dose revision, he developed tremors, convulsions, and
then hypotonia, which abated after the medications were discon-
tinued (96). Another 3-year-old with autism also developed con-
vulsions 2 days after reinitiating imipramine treatment at 75 mg
daily. He had previously been on the drug at 125 mg daily for an
unspecified period but had had a 15-day hiatus. He continued to
have convulsions throughout his early life, despite discontinuation
of the imipramine and initiation of anticonvulsant treatment (97).
Chronic therapeutic TCA dosing in patients 6 years
of age and older
Therapeutic dosages of TCAs have adverse effects on con-
sciousness, cognitive function, and cardiovascular status. There
was a single level 1b prospective trial in which mean dosages of
3 mg/kg/day of either clomipramine or desipramine were associ-
ated with mean increases in heart rate and prolonged PR, QRS,
and QTc intervals (98). In a prospective, unblinded trial of imi-
pramine’s effects on depression in 44 adults, patients receiving
3.5 mg/kg/day in divided doses (mean 245 mg daily in men and
218 mg daily in women) experienced orthostatic hypotension,
dizziness, ataxia, and falls (99). A meta-analysis by Wilens et al.
(100) (level 1a) aggregated 24 studies involving 730 children
and adolescents given imipramine, desipramine, or amitriptyline
at doses of 0.7–5 mg/kg (mean 3.7 mg/kg) or nortriptyline at
doses of 0.6–2 mg/kg and found only minor effects on ECG con-
duction parameters, heart rate, and blood pressure. However,
therapeutic doses of TCA taken chronically have been associ-
ated with cardiovascular complications and sudden death in
older children and adolescents (100–106).
Amitriptyline
Two level 1b trials (107,108) and several level 2b prospective
trials (65,109–112) examined amitriptyline given prospectively.
Among them, the lowest dosage associated with toxicity was
100–200 mg/day, resulting in increased heart rate and the pro-
longation of ECG intervals (110). There were also eight reports
of chronic amitriptyline toxicity in five level 4 articles (110,114–
117). Among these, the lowest dosage associated with toxicity
was 50 mg/day, resulting in pedal edema and adynamic ileus
(110). A 73-year-old woman was erroneously prescribed 100
mg tablets instead of 10 mg of amitriptyline (200 mg daily
instead of 20 mg daily) and developed hallucinations, dysarthria,
and incoordination, reversed by physostigmine after several days
(117). Therapeutic dosages have been associated with deaths in
adults. A 60-year-old woman was started on amitriptyline for
depression at a dosage of 25 mg three times daily for 2 weeks (in
addition to phenobarbital, chlorpromazine, and other drugs).
When the dosage was increased to 50 mg three times daily, she
developed abdominal distention, paralytic ileus, and cardiovas-
cular collapse and died (113).
Clomipramine
There were two level 2b trials in which clomipramine was
given prospectively and in which toxic effects developed
(118,119). The lowest dosage of clomipramine associated
with toxicity in adults was 150 mg/day (119). In a level 2b
open-label trial of clomipramine given for the treatment of
autism with movement disorders, three of five children aged
7–12 years on dosages of 3.9–9.8 mg/kg/day developed agita-
tion and aggression requiring hospitalization. Symptoms
abated upon discontinuation of the drug. The authors recom-
mended that children should not receive doses of clomi-
pramine greater than 3–5 mg/kg/day (118).
Desipramine
There were several articles identified in which
desipramine was given prospectively, resulting in toxic
effects. In a level 1b prospective trial, dosages of 100–200
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Tricyclic antidepressant poisoning 217
mg/day were associated with a mean increase in heart rate
and various ECG intervals (108). Rapoport et al. (120)
described a prospective study of 20 boys with enuresis
given 75 mg desipramine nightly for 24 days who reported
higher rates of dry mouth and daytime drowsiness than
placebo-treated controls. Schroeder et al. (121) studied 20
children taking desipramine titrated to a maximum daily
dose of 5 mg/kg (average dose 4.25 mg/kg) for eating dis-
orders, ADD, or affective disorders and found an 18%
increase in heart rate and 9% increase in QTc interval on
ECG at 8 weeks into the study, neither of which was clini-
cally significant. However, seven of 20 children did not
reach the maximum dosage.
There were also two level 4 retrospective case series
(122,123) and several case reports. Wagner and Fershtman
(124) described a 12-year-old boy diagnosed with depression
taking desipramine (2.5 mg/kg/day) who developed symp-
tomatic QTc prolongation (9.7% increase over his baseline)
during 2 months of therapy. Varley and McClellan (105)
reported the sudden deaths of two children—a 9-year-old 5
weeks after starting desipramine (3.3 mg/kg/day) for depres-
sion and a 7-year-old taking a combination of imipramine
(6 mg/kg/day) and thioridazine (1 mg/kg/day) chronically
for a conduct disorder. A 2001 report by Varley (125) identi-
fied eight cases of sudden death during TCA use in children,
including six deaths related to desipramine. A level 4 case
series of three deaths involved children 8 (two cases) and 9
years of age taking desipramine (50 mg daily for one and
unknown dosages for the other two) for periods ranging from
4–6 weeks to 2 years as therapy for attention deficit hyperac-
tivity disorder (ADHD, two cases) or depression. Serum des-
piramine concentrations were only 10 μg/L (two cases) and
85 μg/L (123). A fourth case reported later was a 12-year-old
girl with ADHD. Her dosage of desipramine was raised from
125 mg daily taken during the preceding 6 months to 150 mg
daily in divided doses; she was found unconscious a few days
after the dosage change and died (126).
Doxepin
There were two level 2b prospective trials in which toxic
effects developed when doxepin was given (111,112).
Between them, dosages as low as 150 mg/day were associ-
ated with a higher mean heart rate, and dosages of 200 mg/
day were associated with ST-T changes on ECG. There was
also a level 4 case series in which one patient developed
convulsions while taking 250 mg/day of doxepin (122).
Imipramine
There were nine articles in which toxicity developed when imi-
pramine was given prospectively. Three of these were level 1b
(120,127,128) and six were level 2b (99,109,112,129–131).
Among these prospective trials, the lowest dosages of imi-
pramine associated with toxicity were 50–200 mg/day, which
were associated with agitation, flushes, and insomnia (129). In
one prospective study of 22 children aged 5–17 years, imi-
pramine titrated to a maximum dosage of 5 mg/kg/day in
divided doses produced increases in the QRS complex duration
on ECG in 19 children and a 10% drop in standing systolic
blood pressure in three (130). Rapoport et al. (120), in a pro-
spective, placebo-controlled study of 20 boys ages 7–12 years
old with enuresis treated with 75 mg imipramine nightly for 24
days, reported increased rates of daytime drowsiness, head-
ache, and dry mouth with imipramine.
There was also one level 3b study (95) and two level 4 retro-
spective case series (122,132) along with 16 individual cases of
chronic imipramine toxicity in nine level 4 articles
(96,105,110,133–138). Bartels et al. (95) reviewed the ECGs of
39 children and adolescents before and after starting imipramine
or desipramine therapy (mean maintenance dosages of imi-
pramine and desipramine were 3 and 2.9 mg/kg/day, respec-
tively) and found increases in the PR intervals of 11 patients and
new first-degree AV block in two patients. In another report, two
children, aged 6 and 8 years with hyperactivity, developed new-
onset convulsions after taking imipramine (75 mg three times
daily) for weeks to months (96). The lowest dosage associated
with toxicity in an adult was 75 mg/day, resulting in syncope,
bradycardia, and asystole after 5 days of therapy in a 37-year-old
man. However, he was on other medications and had a history of
glomerulonephritis, hypertension (treated with guanethidine and
methyldopa), and congestive heart failure (138).
Nortriptyline
There were five articles in which nortriptyline was given
chronically and in which toxic effects developed. Four of
these were level 2b (65,112,139,140) and one was a letter
to the editor describing an unpublished study in which
dosages of 50–150 mg/day were associated with cardiac
conduction defects (141). Two level 4 case reports
described chronic nortriptyline toxicity after 2–5 doses of
200 mg/day (142).
Trimipramine
There were two articles in which toxic effects developed
when trimipramine was given chronically. One of these was a
level 1b quality randomized trial (94) and the other was a
level 2b trial (109). Dosages of 50 mg/day were associated
with minor adverse effects including nausea, vomiting,
drowsiness, and rash (94).
ECG diagnosis
Analyses of ECG changes early in TCA poisoning have
been undertaken in order to attempt to predict the risk of
life-threatening cardiovascular or neurological complications.
In a 5-year retrospective study (level 2b) of 225 TCA over-
doses admitted to an intensive care unit, Hulten and Heath
(143) found that patients with QRS durations longer than 100
msec were more likely to develop respiratory depression,
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218 A.D. Woolf et al.
convulsions, and death. Boehnert and Lovejoy (144) carried
out a level 2b prospective observation study of 49 patients
with acute TCA poisoning presenting within 16 hours of their
overdoses. The 36 patients whose QRS durations exceeded
100 msec had a higher risk of developing convulsions or
arrhythmias. Niemann et al. (145) studied 11 patients with
confirmed TCA poisoning (level 2b) and found that the ter-
minal 40 msec vector on the ECG was the best predictor of
toxicity, although both QRS duration and QTc duration were
also abnormal. Wolfe et al. (146) reviewed (level 2b) the
records of patients with TCA (N = 48) versus other poisoning
(N = 30) and found that a terminal 40 msec axis of 120–270
degrees on the ECG had the highest sensitivity (83%) and
specificity (63%) in predicting TCA toxicity. Liebelt et al.
(147), in a prospective cohort study (level 2b) of 79 TCA
overdoses reported to one poison center, found that an R-
wave greater than 3 mm in lead aVR of the ECG was predic-
tive of both convulsions and dysrhythmias with better sensi-
tivity (81%) and specificity (73%) than either the serum TCA
concentration or QRS duration. A recent systematic review
(level 2a) included 18 studies of the predictors of clinical
severity (arrhythmias, convulsions, or death) in TCA poison-
ing. QRS duration and blood concentration had only fair sen-
sitivity (0.69 and 0.75) and specificity (0.69 and 0.72) in
predicting convulsions and similar sensitivity (0.79 and 0.78)
and worse specificity (0.46 and 0.57) in predicting arrhyth-
mias (148). The panel determined that ECG results are avail-
able from EMS personnel to some poison centers and chose
to consider this parameter for the recommendations offered in
this guideline.
Onset of effects and duration of monitoring
Panel members expressed interest in taking into account the
time for toxicity to develop after TCA exposures, in order to
help make decisions about prehospital transportation and man-
agement. All articles were searched for evidence documenting
or estimating a time of onset. Unfortunately, the vast majority
reported times of presentation to healthcare facilities but not
times of symptom onset, which might have occurred earlier.
Thus, in most cases, it was only possible to establish an upper
limit of time to onset. Care had to be taken when evaluating
these articles not to confuse onset of any adverse effects with
onset of serious or major effects, time to peak effects, or the
occurrence of delayed effects or deterioration. Decontamina-
tion measures might have affected times of onset of symptoms.
It was often not clear whether, or what, symptoms were present
before the late-occurring events emphasized in the reports.
There were few data to distinguish time of onset by patient age
or by individual TCA.
Delayed clinical deterioration
Many patients who developed clinical effects of TCA poison-
ing went on to develop more serious effects later. Those who
did experience significant deterioration tended to do so quite
rapidly, indeed catastrophically in some cases. For example,
Ellison et al. (54) reviewed the charts of 30 patients who
experienced convulsions after TCA overdose (level 4). Con-
vulsions started within 1½ hours of admission in 28 of 30,
23% had been fully alert just prior to the convulsion, and
10% died. Patients in other reports deteriorated progressively
over the course of hours to days after the ingestion
(50,66,68,85,92,149–152). There were also several level 4
reports of delayed toxicity (especially conduction defects or
dysrhythmias) or even death after a period of relative
improvement or stabilization (2,52,66,92,153–155). It is
unclear whether the delayed effects represented recurrence of
direct TCA toxicity (e.g., due to ongoing absorption, inade-
quate decontamination, mobilization of tissue stores) or sec-
ondary complications of hospitalization or treatments (e.g.,
aspiration of gastric contents, adult-type respiratory distress
syndrome), other co-ingestants or co-medications (e.g., ace-
taminophen toxicity, alcohol withdrawal), or a different
pathophysiologic process (e.g., serotonin syndrome, intesti-
nal obstruction, neuropathy due to TCA effects). In some
cases, this deterioration occurred days after the ingestion;
however, in all cases, significant initial toxicity had been pre-
viously documented.
Time of onset
In most cases, the time of effect onset, when noted, appeared
to be within 2 hours after the TCA ingestion. However, in
some, effects did not appear for several hours. Effects were
reported up to 5 hours after amitriptyline or nortriptyline
ingestion in one level 1b therapeutic trial (57).
A 7-year, level 2b review of 88 TCA poisoned patients
found that none developed hemodynamic complications after
12 hours following ingestion (56). A level 4 retrospective
case series of 60 childhood poisonings involving amitrip-
tyline and imipramine reported that symptoms usually devel-
oped within 4 hours of ingestion (38). The longest
documented time to onset of toxicity was 6 hours after an
ingestion of imipramine by a young child (50). In one report
(level 4), a 4-year-old boy with enuresis drank 90 mL imi-
pramine syrup (32 mg/kg), was given a salt-water mixture by
his mother, vomited, “went to sleep,” and 4 hours later devel-
oped convulsions and then ventricular tachycardia and fibril-
lation (150). A 44-year-old man taking 75 mg amitriptyline
daily for months to treat depression ingested 750 mg and pre-
sented to an emergency department 16 hours later with only
drowsiness as a symptom of toxicity (155).
A description of 111 TCA overdose-related deaths (level
4) reported to a coroner’s office reported that most patients
developed major signs within 3 hours of hospital presenta-
tion. Two patients had cardiac arrests more than 3 hours after
presentation; however, the presenting signs and at what time
they arrested were not detailed in the article (3). In a level 2b
review of 102 adults admitted with TCA overdose, the first
manifestation of convulsions and ventricular dysrhythmias
occurred within 6 hours of admission in all patients (156). In
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Tricyclic antidepressant poisoning 219
another level 2b prospective observational series of 49
patients, all convulsions and dysrhythmias occurred within 6
hours of ingestion (144). In a level 2b prospective observa-
tional series of nine adults with severe amitriptyline poison-
ing, the onset of all convulsions, dysrhythmias, and
hypotension occurred within 4 hours of admission (157).
Duration of symptoms
In a level 4 prospective case series of 24 adults admitted with
TCA overdose, two patients developed transient supraven-
tricular tachycardia 2–4 days after ingestion (92). In a retro-
spective review of 316 patients admitted with TCA overdose
(level 4), hypotension and convulsions more than 24 hours
after ingestion were unusual but occurred in two patients and
one patient, respectively (158). In a level 3b observational
series of 40 patients with TCA overdoses, all major effects
occurred within 24 hours of ingestion (40). Similarly, in a
level 2b study of 72 patients admitted with TCA overdose, all
clinical effects, with the exception of aspiration symptoms,
developed within 24 hours of ingestion (83). In a level 4 case
series of 62 adults admitted with TCA overdose, none devel-
oped a new dysrhythmia after 24 hours (159). In a level 3b
report of 40 patients admitted with TCA overdose, maximal
clinical effects and TCA concentrations developed within 24
hours in all patients except one who was on a corticosteroid
for a neurological disorder at the time (160). In a description
(level 4) of 45 patients hospitalized for TCA overdose (60%
of whom presented within 6 hours of the ingestion) no com-
plications occurred after 24 hours. Of note, one patient pre-
sented without any major signs or symptoms but within 6
hours of presentation was comatose (161).
A report (level 4) of 24 adults with convulsions after TCA
overdose found that the onset of convulsions occurred within
18 hours in all patients (6). In a level 4 retrospective review
of 30 patients admitted with convulsions after TCA overdose,
the onset of convulsions ranged from 0.5 to 9.3 hours. Many
of these patients had decreased levels of consciousness prior
to convulsion onset but 23% were awake at the time. Whether
other effects were present in these patients—clinically or
electrocardiographically—is not clear (54). In a level 2b
review of 72 adults admitted to an ICU with TCA overdose,
only one patient developed a new ECG abnormality after
admission (162). A larger level 4 retrospective review of 295
patients admitted to one ICU with TCA overdose found that
multiple patients developed convulsions, circulatory impair-
ment, or ECG abnormalities after admission (48). In a 3-year,
level 2b retrospective review of 75 hospitalized patients with
TCA overdoses, Goldberg et al. (83) found that none of those
who had not aspirated developed any serious new toxicity
more than 24 hours after ingestion. In a level 4 retrospective
review of 38 patients hospitalized for TCA overdoses, all
ECG changes normalized within 24 hours. The authors sug-
gested that patients fully recovered from TCA-related ECG
changes need be monitored only for 12 hours (163).
Emerman et al. (164) performed a 10-year, hospital-based,
level 2b review of the records of 92 adults with TCA over-
dose and found that their initial level of consciousness (Glas-
cow Coma Scale <8: 86% sensitivity, 89% specificity) best
predicted the 37 patients (40%) who developed serious com-
plications—73% developed complications within 30 minutes
of presentation to the emergency department and none devel-
oped new complications more than 2 hours after arrival at the
hospital. In a prospective study of 67 patients, Foulke (165)
concluded that high-risk features predicting late complica-
tions included QRS duration, the presence of arrhythmias or
conduction delays on ECG, altered mental status, convul-
sions, respiratory depression, or hypotension.
Duration of monitoring of asymptomatic patients
The duration of monitoring recommended varies for treated
patients with TCA poisoning. Foulke et al. (156) reviewed
165 TCA overdoses (level 2b) and found that patients with-
out major evidence of toxicity in the emergency department
did not develop serious complications later. Pentel and Sioris
(166), in a level 4 review of 129 adults with TCA overdoses,
found that all who developed neurological or cardiovascular
complications did so within 1 hour of their admission. In their
survey of 30 poison centers, McFee et al. (35) found that all
recommended a monitoring period at least 6 hours; one rec-
ommended 6–12 hours and two recommended 24 hours. In a
review of TCA poisoning, Callaham (167) suggested that
asymptomatic, decontaminated patients should be monitored
for at least 6 hours (but this would be 6 hours after presenta-
tion to a healthcare facility, not 6 hours after the ingestion).
Later, Callaham and Kassel (3) studied 111 TCA-associated
deaths and concluded that 6 hours is an adequate time to
monitor decontaminated patients for the development of
major signs of toxicity. Others have also recommended a 6-
hour observational period for symptoms after decontamina-
tion measures have been taken (161). Banahan and Schelkun
(168) reviewed 33 cases of TCA overdose (level 4) and con-
cluded that a 6-hour observational period can avert the cost of
unnecessary hospitalization.
Underlying medical conditions/special populations
Patients with underlying heart disease or cardiac arrhyth-
mias or conduction disturbances could be especially sensi-
tive to the toxic effects of TCAs (169). Those with
underlying seizure disorders and taking TCAs could experi-
ence a lowering of the seizure threshold (170). TCAs can
interact with many different medications, including other
psychopharmaceuticals such as MAO inhibitors. It is rea-
sonable to assume that patients taking other drugs (e.g., car-
dioactive agents like digitalis, calcium channel blockers, or
ß-blockers) who overdose on TCAs might have increased
risks of toxicity such that they require immediate triage to a
healthcare facility for monitoring.
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220 A.D. Woolf et al.
Prehospital management of TCA Poisoning
There were few level 1, 2, or 3 articles specifically addressing
out-of-hospital management of TCA exposures (although
many articles contained some limited out-of-hospital infor-
mation). It was felt that some in-hospital data could be uti-
lized to develop out-of-hospital guidelines. Therefore, both
in- and out-of-hospital data are included in this review of the
evidence. While physostigmine, phenytoin, and ß-blockers
have been used to treat TCA poisoned patients in the past,
these agents are not used routinely in the current management
of TCA poisoned patients (19). Moreover, the panel deter-
mined that some hospital-based therapies such as glucagon
and hyperventilation would not be included in this guideline.
Gastrointestinal decontamination
Only decontamination measures that could reasonably be
expected to be available and carried out in a prehospital set-
ting and which had a significant amount of data are reviewed
here.
Ipecac-induced emesis
There were no controlled trials of the use of ipecac syrup for
TCA overdose and no prospective volunteer studies examin-
ing the efficacy of ipecac in reducing TCA absorption even
after therapeutic doses. There were multiple case reports in
which ipecac syrup was administered after suspected TCA
overdoses (68,161,166,171–174). In some of these, tablets or
tablet fragments were recovered (68,166). However, most did
not test the recovered fragments to confirm their identity, nor
did they quantify how much of the ingested dose was recov-
ered. These limitations, coupled with the rare reports of
adverse events as a result of ipecac syrup administration,
make the value of these individual reports questionable.
Activated charcoal
Tricyclic antidepressants are adsorbed by activated charcoal.
Crome et al. (175) demonstrated that 1 g of activated charcoal
adsorbed 318 mg nortriptyline in an in vitro model. Activated
charcoal might be effective in decreasing the absorption of
TCA if given early enough after ingestion.
Investigations of activated charcoal’s effectiveness in stud-
ies performed using TCA poisoned patients have yielded
mixed results. There were several level 2–3 articles in which
activated charcoal was used in an uncontrolled fashion but in
which its efficacy was not reported. In addition, there were
numerous level 4 case reports or series in which single or
multiple doses of activated charcoal were given to individuals
with TCA overdoses, but it was impossible to determine the
efficacy of activated charcoal from these reports given the
lack of controls, the concurrent use of other therapies, the fact
that activated charcoal does not produce immediate clinical
improvement (i.e., outcome is generally measured by
improved pharmacokinetic parameters or the prevention of
later clinical sequelae), and that the interval between the time
of TCA ingestion and administration of charcoal is often
unknown. For many studies of TCA poisoned patients given
activated charcoal in emergency departments, the delay in its
administration for many hours beyond the time of TCA
ingestion might account for an observed lack of effectiveness.
A level 1b, randomized, controlled trial investigated three
decontamination methods in 51 adults with acute unspecified
TCA overdose. There were no significant differences in any
of the outcome measures (clinical and laboratory) between
patients receiving activated charcoal 50 g with magnesium
citrate (group 1), patients receiving gastric lavage followed
by activated charcoal 25 g with magnesium citrate (group 2),
or those receiving activated charcoal 25 g followed by gastric
lavage followed again by activated charcoal (group 3). How-
ever, there were no untreated controls so the effectiveness of
charcoal could not be established (176).
A level 1b, prospective randomized trial in 77 patients
admitted with acute TCA overdose compared the efficacy of
gastric lavage alone vs. gastric lavage plus activated charcoal
20 g. Patients randomized to the activated charcoal group had
no significant differences in peak TCA serum concentration,
drug half-life, or AUC when compared to the gastric lavage-
only patients. Slightly fewer patients in the activated charcoal
group developed convulsions, hypotension, or dysrhythmias
or required prolonged intubation, ICU care, or hospitalization,
but these trends did not reach statistical significance (177).
A level 2b study of 48 children less than 6 years of age
who had been reported to one poison center after acute TCA
exposure found that there was no difference in clinical out-
come between those who had received activated charcoal and
those who had not. However, there were no cases of signifi-
cant toxicity in any of the patients, and some patients had also
received gastric lavage and/or a cathartic (46).
Hedges et al. (178), in a level 2b, prospective study of nine
adults with acute TCA poisoning, detected a correlation
between the time to activated charcoal administration (along
with gastric lavage and supportive care) and reduced serum
half-life of the TCA and an inverse correlation between the
dose of activated charcoal given and drug half-life. In a level
1b study, Crome et al. (179) randomized 48 patients with sus-
pected acute TCA overdose to receive either supportive care
alone or supportive care plus activated charcoal 10 g and
detected no differences in clinical outcome or the rate of fall
of serum concentrations.
In addition to the above studies, there were several articles
that looked at the effect of activated charcoal on TCA absorp-
tion in volunteers given relatively low doses of various anti-
depressants. In a level 1b study, a single 5-g dose of activated
charcoal given 30 minutes after a 75-mg dose of nortriptyline
reduced its mean peak serum concentration by 60% in 12
healthy adult volunteers (175). A level 2b, prospective, cross-
over trial in six adult volunteers who ingested 75 mg nortrip-
tyline compared the efficacy of single- and multiple-dose
activated charcoal in reducing nortriptyline absorption (180).
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Tricyclic antidepressant poisoning 221
Subjects given activated charcoal (amount not reported) at 30
minutes had a 58% mean reduction in peak nortriptyline
serum concentrations and a 55% mean reduction in overall
bioavailability. A similar level 1b, prospective, crossover
trial in six adult volunteers compared the efficacy of activated
charcoal when administered at various times after 75 mg
doses of nortriptyline. Activated charcoal 10 g given at 30
minutes after ingestion resulted in a 77% reduction in mean
peak nortriptyline serum concentration and a 74% reduction
in overall bioavailability; the same dose given at 2 hours
resulted in 37% and 38% reductions, respectively; and, when
given at 4 hours, resulted in reductions of 19% and 13%
(181).
A level 1b, prospective, multi-phase, crossover trial in six
volunteers looked at the effects of various interventions on
amitriptyline pharmacokinetics compared to an untreated
control phase after the ingestion of single doses of 75 mg
amitriptyline. Single doses of 50 g activated charcoal given 5
minutes after amitriptyline prevented the drug’s absorption
(as measured by peak serum concentration, AUC, urinary
excretion, and drug half-life) by 99%. Multiple doses of acti-
vated charcoal beginning at 6 hours after ingestion were
much less effective but still reduced amitriptyline’s peak
serum concentration, half-life, AUC, and urinary excretion
(58). A self-controlled, level 2b trial of doxepin 50 mg given
to eight adult volunteers followed either by a single 15-g dose
of activated charcoal 30 minutes later or multiple doses of
activated charcoal over 24 hours (given at 3, 6, 9, 12, and 24
hours after ingestion) found reduced doxepin AUC after both
interventions compared to controls, but only multiple doses
improved the clearance of doxepin (76). An expert panel con-
vened by the American Academy of Clinical Toxicology and
the European Association of Poison Control Centres & Toxi-
cologists recommended that single-dose charcoal be consid-
ered if a patient has ingested a potentially toxic amount of a
poison up to 1 hour previously, noting that there are insuffi-
cient data to support or exclude its use after 1 hour (182).
Although the prehospital administration of activated char-
coal by emergency medical service personnel has been pro-
posed (183–185), there are no studies of its safety or utility
specifically in TCA poisoning. There are important concerns
about the potential for complications when using activated
charcoal in this context. Instillation of activated charcoal
through an orogastric or nasogastric tube in a comatose
patient can be a source of iatrogenic injury. Godambe et al.
(186) described the case of a 13-year-old girl who, after laps-
ing into coma following a multi-drug overdose including
amitriptyline, had pleuropulmonary activated charcoal instil-
lation from a nasogastric tube, which entered the left main-
stem bronchus and then extended into the parenchyma and
through the visceral pleura. TCA poisoned patients have
aspirated activated charcoal, resulting in severe complications
or death (88). Roy et al. (187) studied 82 consecutive TCA
poisoned patients admitted to an intensive care unit and
found evidence of aspirated activated charcoal in the airways
of 18 of 72 (25%) patients who required intubation, although
their survival rate did not differ from that of those who had
not aspirated (level 4). The authors did not state how many
patients, if any, had received charcoal prior to arrival at the
emergency department.
There are also case reports (level 4) of patients suffering
ileus, toxic megacolon, bowel obstruction, or intestinal
ischemia after TCA poisoning (188,189). In such patients,
administration of any oral medication, including charcoal,
would be contraindicated. Gomez et al. (190) reported a 39-
year-old woman who developed an activated charcoal ster-
colith and intestinal perforation requiring surgery during
treatment of an amitriptyline poisoning. A 21-year-old man
presented with coma and convulsions related to amitriptyline
poisoning, received multiple doses of activated charcoal
(with atropine, lidocaine, defibrillation, gastric lavage, and
other therapies), and developed intestinal obstruction from
inspissated activated charcoal requiring surgery (191).
Other treatment measures
There are many different prehospital treatment measures for
TCA overdose reported in the literature including intubation,
intravenous fluids, and typical supportive measures such as
oxygen, atropine, glucose, naloxone, antiarrhythmics, CPR,
defibrillation or cardioversion, and military anti-shock trou-
sers. Anticonvulsants (e.g., diazepam) could be indicated for
patients who have sustained convulsions or are exhibiting
physical signs of an impending convulsion such as hyperre-
flexia, change in consciousness, tremors, and myoclonus.
None of these have controlled prehospital studies specific to
TCA overdoses. Since they are already routinely used in the
prehospital setting, the anecdotal data are not presented here.
Sodium bicarbonate
There is considerable evidence in both animal and human
studies that alkalinization of the blood can be beneficial in
the management of TCA poisoning. In a rat model, sodium
bicarbonate increased the survival rate of animals poisoned
experimentally with amitriptyline and its benefit was additive
to that of an inotropic agent such as epinephrine or norepi-
nephrine (192). An expert panel convened to consider ACLS
measures after TCA poisoning recommended alkalinization
with hypertonic solutions of sodium bicarbonate (193).
In a 1976 level 4 case series, 11 of 12 children with TCA-
induced arrhthymias responded to intravenous sodium bicar-
bonate with conversions to normal cardiac rhythm (194). In a
level 2b review of 184 patients admitted to an ICU after ami-
triptyline overdose, four of eight patients treated with bicar-
bonate had improvements in cardiac conduction (60). A level
2b, retrospective cohort analysis compared the outcomes of
91 patients with TCA overdose who received bicarbonate
with those of 24 patients who did not. While there was no
direct statistical comparison between treated and untreated
groups, hospital stay was shorter for the treated group. Fur-
thermore, within the bicarbonate group, 20 of 21 patients
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222 A.D. Woolf et al.
with hypotension had improvements in blood pressure, 39 of
49 patients with QRS prolongations had narrowing of their
QRSs, 40 of 85 patients with altered mental status had
improvements in consciousness, and 42 of 43 patients had
improvements in acidosis. There were no complications from
bicarbonate (195). Urinary acidification with ammonium
chloride or urinary alkalinization with bicarbonate, beginning
1 hour after the ingestion of 75 mg amitriptyline, resulted in a
cumulative excretion of less than 5% of the ingested dose
over 72 hours (58).
There are numerous cases or case series (level 4) in which
patients with TCA overdoses apparently responded favorably
to sodium bicarbonate (improved vital signs, cessation of
dysrhythmias or convulsions, reduction in acidosis, and/or
improved cardiac conduction) in a temporally consistent
manner (22,23,54,89,90,96,149,152,154,158,171,196–214).
In other cases, bicarbonate was given either without improve-
ment or with an unreported response (3,43,82,92,154,173,
174,197,209,212,213,215–223). There were also cases in
which bicarbonate might have resulted in or contributed to
adverse effects (e.g., pulmonary edema or excessive alkale-
mia) (75,82,202). Other reports used other forms of alkaliniz-
ing therapy (e.g., sodium lactate) or unspecified
alkalinization procedures. In some cases these were benefi-
cial but not in others (6,41,44,224).
Intravenous fluids
Intravenous fluids, lidocaine, and respiratory support were all
found to be helpful in stabilizing blood pressure and the car-
diopulmonary status of TCA-poisoned patients in retrospec-
tive level 4 case series (44,225).
Flumazenil
The administration of flumazenil to comatose patients with
unknown poisonings, as both a diagnostic and therapeutic
measure, has occasionally resulted in the unmasking of
convulsions in TCA-poisoned patients who had co-ingested
benzodiazepines (226).
Limitations of the published data
Overall, the level 4 data were difficult to interpret and sum-
marize. The case reports and case series varied widely in the
extent of clinical detail presented, and the cases varied widely
in the severity and clinical effects of poisoning; the timing,
combination, dose, and routes of various treatments used; and
in a number of other patient- or circumstance-specific factors.
Data on the amount ingested were often inaccurate or
incomplete. The history is often obtained from an intoxicated
patient or an emotionally stressed or elderly caregiver. Parents
might underestimate or overestimate an ingested dose because
of denial or anxiety. Poison center personnel often use the
worst-case scenario to estimate an ingested dose in order to
provide a wide margin of safety. In most case reports and case
series, the history of exposure was not independently verified
or confirmed by laboratory testing. Poor correlation between
reported estimated doses and subsequent concentrations or tox-
icity has been documented for children with unintentional
ingestions of other drugs. In most of the cases reviewed, the
exact time of ingestion was not reported or was not known, and
the time of onset of toxicity could only be estimated as occur-
ring within a range of hours after the suspected ingestion.
Conclusions
The expert consensus panel chose to emphasize the impor-
tance of information that would be needed in order to make a
sound triage decision for a patient with tricyclic antidepres-
sant ingestion. These variables include the patient’s intent,
the time of the ingestion, the patient’s symptoms, any under-
lying medical conditions, the dose of the specific product
ingested, and any co-ingested drugs. The expert consensus
panel agreed that in each case, the judgment of the specialist
in poison information or the poison center medical director or
other poison center clinicians might override any specific rec-
ommendation from this guideline.
Patient intent
The expert consensus panel concluded that all patients with
suicidal intention or in whom a malicious intent is suspected
(e.g., child abuse or neglect) should be transported expedi-
tiously by EMS to an emergency department. Patients with-
out these characteristics are candidates for consideration of
prehospital management of their TCA ingestion.
Time since ingestion
The expert consensus panel concluded that decisions about
referral to an emergency department should be based on the
clinical status of the patient within the first 6 hours after TCA
ingestion. The panel concluded that an asymptomatic patient
who unintentionally ingested a TCA is unlikely to develop
symptoms if the interval between the ingestion and the call is
greater than 6 hours. Patients with unintentional TCA poison-
ing who are more than 6 hours after ingestion at the time of
the first contact with a poison center and are still asymptom-
atic can be safely monitored at home.
Patient’s symptoms or underlying medical conditions
The expert consensus panel concluded that referral to an
emergency department should be considered for any patient
who is experiencing symptoms that might be reasonably
related to the TCA (e.g., dizziness, syncope, convulsions,
chest pain, generalized weakness, shortness of breath), who
has severe underlying neurological (e.g., epilepsy) or cardio-
vascular disease (e.g., end-stage cardiomyopathy), or who is
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Tricyclic antidepressant poisoning 223
on multiple psychopharmaceutical or cardiovascular medi-
cines that could have additive neurological or cardiodepres-
sant effects with the TCA. The importance of each of these
variables can be difficult to judge in a telephone conversation
so a low threshold for emergency department evaluation is
considered prudent. Symptomatic patients should be trans-
ported by EMS.
Dose of the drug
The panel concluded that a specific toxic dose of TCA to trigger
referral to an emergency department has limited support of evi-
dence in medical toxicology textbooks, TESS fatality informa-
tion, or the medical literature. The panel recognized the risk of
serious complications after TCA poisoning at relatively low
doses in both children and adults. The panel noted that it is
widely believed among poison centers that older children and
adults are much more likely to have suicidal or homicidal intent.
It concluded that the severity of poisoning that occurred second-
ary to self-harm, intentional misuse, Munchausen-by-proxy,
child abuse, or other malicious intent appeared to result in more
severe outcomes (e.g., fatalities) compared to unintentional
ingestion. This is likely to be a consequence of larger dose and
delayed time to treatment. There is no evidence that age alone
influences the outcome.
The estimation of dose is based largely on the patient’s his-
tory and the type of product and its packaging (when avail-
able for evaluation). If precise data for the ingestion are
unknown or unclear (package size, unit size, number of units
ingested), poison centers in the US often utilize a method in
which the maximum potential dose is calculated.
For asymptomatic patients with acute, unintentional inges-
tions of TCAs, the expert consensus panel concluded that
home observation might be allowable for very small expo-
sures. However, the panel recognized that a definite threshold
dose for toxicity, based on a confirmed history of exposure,
has not been established. After a thorough review of pub-
lished case reports, recommended therapeutic dosage regi-
mens, current poison control center practices, and expert
experience, the panel concluded that ingestion of either of the
following amounts, whichever is lower, should warrant con-
sideration of referral to an emergency department:
• An amount that exceeds the usual maximum single thera-
peutic dose; or
• An amount equal to or greater than the lowest reported
toxic dose.
Based on this principle, the panel determined that more than
5 mg/kg should be the minimal dose for referral to an emer-
gency department, except in the cases of desipramine (>2.5
mg/kg), nortriptyline (>2.5 mg/kg), trimipramine (>2.5 mg/
kg), and protriptyline (>1 mg/kg). These doses are extrapo-
lated back from the maximum therapeutic adult doses shown
in Table 2. This recommendation applies to both patients who
are naïve to the specific cyclic antidepressant and to patients
currently taking cyclic antidepressants who take extra doses,
in which case the extra doses, when added to the daily dose
taken, should then be compared to the threshold dose for
referral to an ED.
There is support for this threshold dose in retrospective stud-
ies (45–47) that reported little significant toxicity in doses less
than 5 mg/kg, in case reports of minimal doses associated with
sigificant toxicity (Tables 4 and 5), in toxicology textbooks that
often define 10 mg/kg (or 1000 mg) as the dose above which sig-
nificant toxicity is seen, in prospective therapeutic dosing studies
(95,95,112,121,130), and in a meta-analysis in which mean dos-
ing to 3 mg/kg daily of a TCA (2 mg daily for nortriptyline) has
been administered routinely therapeutically to older children and
adults with few significant side effects (106). However, it also
acknowledges recent work showing a comparatively higher case
fatality rate attributable to desipramine exposures compared with
other TCAs, which supports a lower threshold dose of concern
(12,13). This conclusion acknowledges that rare, idiosyncratic
reactions to TCAs, including cardiac arrest, have occurred in
patients taking only therapeutic doses. The panel also concluded
that the toxic dose of doxepin cream preparation, when ingested,
could not be established from the evidence and so chose to
assign the same 5 mg/kg threshold for referral to an emergency
department as oral doxepin dosage forms.
The panel recognized that the decision to send a patient to
an emergency department for monitoring is made on a case-
by-case basis, taking into account the reliability of the
caller’s history, underlying medical status, concomitant use
of other medications (e.g., psychopharmaceutical or cardio-
active agents) that could have additive neurotoxicity or car-
diodepressant effects, and other variables.
Duration of observation for asymptomatic patients
The expert consensus panel concluded that onset and duration
of toxicity were clearly affected by several variables including
the total quantity ingested, co-ingestants, and gastrointestinal
decontamination measures such as activated charcoal. Other
factors, such as type of pharmaceutical product (e.g., capsule
vs. tablet) and the presence or absence of food in the stomach
could also affect the time of onset and duration of toxicity;
however, no studies were found that addressed such differ-
ences directly. After a careful review of the case reports and
observational studies, and considerable discussion, the panel
concluded that a patient with normal sensorium who is asymp-
tomatic 6 hours after ingestion of a TCA is unlikely to subse-
quently develop significant symptoms.
Potential out-of-hospital management
The expert consensus panel concluded that close monitoring
of vital signs, respiratory, cardiovascular, and neurological
status of patients with possible severe TCA poisoning is of
critical importance. When possible, ECG monitoring should
also be included.
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224 A.D. Woolf et al.
Gastrointestinal decontamination
The expert consensus panel concluded that out-of-hospital gas-
trointestinal decontamination offered potential benefit, but that
the magnitude of the benefit and the risks for the patient were
difficult to determine. Inducing emesis with ipecac syrup was
concluded to carry a major risk of pulmonary aspiration of gas-
tric contents if the patient became hypotensive or lost con-
sciousness and is not supported by sufficient evidence of
benefit to warrant its use. Moreover, ipecac syrup would likely
delay or prevent the use of activated charcoal. It might induce a
vagal stimulus that could further depress the heart rate and trig-
ger life-threatening arrhythmias. The panel concluded that ipe-
cac syrup is contraindicated in TCA poisoning.
Activated charcoal was determined by the panel to be a
treatment that could be administered orally as part of the man-
agement of a TCA-poisoned patient, although its effectiveness
and risks have not been evaluated in the prehospital setting.
Aspiration of activated charcoal, with subsequent pulmonary
complications, is a considerable risk of its administration to
TCA-poisoned patients whether in the prehospital or hospital
setting. It cannot be recommended for routine prehospital man-
agement of TCA poisoning at this time, although it might be
considered in some regions in which prehospital activated
charcoal is routinely administered by emergency medical per-
sonnel and there is a long transportation time to an emergency
department. Also, the panel agreed that transportation to an
emergency department should not be delayed in order to
attempt activated charcoal administration.
Specific pharmacological therapy
The expert consensus panel concluded that intravenous flu-
ids would likely be necessary in the prehospital care of
hemodynamically unstable TCA-poisoned patients.
Although the available literature on in-hospital management
of TCA poisoning supports the use of intravenous sodium
bicarbonate, which is often available to paramedics, no
studies were found addressing the effectiveness or safety of
this drug for the out-of-hospital treatment of TCA-induced
hypotension and arrhythmias. However, standard ACLS
doses of sodium bicarbonate can be considered for prehos-
pital patients found to have life-threatening hypotension and
cardiac conduction disturbances evident on an ECG or
rhythm strip. The panel concluded that flumazenil is con-
traindicated if there is any possibility that a comatose
patient may have ingested a TCA.
Recommendations (grades combined
where appropriate)
1. Patients with suspected self-harm or who are the victims
of malicious administration of a TCA should be referred to
an emergency department immediately (Grade D).
2. Patients with acute TCA ingestions who are less than
6 years of age and other patients without evidence of
self-harm should have further evaluation including stan-
dard history taking and determination of the presence of
co-ingestants (especially other psychopharmaceutical
agents) and underlying exacerbating conditions, such as
convulsions or cardiac arrhythmias. Ingestion of a TCA in
combination with other drugs might warrant referral to an
emergency department. The ingestion of a TCA by a
patient with significant underlying cardiovascular or neu-
rological disease should cause referral to an emergency
department at a lower dose than for other individuals.
Because of the potential severity of TCA poisoning, trans-
portation by EMS, with close monitoring of clinical status
and vital signs en route, should be considered (Grade D).
3. Patients who are symptomatic (e.g., weak, drowsy, dizzy,
tremulous, palpitations) after a TCA ingestion should be
referred to an emergency department (Grade B).
4. Ingestion of either of the following amounts (whichever is
lower) would warrant consideration of referral to an emer-
gency department:
• An amount that exceeds the usual maximum single
therapeutic dose or,
• An amount equal to or greater than the lowest reported
toxic dose.
For all TCAs except desipramine, nortriptyline, trimipramine,
and protriptyline, this dose is >5 mg/kg. For despiramine it is
>2.5 mg/kg; and for nortriptyline it is >2.5 mg/kg; for trimi-
pramine it is >2.5 mg/kg; for protriptyline it is >1 mg/kg. This
recommendation applies to both patients who are naïve to the
specific cyclic antidepressant and to patients currently taking
cyclic antidepressants who take extra doses, in which case the
extra doses should be added to the daily dose taken and then
compared to the threshold dose for referral to an emergency
department (Grades B/C).
5. Do not induce emesis (Grade D).
6. The risk-to-benefit ratio of prehospital activated charcoal for
gastrointestinal decontamination in TCA poisoning is unknown.
Prehospital activated charcoal administration, if available,
should only be carried out by health professionals and only if no
contraindications are present. Do not delay transportation in
order to administer activated charcoal (Grades B/D).
7. For unintentional poisonings, asymptomatic patients are
unlikely to develop symptoms if the interval between the
ingestion and the initial call to a poison center is greater
than 6 hours. These patients do not need referral to an
emergency department facility (Grade C).
8. Follow-up calls to determine the outcome for a TCA
ingestions ideally should be made within 4 hours of the
initial call to a poison center and then at appropriate
intervals thereafter based on the clinical judgment of the
poison center staff (Grade D).
9. An ECG or rhythm strip, if available, should be checked
during the prehospital assessment of a TCA overdose
patient. A wide-complex arrhythmia with a QRS duration
longer than 100 msec is an indicator that the patient
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Tricyclic antidepressant poisoning 225
should be immediately stabilized, given sodium bicar-
bonate if there is a protocol for its use, and transported to
an emergency department (Grade B).
10. Symptomatic patients with TCA poisoning might require
prehospital interventions, such as intravenous fluids, car-
diovascular agents, and respiratory support, in accor-
dance with standard ACLS guidelines as outlined by the
American Heart Association (227) (Grade D).
11. Administration of sodium bicarbonate might be benefi-
cial for patients with severe or life-threatening TCA tox-
icity if there is a prehospital protocol for its use (Grades
B/D).
12. For TCA-associated convulsions, benzodiazepines are
recommended (Grade D).
13. Flumazenil is not recommended for patients with TCA
poisoning (Grade D).
Dosage and follow-up recommendations are summarized in
Appendix 4.
Implications for research
The expert consensus panel identified the following topics
where additional research might be useful.
1. A prospective study of the dose of acute pediatric TCA inges-
tion requiring observation at a healthcare facility could help
to reduce unnecessary utilization of healthcare resources.
2. A large-scale, prospective study of unintentional TCA
ingestions is needed.
3. An additional need is a better correlation between the esti-
mated ingested dose, clinical symptoms, and outcome in
patients with serious overdoses.
4. Research is needed into the adverse effects of TCAs in
pregnant women.
5. The efficacy and safety of prehospital decontamination
with activated charcoal for TCA poisoning is unknown
and merits investigation.
6. The efficacy and safety of glucagon, sodium bicarbonate,
or other measures given in a prehospital setting for the
treatment of TCA poisoning is unknown.
Disclosures
Dr. Booze’s husband is employed by AstraZeneca. Dr. Erdman
is currently employed by Genentech but was not during his
contribution to the development of this guideline. There are
no other potential conflicts of interest reported by the expert
consensus panel or project staff regarding this guideline.
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Appendix 1
Expert consensus panel members
Lisa L. Booze, Pharm.D.
Certified Specialist in Poison Information
Maryland Poison Center
University of Maryland School of Pharmacy
Baltimore, Maryland, USA
E. Martin Caravati, M.D., M.P.H., FACMT, FACEP
Professor of Surgery (Emergency Medicine)
University of Utah
Medical Director
Utah Poison Center
Salt Lake City, Utah, USA
Gwenn Christianson, R.N., M.S.N.
Certified Specialist in Poison Information
Indiana Poison Center
Indianapolis, Indiana, USA
Peter A. Chyka, Pharm.D., FAACT, DABAT
Professor, Department of Clinical Pharmacy
College of Pharmacy
University of Tennessee Health Science Center
Memphis, Tennessee, USA
Daniel J. Cobaugh, Pharm.D., FAACT, DABAT
Director of Research
American Society of Health-System Pharmacists Research
and Education Foundation
Bethesda, Maryland, USA
Former Associate Director, American Association of Poison
Control Centers
Anthony S. Manoguerra, Pharm.D., DABAT, FAACT
Professor of Clinical Pharmacy and Associate Dean
School of Pharmacy and Pharmaceutical Sciences
University of California San Diego
Former Director, California Poison Control System, San Diego
Division
San Diego, California, USA
Lewis S. Nelson, M.D., FACEP, FACMT
Associate Professor of Emergency Medicine
New York University School of Medicine
Associate Medical Director
New York City Poison Control Center
New York, New York, USA
Kent R. Olson, M.D., FACEP, FAACT, FACMT
Medical Director
California Poison Control System, San Francisco Division
Clinical Professor of Medicine & Pharmacy
University of California, San Francisco
San Francisco, California, USA
Elizabeth J. Scharman, Pharm.D., DABAT, BCPS, FAACT
Director, West Virginia Poison Center
Professor, West Virginia University School of Pharmacy
Department of Clinical Pharmacy
Charleston, West Virginia, USA
Paul M. Wax, M.D., FACMT
Attending Toxicologist
UT Southwestern Medical Center
Dallas, Texas, USA
Alan D. Woolf, M.D., M.P.H., FACMT
Director, Program in Environmental Medicine
Children’s Hospital, Boston
Associate Professor of Pediatrics
Harvard Medical School
Boston, Massachusetts, USA
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232 A.D. Woolf et al.
Appendix 2
Grades of recommendation and levels of evidence
Appendix 3
Secondary review panel organizations
Ambulatory Pediatric Association
American Academy of Breastfeeding Medicine
American Academy of Emergency Medicine
American Academy of Pediatrics
American Association for Health Education
American College of Clinical Pharmacy
American College of Emergency Physicians
American College of Occupational and Environmental
Medicine
American Pharmacists Association
American Public Health Association
American Society of Health-System Pharmacists
Association of Maternal and Child Health Programs
Association of Occupational and Environmental Clinics
Association of State and Territorial Health Officials
Canadian Association of Poison Control Centres
Centers for Disease Control and Prevention – National
Center for Injury Prevention and Control
Consumer Federation of America
Consumer Product Safety Commission
Department of Transportation
Emergency Medical Services for Children
Emergency Nurses Association
Environmental Protection Agency
Food and Drug Administration
National Association of Children’s Hospitals and
Related Institutions
National Association of Emergency Medical Services
Physicians
National Association of Emergency Medical
Technicians
National Association of School Nurses
National Association of State Emergency
Medical Services Directors
National Safe Kids Campaign
Teratology Society
World Health Organization International Programme on
Chemical Safety
Grade of
recommendation Level of evidence Description of study design
A 1a Systematic review (with homogeneity) of randomized clinical trials
1b Individual randomized clinical trials (with narrow confidence interval)
1c All or none (all patients died before the drug became available,
but some now survive on it; or when some patients died before
the drug became available, but none now die on it.)
B 2a Systematic review (with homogeneity) of cohort studies
2b Individual cohort study (including low quality randomized clinical trial)
2c “Outcomes” research
3a Systemic review (with homogeneity) of case-control studies
3b Individual case-control study
C 4 Case series, single case reports (and poor quality cohort and case control studies)
D 5 Expert opinion without explicit critical appraisal or based on
physiology or bench research
Z 6 Abstracts
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Tricyclic antidepressant poisoning 233
Appendix 4
Algorithm for triage of tricyclic antidepressant ingestion
Is suicidal, abuse, or malicious intent suspected?
YES → Refer to emergency department.
NO ↓
Is the home situation of concern? (e.g., patient lives alone or family/caregiver
seems unreliable)
YES → Refer to emergency department.
NO ↓
Is the patient symptomatic? (e.g., weak, drowsy, dizzy, tremulous,
palpitations)
YES → Refer to emergency department.
NO ↓
Have more than 6 hours elapsed since the TCA ingestion and the patient is
still asymptomatic?
YES → Continue to follow closely at home.
NO ↓
Does the patient have significant underlying cardiovascular or neurological
disease, or is he/she taking a cardiodepressant drug or MAO inhibitor?
YES → Consider referral to emergency department.
NO ↓
Can you estimate the maximum amount ingested?
NO → Refer to emergency department.
YES ↓
Has the patient ingested a potentially toxic dose?
*
YES → Refer to emergency department.
Amitriptyline >5 mg/kg
Clomipramine >5 mg/kg
Desipramine >2.5 mg/kg
Doxepin >5 mg/kg
Doxepin cream
†
>5 mg/kg
Imipramine >5 mg/kg
Nortriptyline >2.5 mg/kg
Protriptyline >1 mg/kg
Trimipramine >2.5 mg/kg
NO ↓
Observe at home. Instruct caller to call poison center back if symptoms
appear. Consider poison center-initiated follow-up within 4 hours of initial
call. Consider referral to emergency services should new symptoms develop.
*Algorithm applies only to ingested TCAs, not to parenteral use or other routes of exposure. Algorithm applies only to acute ingestions.
†
A toxic dose for dermal exposures could not be established from available evidence. The dose represents the ingestion of a dermal preparation.
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