a) AMITRIPTYLINE: 5 mg/kg or less; Maximum daily dose 150 to 300 mg adults, 200 mg adolescents and elderly
b) CLOMIPRAMINE: 5 mg/kg or less; Maximum daily dose 300 mg adults, 200 mg children 10 to 18 years
c) DESIPRAMINE: 2.5 mg/kg or less; Maximum daily dose 300 mg adults, 150 mg adolescents and elderly
d) DOXEPIN: 5 mg/kg or less; Maximum daily dose 300 mg adults
e) DOXEPIN CREAM: 5 mg/kg or less
f) IMIPRAMINE: 5 mg/kg or less; Maximum daily dose 300 mg adults; 100 mg adolescents and elderly
g) NORTRIPTYLINE: 2.5 mg/kg or less; Maximum daily dose 150 mg adults, 50 mg adolescents and elderly
h) PROTRIPTYLINE: 1 mg/kg or less; Maximum daily dose 60 mg adults; 20 mg adolescents and elderly
i) TRIMIPRAMINE: 2.5 mg/kg or less; Maximum daily dose 200 mg adults, 100 mg adolescents and elderly

a) AMITRIPTYLINE: greater than 5 mg/kg; Maximum daily dose 150 to 300 mg adults, 200 mg adolescents and elderly
b) CLOMIPRAMINE: greater than 5 mg/kg; Maximum daily dose 300 mg adults, 200 mg children 10 to 18 years
c) DESIPRAMINE: greater than 2.5 mg/kg; Maximum daily dose 300 mg adults, 150 mg adolescents and elderly
d) DOXEPIN: greater than 5 mg/kg; Maximum daily dose 300 mg adults
e) DOXEPIN CREAM: greater than 5 mg/kg
f) IMIPRAMINE: greater than 5 mg/kg; Maximum daily dose 300 mg adults; 100 mg adolescents and elderly
g) NORTRIPTYLINE: greater than 2.5 mg/kg; Maximum daily dose 150 mg adults, 50 mg adolescents and elderly
h) PROTRIPTYLINE: greater than 1 mg/kg; Maximum daily dose 60 mg adults; 20 mg adolescents and elderly
i) TRIMIPRAMINE: greater than 2.5 mg/kg; Maximum daily dose 200 mg adults, 100 mg adolescents and elderly

a) ECG changes may include sinus tachycardia, prolonged PR interval, widening of the QRS complex, QTc prolongation, rightward shift in the axis of the terminal 40 milliseconds of the QRS complex, T-wave flattening or inversion, ST-segment depression, right bundle branch block, junctional rhythm, and atrioventricular block (Clark et al, 2015; Hon et al, 2015; Grover et al, 2012; Blaber et al, 2012; Kiberd & Minor, 2012; Frank & Kierdorf, 2000; Keller et al, 2000; Mehta & Alexandrou, 2000; James & Kearns, 1995; Caravati & Bossart, 1991; Foulke & Albertson, 1986) Neimann et al, 1986; (Goldberg et al, 1985; Fasoli & Glauser, 1981; Langou et al, 1980) .
b) Buckley et al (2003) conducted a retrospective review to identify the utility of using ECG findings for determining subsequent risk of psychotropic drug-induced dysrhythmias The study compared 39 patients with significant dysrhythmias (supraventricular tachycardia, ventricular tachycardia, cardiac arrest) following either tricyclic antidepressant overdose or thioridazine overdose with 117 controls with matched overdose ingestions but without the presence of dysrhythmias. The ECG findings of QRS of at least 100 ms (82% vs 76%), a QTc interval greater than 500 (74% vs 50%) and an R/S ratio in aVR greater than 0.7 (28% vs 3%) were more common in the dysrhythmia group as compared to the controls, respectively. However, in general, the association was weak, as evidenced by the following positive (PPV) and negative (NPV) predictive value:
c) CASE REPORT (CHILD): A 6-year-old girl developed seizures and ECG abnormalities after taking 300 mg (15 mg/kg) of amitriptyline every night for 1 month instead of the prescribed 30 mg nightly for treatment of insomnia secondary to ADHD. Initial ECG revealed sinus tachycardia with QRS widening, QTc interval prolongation, and right bundle branch block. Her total amitriptyline/nortriptyline concentration, obtained at hospital admission, was 1676 ng/mL (normal therapeutic, 50 to 300 ng/mL). With continued administration of sodium bicarbonate, the patient gradually recovered with resolution of ECG findings, and was subsequently discharged approximately 7 days post-admission (Clement et al, 2012).
d) CASE REPORT: A 56-year-old woman was found unresponsive after ingesting an unknown amount of amitriptyline tablets. At presentation to the ED, 45 minutes later, the patient's Glasgow Coma Scale was 3, and she developed seizures and hypotension. An initial ECG demonstrated sinus bradycardia with bigeminal premature ventricular contractions, first degree AV block, widening of the QRS complex and a prolonged QTC. With supportive therapy, including intranasal midazolam, IV sodium bicarbonate, and norepinephrine for refractory hypotension, the patient gradually recovered and was discharged without sequelae (Clark et al, 2015).
e) QRS WIDENING
f) TERMINAL QRS AXIS

a) The Type I Brugada electrocardiographic pattern, characterized by ECG findings of coved, downsloping ST-segment elevations of 2 mm or greater in the V1-V2 precordial leads, followed by T-wave inversions, has been reported following tricyclic antidepressant overdose. The Brugada ECG pattern may be accompanied by right bundle branch block, not associated with ischemia, electrolyte abnormalities, or structural heart defect (Akhtar & Goldschlager, 2006; Monteban-Kooistra et al, 2006).
b) CASE REPORT: A 48-year-old man, with a past medical history of hypertension and noncardiac chest pain, ingested an unknown amount of nortriptyline, diazepam, zopiclone, and paroxetine and, approximately 40 hours postingestion, developed typical ECG changes of Brugada syndrome, characterized by J point elevation with downsloping ST-segment elevation in V1-V2 leads and T wave inversion. A serum tox screen was positive only for tricyclic antidepressants. The patient's ECG showed a normal PR interval, a QRS duration of 0.12 seconds and a QTc of 0.46 sec. His troponin I level remained within normal limits (0.9 mcg/L; normal 0 to 2 mcg/L). The patient's ECG abnormalities spontaneously resolved over the next 4 days and he was discharged to psychiatric care (Bigwood et al, 2005).

a) Patients with more severe overdoses may develop supraventricular tachycardia, atrial fibrillation, atrioventricular block, multifocal PVCs, junctional rhythm, ventricular tachycardia, torsades de pointes, ventricular fibrillation and cardiopulmonary arrest (Clark et al, 2015; Blaber et al, 2012; Kiberd & Minor, 2012; Alter et al, 2001; Roberge & Krenzelok, 2001; Lappa et al, 2000; Zakynthinos et al, 2000; Zell-Kanter et al, 2000; Buckley et al, 1994; Peters et al, 1992; Goldberg et al, 1985; Kresse-Hermsdorf et al, 1985; Stern et al, 1985; Carpenter et al, 1982; Fasoli & Glauser, 1981; Langou et al, 1980; Freeman et al, 1969) . Bradycardia and atrial flutter have also been reported (Chakrabarti et al, 2010; Winrow, 1999).
b) ONSET: Life-threatening dysrhythmias usually develop within 6 hours of overdose (Dziukas & Vohra, 1991).

a) Several case reports have described patients who developed significant dysrhythmias, some of which were fatal, after initial recovery from a tricyclic antidepressant overdose. These patients had clinical evidence of significant tricyclic toxicity prior to the onset of delayed dysrhythmia, and most received inadequate gastrointestinal decontamination (McAlpine et al, 1986; Callaham, 1982; Sedal et al, 1972; Slovis et al, 1971; Barnes et al, 1968; Giles, 1963) .
b) CASE REPORT/CHILD: A 13-year-old girl presented comatose ingesting an unknown amount of 150-mg amitriptyline tablets. GI decontamination was not performed. She developed pulseless wide-complex dysrhythmias approximately 19 hours after ingestion. Despite aggressive resuscitative efforts, the patient's rhythm degenerated to torsades de pointes. Approximately 30 minutes after initiation of resuscitation, 20% IV lipid emulsion therapy was started. The patient initially received 2 IV boluses of 1.5 mg/kg each, administered over a 3-minute period, with each bolus administered 5 minutes apart, followed by a continuous infusion of 0.25 mg/kg/minute for 30 minutes. Following administration of the second bolus, the patient's cardiac status improved with termination of her dysrhythmias (Levine et al, 2012)
c) CASE SERIES: In 2 retrospective studies totalling 204 patients, none developed any significant dysrhythmia after maintaining a normal level of consciousness and a normal electrocardiogram for 24 hours (Goldberg et al, 1985; Pentel & Sioris, 1981) .
d) RECOMMENDATION: In symptomatic patients adequate gastrointestinal decontamination including activated charcoal, and a 24 hour period of inpatient monitoring after normalization of the ECG and mental status is suggested as sufficient follow up provided there is no underlying cardiac disease (Pentel & Sioris, 1981).

a) CASE REPORT: A 54-year-old woman presented with hypertension and a decreased level of consciousness (Glasgow Coma Scale (GCS) score of 8) approximately 8 hours after intentionally ingesting 1000 mg nortriptyline. An ECG at admission revealed sinus tachycardia (114 bpm), and a wide QRS complex. Laboratory data indicated a normal creatine kinase level of 68 international units/L (normal less than 200) but an elevated troponin I level of 0.23 ng/mL (normal less than 0.06). Serum nortriptyline concentration was 858 ng/mL. After intravenous sodium bicarbonate administration, the patient's QRS widening reverted; however, approximately 44 hours postingestion, the patient complained of chest pain. A repeat ECG showed deeply negative T waves and an echocardiography indicated apical akinesia with mildly decreased systolic function. Cardiac catheterization demonstrated left ventricular apical ballooning, characteristic of "tako-tsubo" syndrome. According to repeat laboratory analysis, there appeared to be no increase in creatine kinase or troponin I levels. Following daily administration of 160 mg acetylsalicylic acid and 5 mg bisoprolol, the patient gradually recovered . On hospital day 8, a cardiac MRI demonstrated normal regional wall motion with no evidence of necrosis (De Roock et al, 2008).

a) Hypotension is common in severe tricyclic antidepressant overdose (Clark et al, 2015; Hon et al, 2015; Magdalan et al, 2013; Chakrabarti et al, 2010; Engels & Davidow, 2010; Roberge & Krenzelok, 2001; Frank & Kierdorf, 2000; Keller et al, 2000; Winrow, 1999; Toerne et al, 1997; Frommer et al, 1987; Biggs et al, 1977) . Hypotension has been associated with the development of dysrhythmia or pulmonary edema in patients with QRS interval greater than or equal to 0.10 sec, TCA level greater than 500 ng/mL, or grade IV coma.
b) INCIDENCE: Twenty-two of 64 patients (34%) who presented with acute tricyclic overdose had systolic BP of less than 95 mmHg on admission (Shannon et al, 1988).
c) ASSOCIATED COMPLICATIONS: In a prospective study of 64 tricyclic antidepressant overdose patients with QRS interval greater than or equal to 0.10 sec, TCA level greater than 500 ng/mL, or grade IV coma, patients with hypotension on admission were more likely to develop dysrhythmias or pulmonary edema than patients who were normotensive on admission (P<0.01) (Shannon et al, 1988).
d) A retrospective review of amitriptyline poisoning cases in pediatric patients (mean age 4.6 +/- 2.9 years) reported the occurrence of hypotension in 21.2% of patients (n=52). The mean dose ingested was 9.4 +/- 5.8 mg/kg (Olgun et al, 2009).

a) Orthostatic hypotension, which may develop as a result of peripheral alpha-receptor blockade (Frommer et al, 1987), is very common during initiation of tricyclic antidepressant therapy (Goldman et al, 1986; Mortensen, 1984) .

a) Myocardial infarction has been reported with therapeutic use (Barefoot & Williams, 2000; Smith & Tyznik, 1987).
b) CASE REPORT: One patient was described as having ECG findings suggestive of a transmural myocardial infarction that resolved when the patient's desipramine was discontinued; coronary angiography was normal (Smith & Tyznik, 1987).

a) Myocardial infarction has been reported following overdose (Arya et al, 2004; Cohen et al, 2000; Chamsi-Pasha & Barnes, 1988) .
b) CASE REPORT: Elevation of creatine kinase (CK) and CK-MB fraction was described in a tricyclic overdose patient who subsequently had a normal coronary angiogram (Guthrie & Lott, 1986).
c) CASE REPORT: A 22-year-old woman who ingested 300 mg of amitriptyline developed ECG changes and serial cardiac enzyme pattern consistent with an acute anteroseptal myocardial infarction approximately 26 hours postingestion. CK-MB elevation and septal hypokinesia on echocardiogram after an overdose of amitriptyline and diazepam. Coronary angiography was not done (Chamsi-Pasha & Barnes, 1988).
d) Abnormal ventricular conduction following dothiepin overdose simulating acute myocardial infarction has been reported (Steeds & Muthusamy, 2000).
e) CASE REPORT: A 33-year-old woman with persistent sinus tachycardia after ingesting 300 mg amitriptyline developed chest pain with diaphoresis approximately 40 hours after ingestion. An ECG showed ST-segment depression and T-wave inversion, and laboratory analysis revealed elevated cardiac enzyme levels (CK 698 units/liter, CK-MB 77.7 ng/mL, troponin I 27.5 ng/mL, myoglobin 80.2 ng/mL), consistent with acute myocardial infarction. Echocardiogram showed no wall motion abnormalities and single photon emission CT showed normal myocardial perfusion; angiography was not performed. The patient recovered with supportive therapy (Kiyan et al, 2006).

a) CASE SERIES: Thrombotic, nonbacterial endocarditis was found on autopsy in 3 patients who died after amitriptyline overdose (Lindstrom et al, 1977). All 3 patients developed thrombocytopenia and ARDS prior to death and had evidence of infarction of multiple organs (kidney, spleen, lung, heart) and emboli/thrombus formation at other sites (lung, radial, coronary and cerebral arteries).

a) Amitriptyline was the TCA ingested in 40 of the 58 TCA alone overdoses. Perphenazine was the neuroleptic drug combined with amitriptyline in 8 of the 12 patients that coingested drugs.
b) The mean tricyclic serum concentrations were not significantly different between the two groups.

a) CASE SERIES: Sudden death has been reported in four 8- to 9-year-old children during routine treatment with desipramine. Two of these children had a family history of cardiac problems (Riddle et al, 1993; Riddle et al, 1991; Tingelstad, 1991; Abramowicz, 1990) .
b) Using the baseline rate of sudden death in this age group and the numbers of children taking desipramine, there does not appear to be an increased risk of sudden death in children taking therapeutic doses of desipramine (Biederman et al, 1995).
c) CASE REPORT: Two other cases of sudden death were reported after therapy with tricyclic antidepressants. The first child, aged 9 years, died after 5 weeks of therapy with desipramine 50 mg twice daily. The second child collapsed after 8 months of imipramine therapy plus thioridazine; the imipramine dose had been increased to 150 mg at bedtime 2 months before death (Varley & McClellan, 1997).

a) CASE REPORT: A 37-year-old man with endogenous depression developed cardiac arrest, severe hypotension, and wide QRS complexes (230-260 ms) after ingestion of at least 5000 milligrams of doxepin. Although fluid load, alkalinization, hypertonic saline and high-dose vasoactive substances did not improve the patient's condition, he improved after treatment with hemoperfusion/hemodialysis (Frank & Kierdorf, 2000).

a) CASE REPORT: Hyperventilation secondary to nortriptyline therapy was described in a 61-year-old man with end-stage renal disease. Symptoms recurred upon rechallenge with the drug and the patient required intubation, paralysis and mechanical ventilation twice for severe respiratory alkalosis (Sunderragan et al, 1985).

a) Generalized seizures are a major complication that may result in hemodynamic instability, brain damage, hyperthermia, metabolic acidosis, rhabdomyolysis, and myoglobinuria if uncontrolled. Seizures generally occur within 8 hours of ingestion and are usually short lived; however status epilepticus has been reported.
b) COMPLICATIONS: Abrupt hemodynamic deterioration has been reported following seizures (Engels & Davidow, 2010; Lipper et al, 1994; Taboulet P, Michard F & Muszynski J et al, 1994; Ellison & Pentel, 1989) . Generalized seizures may result in brain damage, hyperthermia, metabolic acidosis, rhabdomyolysis, and myoglobinuria if uncontrolled.
c) ONSET: Patients who develop seizures after TCA overdose generally do so within 3 hours of ingestion (28 of 30 patients (93%) in one study and 10 of 10 in another) (Shannon, 1992; Ellison & Pentel, 1989). Onset may be very abrupt, with seizures developing in patients who are awake and alert (Ellison & Pentel, 1989). A single tonic-clonic seizure occurred approximately 16 hours after ingestion of 100 x 50-mg modified-release amitriptyline tablets (O'Connor et al, 2006).
d) DELAYED-ONSET: A 13-year-old girl presented comatose ingesting an unknown amount of 150-mg amitriptyline tablets. GI decontamination was not performed. She experienced a generalized tonic-clonic seizure approximately 19 hours after ingesting an unknown amount of 150-mg amitriptyline tablets. The seizure continued intermittently for 1 hour and resolved with administration of IV lorazepam and phenobarbital (Levine et al, 2012).
e) DURATION: Single seizures lasted 2 minutes or less in 57% (17 of 30) cyclic antidepressant overdose patients (serum drug concentration 639 to 9,530 ng/mL). Six patients had more than 2 seizures and one was in status epilepticus for 104 minutes (Ellison & Pentel, 1989). Seizures generally cease by 8 hours after ingestion (Shannon, 1992).
f) STATUS EPILEPTICUS: Status epilepticus has been reported after overdose with doxepin, imipramine, clomiPRAMINE, desipramine and amitriptyline (Ellison & Pentel, 1989; Sawyer et al, 1984; Flechter et al, 1983; Walter & Kauffman, 1980) Sunshine & Yaffe, 1963.
g) CASE REPORT: A 29-year-old woman had a generalized tonic-clonic seizure following chronic ingestion of greater than 800 mg amitriptyline per day for 3 years (Wohlreich & Welch, 1993).
h) CASE REPORT: A 56-year-old woman was found unresponsive after ingesting an unknown amount of amitriptyline tablets. At presentation to the ED, 45 minutes later, the patient's Glasgow Coma Scale was 3, and she developed seizures and hypotension. An initial ECG demonstrated sinus bradycardia with bigeminal premature ventricular contractions, first degree AV block, widening of the QRS complex and a prolonged QTC. With supportive therapy, including intranasal midazolam, IV sodium bicarbonate, and norepinephrine for refractory hypotension, the patient gradually recovered and was discharged without sequelae (Clark et al, 2015).
i) CASE REPORT (CHILD): Generalized tonic-clonic seizures were reported in a 6-year-old child who had been receiving 300 mg (15 mg/kg) amitriptyline every night for 1 month instead of the prescribed 30 mg nightly for treatment of insomnia secondary to ADHD (Clement et al, 2012).
j) CASE REPORT (CHILD): Seizure-like movements and altered mental status were reported in an 8-year-old child who ingested one 25-mg (0.8 mg/kg) amitriptyline tablet (Grover et al, 2012).
k) CASE REPORT (CHILD): An 18-month-old child developed facial twitching, up-rolling of eyes, and lost consciousness for 5 minutes after a suspected ingestion of approximately 7 25-mg imipramine tablets. Intravenous diazepam (2 mg) was administered due to a suspected seizure, and the symptoms resolved (Hon et al, 2015).
l) CASE REPORT (MUNCHAUSEN-BY-PROXY): A 2-year-old boy who was initially diagnosed with idiopathic seizure disorder after presenting on multiple occasions with generalized tonic-clonic seizures was actually being given amitriptyline 1 to 2 times daily by the patient's grandmother (Mullins et al, 1999).
m) A retrospective study of acute amitriptyline intoxication in children reported the development of seizures in 11 of 44 patients (25%) (Caksen et al, 2006).
n) A retrospective review of amitriptyline poisoning cases in pediatric patients (mean age 4.6 +/- 2.9 years) reported the occurrence of seizures in 7.7% of patients (n=52). The mean dose ingested was 9.4 +/- 5.8 mg/kg (Olgun et al, 2009).
o) PROGNOSTIC INDICATOR: A retrospective case control study was conducted, involving 25 patients with tricyclic antidepressant (TCA) poisoning who did not survive and 72 TCA-poisoned patients who did survive. Ten of the 25 non-survived patients (40%) exhibited advanced ECG changes, including ventricular fibrillation, torsades de pointes, or asystole, as compared to the control group who did not show any advanced ECG changes. The primary causes of death were refractory hypotension (n=6), ventricular tachycardia leading to cardiac arrest (n=13), and seizure or status epilepticus followed by cardiac arrest (n=2 and n=4, respectively). A statistically significant difference occurred between the two groups with respect to the pulse rate and respiratory rate at presentation, the occurrence of seizures (before or after presentation, or both), the height of the R wave in a lead aVR, T40-ms frontal plane QRS axis, and the occurrence of premature ventricular contractions. However, further statistical analysis, using forward logistic regression, showed that only the occurrence of seizures after hospital presentation was a predictive indicator for death in these patients (odds ratio = 40.88; 95% confidence interval (CI) = 9.93 to 168.39; p<0.001) (Sanaei-Zadeh et al, 2011).

a) NMS has been reported in patients receiving therapeutic doses of trimipramine and desipramine (Langlow & Alarcon, 1989) Baca & Martinelli, 1990.
b) NMS may be caused by a central imbalance between dopamine and norepinephrine rather than by dopamine depletion alone (Baca & Martinelli, 1990).
c) CASE REPORT: A 62-year-old man developed neuroleptic malignant syndrome possibly associated with nortriptyline use (dose and therapy duration not specified). He presented with a temperature of 107.1 degrees F, pulse 114, blood pressure 80/30 mmHg, and blood sugar 400. His creatine kinase and creatine kinase MB were 1046 IU/L and 2.3 IU/L, respectively. The patient developed disseminated intravascular coagulation and expired 2 days later (June et al, 1999).

a) NMS has been reported in several patients taking therapeutic doses of tricyclic antidepressants in combination with neuroleptics or monoamine oxidase inhibitors (Heyland & Sauve, 1991; Corrigan & Coulter, 1988; Horn et al, 1988; Merriam, 1987; Ansseau et al, 1986; Eiser et al, 1982) .

a) CASE REPORT/CHILD: A 4-year-old child presented with dysequilibrium, impaired speech, and fainting after a suspected ingestion of 20 amitriptyline tablets (unknown strength). At presentation, her Glasgow Coma Scale score was 9, blood pressure was 90/50 mmHg, and heart rate was 125 beats/min. Approximately 15 minutes after presentation, ECG changes developed, blood pressure decreased to 50/10 mmHg, and she experienced 2 tonic-clonic seizures. An initial brain CT was normal; however, a second brain CT and MRI showed bilateral hypodense edema in the cerebellar hemispheres and an increased signal and mass with diffusion restrictions, indicative of cerebellitis. A urine toxicology panel revealed an elevated tricyclic antidepressant concentration. Following symptomatic therapy and 2 courses of hemoperfusion, the patient gradually recovered and was discharged on hospital day 13 (Tatli et al, 2013).

a) CASE REPORT: A 42-year-old man presented to the emergency department after having been found unconscious. At presentation, Glasgow Coma Scale score was 9. Neurological examination revealed dysconjugate gaze, bilaterally unresponsive to visual threat, left arm weakness, and upper and lower limb drifts. A brain CT scan revealed a hyperdense basilar artery indicative of a thrombus, suggesting a diagnosis of acute basilar artery ischemic stroke. The patient completely recovered with a normal MRI and angiogram approximately 12 hours after receiving 0.9 mg/kg alteplase 3 hours after symptom-onset. Subsequent interview of the patient revealed that he had ingested an unknown quantity of amitriptyline tablets several hours prior to presentation, confirming a final diagnosis of amitriptyline toxicity (Birns et al, 2013).

a) CASE REPORT: A 44-year-old man with no past history of altered bowel habit developed intestinal pseudoobstruction and spontaneous cecal perforation after an overdose of 750 mg of amitriptyline. Longstanding hydrocephalus may have contributed to this complication. (McMahon, 1989).

a) CASE REPORT: Diffuse esophageal spasm without lesions occurred in a 45-year-old man following ingestion of 8 grams of amitriptyline (Rinder et al, 1988).

a) CASE REPORT: Acute pancreatitis leading to prolonged ileus has been reported in a 48-year-old woman following ingestion of 750 to 1500 mg of clomiPRAMINE. No other drugs or alcohol were found on a drug screen. Serum lipase level on day 3 was 350 IU, and rose to 2546 IU on day 5 with a corresponding serum amylase level of 112 IU. Abdominal studies showed no evidence of biliary tract, renal, or pancreatic disease. Total parenteral nutrition was required as the patient recovered over a 2 week period (Roberge et al, 1994).
b) CASE REPORT: A 30-year-old woman who ingested 800 mg amitriptyline in a suicide attempt developed elevated pancreatic enzymes, with serum amylase and lipase of 823 IU/L and 1054 IU/L, respectively and no associated clinical symptoms. The pancreas appeared normal on ultrasonography. Pancreatic enzymes continued to increase, peaking on the fourth day, and then progressively decreased (Pezzilli et al, 1998).

a) CASE REPORTS: Bezoars developed in 2 patients following overdose ingestions of slow-release clomiPRAMINE. The first patient, a 28-year-old woman, intentionally ingested 60 75-mg tablets of slow-release clomiPRAMINE (total dose 4.5 grams). Following unsuccessful retrieval of tablets using gastric lavage and activated charcoal, a pharmacobezoar was detected with an abdominal radiograph, and was successfully removed endoscopically. The second patient, a 25-year-old woman, intentionally ingested at least 6 grams of slow-release clomiPRAMINE and 120 mg oxazepam, and subsequently developed sinus tachycardia and a decreased level of consciousness. Following an inability to pass a gastric tube through the esophagus for gastric lavage, a gastroscopy was performed. A esophageal pharmacobezoar was detected and was successfully removed with an endoscope, pliers, flushing, and suction. Both patients completely recovered without complications (Hojer & Personne, 2008).
b) CASE REPORT: A 42-year-old woman presented comatose (Glasgow Coma Scale score of 5), hypotensive (90/50 mmHg), and tachycardic (120 bpm) approximately 14 hours after intentionally ingesting 60 75-mg sustained-release clomiPRAMINE tablets and 30 25-mg doxepin capsules. Gastric lavage was initiated, with no evidence of a tablet mass, followed by activated charcoal, and over the next 12 hours, the patient was responsive with normalization of blood pressure and heart rate. Approximately 10 hours later, the patient's condition deteriorated with development of respiratory insufficiency, seizures, severe hypotension, and coma. A chest radiograph showed a large round white mass and a CT scan confirmed the presence of a tablet mass in the gastric lumen, necessitating surgical removal. Following removal, crushing of the pharmacobezoar showed that it was comprised entirely from tablets, which had the appearance of clomiPRAMINE tablets. Despite removal of the bezoar, the patient's condition continued to deteriorate and, 32 hours later, she died from multi-organ failure (Magdalan et al, 2013).

a) Drug induced hepatitis has been described in a 39-year-old woman, first from the tricyclic amineptine and then from clomiPRAMINE (Larrey et al, 1986).

a) Moderate elevations in hepatic enzymes developed in a patient with fatal amitriptyline overdose (Lindstrom et al, 1977).

a) Fulminant hepatic failure developed in an 82-year-old woman taking therapeutic doses of nortriptyline (Berkelhammer et al, 1995).

a) CASE REPORT: A 44-year-old woman developed abnormal atrial and ventricular repolarization resembling acute infarction following amitriptyline intoxication (serum amitriptyline 4880 ng/mL at presentation). In addition, a slight metabolic acidosis was observed (Zakynthinos et al, 2000).
b) MODIFIED-RELEASE PREPARATION: A 40-year-old woman experienced metabolic acidosis up to 98 hours following ingestion of 100 x 50-mg modified-release amitriptyline, 13 x 50-mg clomiPRAMINE, and 10 x 20-mg fluoxetine. Her initial serum amitriptyline concentration, obtained 17.5 hours postingestion, was 1100 ng/mL and her peak serum amitriptyline concentration, obtained 42 hours postingestion, was 2100 ng/mL. She gradually recovered following supportive therapy and was hospital discharged approximately 9 days postingestion (O'Connor et al, 2006).
c) CASE REPORT: Metabolic acidosis, hypotension, and ECG abnormalities were reported in an 18-month-old child following a suspected ingestion of 7 25-mg imipramine tablets. The patient gradually recovered following supportive therapy, including IV sodium bicarbonate and dopamine infusions (Hon et al, 2015).

a) CASE REPORT: A 68-year-old woman developed thrombocytopenia (platelet count of 31,000//mm(3)) and a pruritic erythematous rash while on amitriptyline 60 mg and flunitrazepam 2 mg for 4 months. She was treated with prednisone 40 mg daily and fluocinonide cream. A patch and photopatch testing were done with amitriptyline and flunitrazepam and both were negative. Amitriptyline 10 mg was restarted orally and after 2 days the rash reappeared and thrombocytopenia developed (Taniguchi & Hamada, 1996).

a) CASE REPORT: A slate-gray discoloration of sun exposed skin developed in a woman taking desipramine (Steele & Ashby, 1993).
b) CASE SERIES: Ming et al (1999) reported 4 cases of golden-brown or slate-gray skin hyperpigmentation on the face, arms, and backs of the hands of women taking imipramine for at least 2 years. In 2 patients, discontinuation of imipramine resulted in nearly complete clearing of hyperpigmentation (Ming et al, 1999).

a) A retrospective study of acute amitriptyline intoxication in children reported the development of hyperglycemia in 14 of 44 patients (31.8%) (Caksen et al, 2006).
b) A retrospective review of amitriptyline poisoning cases in pediatric patients (mean age 4.6 +/- 2.9 years) reported the occurrence of hyperglycemia in 21.2% of patients (n=52). The mean dose ingested was 9.4 +/- 5.8 mg/kg (Olgun et al, 2009).

a) CASE REPORT: Three weeks after starting amitriptyline 25 mg twice daily for mild depression, a 24-year-old woman developed a pruritic morbilliform rash on the trunk. She was admitted to the hospital with fever and elevated pulse and respiration rates. Serum liver enzymes were elevated, and eosinophils were highly elevated. Her condition was diagnosed as hypersensitivity syndrome, a specific severe idiosyncratic drug reaction. Amitriptyline was withdrawn, and 5 days later the patient was afebrile. One month later, skin lesions and blood tests had normalized (Milionis et al, 2000).

1) AMITRIPTYLINE
2) DOTHIEPIN
3) IMIPRAMINE
4) NORTRIPTYLINE

1) CLOMIPRAMINE HYDROCHLORIDE
2) DESIPRAMINE
3) DOXEPIN (Prod Info SILENOR(R) oral tablets, 2010)
4) PROTRIPTYLINE

a) The infant remained asymptomatic despite initiation of breastfeeding at 7 days of age. A milk to plasma ratio of 0.8 to 1.6 was calculated. Maternal and neonatal plasma levels drawn 10, 14, and 35 days after birth demonstrated that the infant achieved approximately 6% of maternal clomiPRAMINE concentrations through nursing (Schimmell et al, 1991).

a) Monitor serial ECGs and institute continuous cardiac monitoring in all patients with suspected tricyclic overdose. ECG changes may include sinus tachycardia, prolonged PR interval, widening of the QRS complex, QTc prolongation, rightward shift in the axis of the terminal 40 milliseconds of the QRS complex, T-wave flattening or inversion, ST segment depression, right bundle branch block, junctional rhythm and atrioventricular block (Goldberg et al, 1985) Neimann et al, 1986; (Caravati & Bossart, 1991; Foulke & Albertson, 1986; Langou et al, 1980; Fasoli & Glauser, 1981).

1) Patients who remain symptomatic at 6 hours should be admitted to an intensive care unit. Serial monitoring of mental/respiratory status, acid-base status, and ECG should be performed. Patients who have resolved all clinical effects, have a normal QRS and QTc and are eating with normal bowel activity and no recurrent effects may be discharged.
2) Patients should have a baseline electrocardiogram and be monitored for a minimum of 6 hours and the ECG repeated at the end of this observation period. Patients with significant symptoms or any ECG changes during this period, or with mild persistent symptoms (sinus tachycardia or lethargy), should be admitted and monitored in the ICU until mental status is baseline and the ECG has returned to normal for 24 hours (Tokarski & Young, 1988; Banahan & Schelkun, 1990).

1) AMITRIPTYLINE: 5 mg/kg or less; Maximum daily dose 150 to 300 mg adults, 200 mg adolescents and elderly
2) CLOMIPRAMINE: 5 mg/kg or less; Maximum daily dose 300 mg adults, 200 mg children 10 to 18 years
3) DESIPRAMINE: 2.5 mg/kg or less; Maximum daily dose 300 mg adults, 150 mg adolescents and elderly
4) DOXEPIN: 5 mg/kg or less; Maximum daily dose 300 mg adults
5) DOXEPIN CREAM: 5 mg/kg or less
6) IMIPRAMINE: 5 mg/kg or less; Maximum daily dose 300 mg adults; 100 mg adolescents and elderly
7) NORTRIPTYLINE: 2.5 mg/kg or less; Maximum daily dose 150 mg adults, 50 mg adolescents and elderly
8) PROTRIPTYLINE: 1 mg/kg or less; Maximum daily dose 60 mg adults; 20 mg adolescents and elderly
9) TRIMIPRAMINE: 2.5 mg/kg or less; Maximum daily dose 200 mg adults, 100 mg adolescents and elderly

1) AMITRIPTYLINE: greater than 5 mg/kg; Maximum daily dose 150 to 300 mg adults, 200 mg adolescents and elderly
2) CLOMIPRAMINE: greater than 5 mg/kg; Maximum daily dose 300 mg adults, 200 mg children 10 to 18 years
3) DESIPRAMINE: greater than 2.5 mg/kg; Maximum daily dose 300 mg adults, 150 mg adolescents and elderly
4) DOXEPIN: greater than 5 mg/kg; Maximum daily dose 300 mg adults
5) DOXEPIN CREAM: greater than 5 mg/kg
6) IMIPRAMINE: greater than 5 mg/kg; Maximum daily dose 300 mg adults; 100 mg adolescents and elderly
7) NORTRIPTYLINE: greater than 2.5 mg/kg; Maximum daily dose 150 mg adults, 50 mg adolescents and elderly
8) PROTRIPTYLINE: greater than 1 mg/kg; Maximum daily dose 60 mg adults; 20 mg adolescents and elderly
9) TRIMIPRAMINE: greater than 2.5 mg/kg; Maximum daily dose 200 mg adults, 100 mg adolescents and elderly

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) A single 50 gram dose of activated charcoal (given 5 minutes after amitriptyline) reduced absorption of a 75 milligram amitriptyline dose by 99 percent (Karkkainen & Neuvonen, 1986).
b) Two single-dose charcoal studies in overdosed patients did not demonstrate a significant clinical benefit in symptoms or elimination kinetics, however most patients were treated several hours postingestion. (Crome, 1983; Hulten et al, 1988).
c) Another study of single dose activated charcoal administration following amitriptyline overdose found a correlation between time to activated charcoal administration and drug half life; clinical endpoints were not evaluated (Hedges et al, 1987).

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Outcome variables examined were length of hospital and ICU stay, duration of sinus tachycardia, duration of mechanical ventilation, seizures, QRS duration >100 milliseconds, hypotension, ventricular dysrhythmias and death.

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

a) A 39-year-old woman on methadone maintenance received multiple dose activated charcoal after tricyclic antidepressant overdose (Gomez et al, 1994). Four days after admission she developed a charcoal stercolith and colonic perforation.
b) A 17-year-old boy with anorexia nervosa, laxative and diuretic abuse and surgical gastric reduction was treated with multiple dose activated charcoal after overdose with codeine, temazepam and dothiepin (Merriman & Stokes, 1995). He developed a charcoal bezoar with jejunal impaction that required surgical removal.

a) Dysrhythmias are often torsade de pointes and may respond to alkalinization therapy. For those unresponsive consider magnesium, beta 1-sympathomimetics, or overdrive pacing. Lidocaine, although a type 1b agent may also be tried. Disopyramide, quinidine, procainamide are type 1a and are CONTRAINDICATED.

a) SUMMARY - Sodium bicarbonate administration appears to have a beneficial effect on TCA induced conduction defects and dysrhythmias in humans and in animal models (Nattel et al, 1984; Nattel & Mittleman, 1984; Hedges et al, 1985; Hoffman et al, 1993). Studies have suggested that this effect may be secondary to increased pH (Brown et al, 1973; Brown, 1976; Nattel & Mittleman, 1984; Stone et al, 1995), increased concentration of sodium ion (Pentel & Benowitz, 1984; Hoffman et al, 1993; McCabe et al, 1993; McCabe et al, 1994) or both (Sasyniuk et al, 1986; Shanon & Liebelt, 1998; McCabe et al, 1998).
b) SODIUM BICARBONATE DOSE - 1 to 2 milliequivalents/kilogram as needed to achieve a physiologic pH or slightly above (7.45 to 7.55) (Nattel & Mittleman, 1984). In some cases alkalinization of blood to a pH above physiologic may be necessary to reverse dysrhythmias (Sasyniuk et al, 1986).
c) MECHANICAL HYPERVENTILATION - Induction of respiratory alkalosis by mechanical hyperventilation may be as effective as intravenous sodium bicarbonate (Bessen et al, 1983; Bessen & Niemann, 1985-86). A pH greater than 7.60 or a pCO2 less than 20 mmHg is probably undesirable(Bessen & Niemann, 1985-86).

a) CASE REPORT - HYPERTONIC SODIUM CHLORIDE - A 29-year-old woman was comatose and had a widened QRS interval after ingestion of approximately 8 grams nortriptyline. The patient developed refractory hypotension and worsening cardiac conduction despite fluid resuscitation, serum alkalinization, and high-dose catecholamine therapy. After a 200 mL bolus of 7.5% saline infused over 3 minutes, QRS interval narrowed from 139 milliseconds to 120 milliseconds and blood pressure increased; the patient survived without further sequelae (McKinney & Rasmussen, 2003; Rasmussen & McKinney, 1999).
b) ANIMAL DATA - HYPERTONIC SODIUM CHLORIDE - In a randomized, controlled study of 24 domestic swine, hypertonic sodium chloride solution (15 mEq sodium per kilogram) was more effective in reversing induced severe tricyclic antidepressant toxicity compared to sodium bicarbonate, hyperventilation, or dextrose 5% in water. The authors suggested that in this animal model, sodium loading may be the most important factor in reversing tricyclic toxicity (McCabe et al, 1998). This study has been reported to have methodological flaws, in which the 3 groups may have been treated differently and thus affected survival outcome (Dick & Hack, 1999).

a) STUDY/ANIMAL - In a canine model of amitriptyline overdose, 2 milligrams/kilogram of lidocaine was only transiently effective in reducing the frequency of ventricular ectopic complexes(Nattel & Mittleman, 1984a). Significant blood pressure reduction was an adverse effect of lidocaine use in this study.
b) LIDOCAINE/DOSE
c) LIDOCAINE/MAJOR ADVERSE REACTIONS
d) LIDOCAINE/MONITORING PARAMETERS

a) Phenytoin may be useful in improving cardiac conduction (Hagerman & Hanashiro, 1981; Boehnert & Lovejoy, 1985) and in treating ventricular dysrhythmias (Postlethwaite & Price, 1974; Mayron & Ruiz, 1986).
b) In a dog model of amitriptyline intoxication phenytoin increased the duration and frequency of ventricular tachycardia (Callaham et al, 1988). Routine use of phenytoin as prophylaxis for seizures or dysrhythmias is not recommended, but it may be useful in treating dysrhythmias unresponsive to other therapy (Hagerman & Hanashiro, 1981; Mayron & Ruiz, 1986).
c) PHENYTOIN LOADING DOSE (ADULT and CHILD) - Administer 15 milligrams/kilogram, up to 1 gram, intravenously not to exceed a rate of 0.5 milligram/kilogram/minute.
d) PHENYTOIN MAINTENANCE DOSE (ADULT) - 2 milligrams/kilogram intravenously every 12 hours as needed. Monitor serum phenytoin levels just prior to initiating and during maintenance therapy to assure therapeutic levels of 10 to 20 micrograms/milliliter.
e) PHENYTOIN MAINTENANCE DOSE (CHILD) - 2 milligrams/kilogram intravenously every 8 hours as needed. Monitor serum phenytoin levels just prior to initiating and during maintenance therapy to assure therapeutic levels of 10 to 20 micrograms/milliliter.

a) Knudsen & Abrahamson (1997) reported the successful use of magnesium sulfate in the treatment of refractory ventricular fibrillation after TCA overdose(Knudsen & Abrahamsson, 1997). Two doses of 20 mmol magnesium sulfate and defibrillation resulted in successful treatment of amitriptyline-induced refractory ventricular fibrillation in a 44-year-old woman. The patient had not previously responded to sodium bicarbonate, lidocaine, or epinephrine.
b) RANDOMIZED CONTROLLED TRIAL: A randomized controlled trial was conducted to determine the effectiveness of magnesium sulfate in the treatment of TCA intoxication, involving patients with a history of TCA overdose who presented to the emergency department in Tehran, Iran from March, 2009 to April, 2010. Inclusion criteria consisted of patients ingesting more than 20 mg/kg of a TCA, QRS duration greater than 10 ms, and the development of seizures or a blood pH of less than 7.2 after overdose. Exclusion criteria included any patients with a prior history of cardiovascular disease and the concomitant use of cardiac, anticholinergic, and antipsychotic agents. The patients were randomly divided into two groups: The control group who received sodium bicarbonate infusion and supportive therapy (n=36), and the case group who received IV magnesium sulfate (1 g every 6 hours) in addition to sodium bicarbonate infusion and supportive therapy (n=36). Eighteen patients from the case group (50%) and 19 patients from the control group (52.8%) were admitted to the ICU. Following their respective treatments, the mean ICU stay was 25.63 +/-9.33 hours and 82.67 +/-21.66 hours in the case and control groups, respectively (p<0.001). The mortality rate of the case and control groups was 13.9% and 33.3%, respectively (p=0.052). This suggests that magnesium sulfate may be effective when used with sodium bicarbonate and other supportive therapy in the treatment of TCA poisoning, although further studies are warranted (Emamhadi et al, 2012).
c) Animal studies of the effects of magnesium on tricyclic-induced dysrhythmias have yielded conflicting results.

a) CASE REPORT/ADOLESCENT: A 15-year-old girl presented to the emergency department with vomiting and fatigue approximately 12 hours after intentionally ingesting 12 25-mg imipramine tablets (approximately 6 mg/kg). The patient was hypotensive (70/30 mmHg) and an ECG revealed junctional escape rhythm (46 beats/min), no P waves, QRS widening, right bundle branch-like pattern, and QT interval prolongation. Despite supportive measures (including administration of IV fluids, vasopressors, sodium bicarbonate and atropine), the patient remained hypotensive and bradycardic. Following placement of a temporary pacemaker, as well as hemodialysis and hemoperfusion, the patient's blood pressure normalized and her urine toxicological screening for tricyclic antidepressants was negative. After removal of the pacemaker, a repeat ECG showed sinus bradycardia with QRS widening and a right bundle branch-like pattern; however, she was discharged on day 5 without sequelae, and a follow-up examination indicated no ECG abnormalities (Sert et al, 2011).

a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

a) ADULT
b) ADOLESCENT

a) An animal study, involving clomiPRAMINE administration in rabbits, was conducted to determine the efficacy of intralipid infusion as compared with sodium bicarbonate administration in the setting of clomiPRAMINE toxicity. Sedated and mechanically ventilated rabbits were infused with clomiPRAMINE at 320 mg/kg/hour, and subsequently developed severe hypotension. Sodium bicarbonate 8.4% at 3 mL/kg or 20% Intralipid at 12 mL/kg was then administered as rescue therapy. Three and 5 minutes following rescue therapy, the rate of change in mean arterial pressure was greater in the intralipid treated group as compared with the sodium bicarbonate-treated group (6.2 mmHg/min versus -0.25 mmHg/min, respectively, at 3 minutes; 4.4 mmHg/min versus 0.06 mmHg/min, respectively, at 5 minutes).

a) Animal studies suggest that preventing tachycardia by sinus node destruction (Ansel et al, 1993) or by using bradycardic agents that impede sinus node automaticity without affecting myocardial repolarization or contractility may prevent the development of tricyclic induced ventricular dysrhythmias (Ansel et al, 1994). The use of beta blocking agents in this setting may result in abrupt hemodynamic collapse because of the combined negative inotropic effects of beta blocking agents and tricyclic antidepressants.

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

a) If alkalinization and volume repletion are ineffective in reversing hypotension, consider the use of pressor or inotropic agents (Frommer et al, 1987). Hemodynamic interventions may be guided by right-sided heart catheterization (Frommer et al, 1987). Dopamine and norepinephrine are the most commonly used agents. Animal data support the use of either agent (Vernon et al, 1991).
b) Infusion of lipid emulsion should be considered in patients with refractory hypotension or dysrhythmias.
c) Intra-aortic balloons have been used successfully when pressors have failed.
d) SUMMARY

a) Hypotension may be a result of antidepressant-induced depletion of norepinephrine due to inhibition of neuronal uptake. Theoretically, norepinephrine and phenylephrine may be more effective agents due to their alpha-stimulating effects (Frommer et al, 1987).
b) Norepinephrine, in doses of 15 and 30 micrograms/minute for 5 and 24 hours respectively, was successful in reversing circulatory shock refractory to dopamine in two adults with tricyclic antidepressant overdose (Teba et al, 1988).
c) Disadvantages of using norepinephrine include the need for continuous nursing supervision, a central venous line, and the tissue damage caused by extravasation.
d) NOREPINEPHRINE

a) While there are reports of patients whose TCA-induced shock was refractory to dopamine, but not to other agents (Heath et al, 1984; Teba et al, 1988; Hagerman & Hanashiro, 1981; Tran et al, 1997), most patients respond adequately to dopamine. Animal studies have yielded conflicting results regarding the efficacy of dopamine for TCA-induced hypotension; dosages used and varying experimental conditions limit the usefulness of these studies.
b) HUMAN DATA
c) ANIMAL DATA
d) DOSE

a) In a rat model, epinephrine infusion reversed tricyclic-induced hypotension (Knudsen & Abrahamsson, 1993; Knudsen & Abrahamsson, 1994). Another study showed that epinephrine and norepinephrine increased survival in a rat model of tricyclic poisoning; sodium bicarbonate had additive beneficial effects with the most effective treatment being epinephrine and sodium bicarbonate (Knudsen & Abrahamsson, 1997a).

a) CASE REPORT - A 25-year-old woman presented with respiratory arrest, hypotension, widened QRS complexes (129 milliseconds with a rate of 99/minute) and seizures after ingesting 300 imipramine 25 milligrams and unknown amount of propranolol and temazepam (Sener et al, 1995). She was treated with intubation and ventilation, polygeline, diazepam, gastric lavage, activated charcoal, phenytoin, sodium bicarbonate and 1 milligram of glucagon without improvement.
b) CASE REPORT - A 36-year-old woman who took an overdose of dothiepin (admission serum level of 2.58 mg/L) presented with tachycardia, hypotension (60/30 mmHg), mydriasis, and a Glasgow coma score of 7. She was intubated and ventilated after respiratory arrest. ECG revealed broad complex tachycardia with a QRS interval of 0.16 to 0.2 seconds.

a) A 56-year-old man presented to the emergency department (ED) unresponsive with tachycardia (105 bpm), hypotension (48/23 mmHg), and seizures after ingesting an unknown quantity of amitriptyline. He was given sodium bicarbonate, lorazepam, and a norepinephrine infusion. Despite administration of norepinephrine titrated to 20 mcg/min, his hypotension persisted. Five hours after presentation to the ED, a vasopressin infusion was initiated at 0.04 units/minute. Over the next 3 hours, his blood pressure improved, and the norepinephrine infusion was decreased. Over the next 30 hours, the patient was weaned off of all vasopressor agents (Barry et al, 2006).

a) CASE REPORT - A 65-year-old woman developed cardiopulmonary arrest following multi-drug ingestion, including amitriptyline and citalopram. After successful resuscitation, hypotension and bradycardia continued to persist and an ECG demonstrated wide complex bradycardia with QRS widening and QTC interval prolongation, an ejection fraction of 55%, and mild left ventricular hypertrophy. Despite infusions of norepinephrine (40 mcg/minute), vasopressin (4 units/hour), sodium bicarbonate, and insulin (80 units/hour), the patient's condition continued to deteriorate. In order to improve cardiac inotropic function and peripheral perfusion, the insulin infusion was then increased incrementally at doses of 1 unit/kg/hour (100 units/hour increases) over a 5-hour period, with concomitant decreases of norepinephrine and vasopressin. At a total dose of 600 units of insulin/hour (6 units/kg/hour), the vasopressors were discontinued. The patient's hemodynamic status began to stabilize, and after 36 hours of high-dose insulin infusion of 500 units/hour or greater, the infusion was gradually weaned by 50 units/hour increments. The patient gradually recovered with residual confusion and unsteadiness requiring some assistance (Holger et al, 2009).

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

a) DIAZEPAM
b) LORAZEPAM
c) RECURRING SEIZURES
d) PHENOBARBITAL

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

a) Although coma altered mental status may be reversed dramatically in some cases (Heiser & Wilbert, 1974; Granacher & Baldessarini, 1975; Aquilonius & Hedstrand, 1978), physostigmine should not be used just to reverse coma in cases of tricyclic antidepressant overdose.
b) Use of physostigmine in patients with acute tricyclic antidepressant overdose has been associated with seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980). Rapid IV administration of physostigmine may cause seizures, bradycardia, and asystole.

a) HUMAN STUDY - In a study of 4 patients who overdosed on tricyclic antidepressants with a QRS interval greater than 100 milliseconds, administration of ovine anti-TCA immune Fab fragments resulted in increased total TCA serum and urine levels and inconsistent changes in free TCA levels. The authors speculated that Fab administration resulted in redistribution of TCA's into serum from tissue (Heard et al, 1999).
b) Drug specific antibody Fab fragments have been shown to reduce tricyclic antidepressant-induced QRS prolongation in rats.
c) Brunn et al (1992) found the combined treatment with anti-TCA Fab and sodium bicarbonate reduced desipramine-induced QRS prolongation in rats to a greater extent than either treatment alone(Brunn et al, 1992).
d) In a rat model of severe tricyclic antidepressant toxicity administration of less than equimolar doses of antidesipramine Fab produced greater and more rapid improvement in cardiovascular status than no treatment (Dart et al, 1991).
e) In a rat model of desipramine toxicity, administration of ovine desipramine-specific Fab antibody fragments resulted in rapid reversal of cardiotoxicity with narrowing of the QRS interval observed in a dose-response relationship (Dart et al, 1996).
f) Hursting et al (1989), using a rabbit model of desipramine overdose, found that treatment with Fab induced significant changes in the concentrations of free and total desipramine in both serum and urine(Hursting et al, 1989).
g) Active immunization of rabbits against nortriptyline increased survival and reduced the fraction of unbound drug in plasma while increasing the plasma concentration of total drug after intraperitoneal amitriptyline injection (Sabouraud et al, 1990).
h) Rats treated with monoclonal anti-imipramine antibodies had reduced brain and heart imipramine concentration and increased serum imipramine concentrations compared with controls, suggesting that antibodies redistribute imipramine and reduce target tissue concentrations (Pentel et al, 1991).
i) Fab administration reduced QRS duration and increased blood pressure in desipramine poisoned rats (Pentel et al, 1994).
j) Fab prolonged survival during desipramine infusion by 58% compared with saline or albumin treated controls in a rat model (Pentel et al, 1995). The molar ratio of Fab to desipramine was 0.11.
k) In a rat model of severe desipramine toxicity, high doses of Fab (4 grams/kilogram) were associated with decreased QRS duration and increased blood pressure but increased mortality (3 of 18 Fab treated rats compared with 0 of 6 controls) (Keyler et al, 1994).

a) ORAL: Usual initial oral dose is 75 milligrams/day in divided doses. Dose can be increased to 150 milligrams/day in outpatients and 200 to 300 milligrams/day in hospitalized patients (Prod Info ELAVIL(R) oral tablets injection, 2000)..
b) INTRAMUSCULAR: Initially, the recommended dose is 20 to 30 milligrams (2 to 3 milliliters) four times daily (Prod Info ELAVIL(R) oral tablets injection, 2000).

a) ORAL: Usual oral dose is 100 to 200 milligrams/day to a maximum of 300 milligrams/day (Prod Info desipramine hcl oral tablets, 2006).

a) ORAL: For mild to moderate depression/anxiety, the usual dosage regimen is 75 to 150 milligrams/day, up to 300 milligrams/day in patients with severe depression/anxiety (Prod Info SINEQUAN(R) oral capsule, 2005).

a) HOSPITALIZED PATIENTS: The usual initial dose is 100 milligrams/day in divided doses. The dose may be increased up to 300 milligrams/day if needed (Prod Info TOFRANIL(R) tablets, 2005).
b) OUTPATIENTS: The usual initial dose is 75 milligrams/day. The dose may be increased up to 150 milligrams/day if needed. The maximum dose is 200 milligrams/day (Prod Info TOFRANIL(R) tablets, 2005).

a) ORAL: Usual initial dose is 75 to 100 milligrams/day in three or four divided doses. Dose can be increased to a maximum of 150 milligrams/day (Prod Info PAMELOR(R) oral capsules, oral solution, 2006).

a) ORAL: The recommended dose is 15 to 40 milligrams/day in divided doses, up to 60 milligrams/day (Prod Info VIVACTIL(R) tablets, 2004).

a) HOSPITALIZED PATIENTS: Initially, the recommended dose is 100 milligrams/day in divided doses, up to a MAXIMUM dose of 300 milligrams/day (Prod Info trimipramine maleate oral capsules, 2006).
b) OUTPATIENTS: Initially, the recommended dose is 75 milligrams/day in divided doses, up to a MAXIMUM dose of 200 milligrams/day if needed (Prod Info trimipramine maleate oral capsules, 2006).

a) Doses above 3.5 milligrams/kilogram of tricyclic antidepressants or serum concentrations higher than 150 nanograms/milliliter may increase the risk of asymptomatic electrocardiographic changes (slight prolongation of PR interval, moderate increase in QRS duration) indicative of delayed cardiac conduction in children and adolescents (Biederman, 1991).

a) DEPRESSION

a) 13 to 17 years: The usual recommended oral dose is 25 to 100 milligrams/day, up to a maximum dose of 150 milligrams/day (Prod Info NORPRAMIN(R) oral tablets, 2012).
b) 12 years and younger: Safety and efficacy have not been established (Prod Info NORPRAMIN(R) oral tablets, 2012).

a) DEPRESSION
b) ENURESIS

a) 13 to 17 years: The recommended dose is 30 to 50 milligrams/day given either as a single dose once daily or in divided doses (Prod Info PAMELOR(TM) oral capsules, oral solution, 2012).
b) 12 years and younger: Safety and efficacy have not been established (Prod Info PAMELOR(TM) oral capsules, oral solution, 2012).

a) ADOLESCENTS: The recommended dose is 5 milligrams 3 times daily, up to 20 milligrams/day (Prod Info VIVACTIL(R) tablets, 2004).

a) ADOLESCENTS: 50 milligrams/day, up to 100 milligrams/day (Prod Info trimipramine maleate oral capsules, 2006).

1) A 39-year-old woman experienced prolonged coma (for 5 days) and loss of brainstem reflexes following amitriptyline overdose. Two and 8 hours after the patient was found comatose, the GC/MS serum analysis revealed total TCA levels of 1,348 ng/mL (amitriptyline 1,310 ng/mL, nortriptyline 39 ng/mL) and 1,020 ng/mL (amitriptyline 868 ng/mL, nortriptyline 152 ng/mL), respectively (Roberge & Krenzelok, 2001).
2) A 44-year-old woman developed coma and abnormal atrial and ventricular repolarization resembling acute infarction following ingestion of an unknown amount of amitriptyline (serum amitriptyline 4880 ng/mL at presentation). In addition, migrating ST segment elevation to another territory with abnormally inflected T wave (mimicking subepicardial injury) was noted. After 10 days in the intensive care unit, she recovered with no apparent neurological sequelae (Zakynthinos et al, 2000).
3) A 27-year-old man, who intentionally ingested 85 50-mg amitriptyline tablets (total dose 4.25 g) was comatose (Glasgow coma score [GCS] of 3) and developed hypotension, seizures, and persistent pulseless ventricular tachycardia requiring continued resuscitative efforts with CPR and IV boluses of epinephrine and sodium bicarbonate. With administration of intralipids with IV infusions of epinephrine and norepinephrine, the patient gradually recovered (Engels & Davidow, 2010).

1) A 2-year-old child presented to the emergency department comatose (Glasgow Coma Scale of 8), tachycardic (170 bpm) and hypotensive (60/40 mmHg) approximately 1 hour after ingestion of 500 mg (35.7 mg/kg) of amitriptyline. Within 10 min post-presentation, the patient developed generalized seizures responsive to IV benzodiazepines. With supportive therapy, he gradually recovered, without sequelae, and was discharged 2 weeks post-ingestion (Deegan & O'Brien, 2006).
2) Seizure-like movements and altered mental status were reported in an 8-year-old child who ingested one 25-mg (0.8 mg/kg) amitriptyline tablet (Grover et al, 2012).
3) ADOLESCENTS: Intentional overdose ingestions of amitriptyline were reported in 3 adolescent girls. The first patient, a 13-year-old, ingested 25 mg/kg amitriptyline and subsequently became comatose (Glasgow Coma Scale (GCS) score of 3) and acidotic. The second patient, a 14-year-old, was unresponsive (GCS of 4), and developed hypotension and first degree AV block after ingesting 18 mg/kg amitriptyline. The third patient, a 16-year-old, developed hypotension, first degree AV block, pancytopenia, and hypokalemia after ingesting 12 mg/kg amitriptyline and 0.15 mg/kg colchicine. All 3 patients recovered without sequelae after receiving therapeutic plasma exchange and supportive care (Bayrakci et al, 2007).
4) A retrospective review of amitriptyline poisoning cases in pediatric patients (n=52; age range 1 to 14 years, mean age 4.6 years) reported the development of lethargy, coma, hypotension, tachycardia, and seizures. The mean ingested amitriptyline dose, known in 23 patients, was 9.4 +/- 5.8 mg/kg (range 2.3 to 27 mg/kg, median 8.6 mg/kg) (Olgun et al, 2009).
5) CASE REPORT/INFANT: An 18-month-old infant ingested approximately 57 mg/kg amitriptyline and, within 3 hours, became comatose (Glasgow coma score of 6), and developed supraventricular tachycardia, hypotension, and seizures. Following hemoperfusion, the patient gradually recovered and was discharged approximately 5 days post-ingestion (Mutlu et al, 2011).
6) CHRONIC OVERDOSE: Generalized tonic-clonic seizures and ECG abnormalities were reported in a 6-year-old child who had been receiving 300 mg (15 mg/kg) amitriptyline every night for 1 month instead of the prescribed 30 mg nightly for treatment of insomnia secondary to ADHD. With supportive treatment, the patient recovered and was discharged on hospital day 7 (Clement et al, 2012).

1) A 30-year-old woman ingested 2950 mg desipramine, developed seizures, respiratory arrest, cardiac dysrhythmia and circulatory collapse, and survived (Hughes & Rome, 1984).

1) A 3-year-old girl (weight unknown, estimated 15 kilograms) ingested 100 mg desipramine and developed severe toxicity including cardiac dysrhythmias and seizures. The child survived without permanent sequelae (Jue, 1976).

1) A successful treatment with hemoperfusion over hemoresin and hemodialysis in a 37-year-old man (after ingestion of at least 5000 mg doxepin) lowered the doxepin plasma level from 5150 (toxic>500, therapeutic 100-250 mcg/L) to 1150 mcg/L (Frank & Kierdorf, 2000).
2) Torsade de pointes tachycardia due to the long QT syndrome was reported in a 50-year-old woman after taking 60 doxepin tablets (6 grams); maximum serum level of doxepin was 2845 nmol/L 12 hours after admission (Alter et al, 2001).

1) A 5-year-old girl developed CNS depression, hypotension, and tachycardia after receiving a total of 1329 mg doxepin-containing cream topically used for exanthematous rash. The patient completely recovered 18 hours after presentation (Toerne et al, 1997).
2) Topical administration of 30 grams of doxepin 5% cream in 24 hours for a generalized eczematous rash resulted in altered mental status and ECG changes in a 5-year-old girl. Serum concentrations of doxepin and desmethyldoxepin (major active metabolite) were 11.95 nanograms per milliliter (ng/mL) and 17.71 ng/mL, respectively. Eighteen hours following skin decontamination with soap and water, a full recovery was made and the patient was discharged (Zell-Kanter et al, 2000).

1) A 27-year-old woman survived ventricular fibrillation, cardiovascular collapse, and seizures after a massive ingestion of imipramine in a suicide attempt. Plasma imipramine levels reached a peak of 6000 nanograms/mL (Sandeman et al, 1997).

1) A 13 year-old boy ingested 1000 mg imipramine, developed seizures, respiratory arrest, and coma, and survived (Pulst & Lombroso, 1983).
2) A 15-year-old girl required a temporary pacemaker, as well as hemodialysis and hemoperfusion, after intentionally ingesting 12 25-mg imipramine tablets (approximately 6 mg/kg) and subsequently developing hypotension and junctional escape rhythm, refractory to standard supportive measures (Sert et al, 2011).
3) An 18-month-old child lost consciousness for 5 minutes, and developed facial twitching, up-rolling eyes, metabolic acidosis, hypotension, and ECG abnormalities (widened QRS complex, sinus tachycardia) after a suspected ingestion of approximately 7 25-mg imipramine tablets. The patient gradually recovered following supportive therapy, including IV sodium bicarbonate and dopamine infusions (Hon et al, 2015).

1) Ingestions of up to 1.875 grams have been reported with recovery in adults (Rendoing et al, 1969).

a) The therapeutic range for most tricyclic antidepressants is 100 to 260 nanograms/milliliter.
b) Sirota et al (1990) studied 20 patients taking up to 150 milligrams/day amitriptyline. Levels found 3 weeks after initiation of treatment were: amitriptyline, approximately 114 nanograms/milliliter; and nortriptyline, 178 nanograms/milliliter (Sirota et al, 1990).
c) Therapeutic doses of nortriptyline in elderly patients resulted in an increased PR interval associated with increasing nortriptyline concentrations, and increased QRS duration and QTc intervals associated with increasing Z-10 hydroxynortriptyline metabolite concentration (Schneider et al, 1988).

a) TRIMIPRAMINE: Therapeutic blood or plasma concentrations: 0.01-0.24 milligram/liter (Musshoff et al, 1999).

a) The therapeutic range for most tricyclic antidepressants is 100 to 260 nanograms/milliliter with toxic symptoms sometimes seen below 500 nanograms/milliliter. Serious symptoms are usually associated with levels greater than 1000 nanograms/milliliter.
b) The development of delirium and seizures was associated with TCA plasma levels above 300 nanograms/milliliter and 1000 nanograms/milliliter respectively.
c) Lethal tricyclic antidepressant levels reported from forensic studies have ranged from 4000 to 80000 nanomoles/liter (1100 to 21800 nanograms/milliliter).
d) Patients with severe burns may have unusually high therapeutic levels of tricyclics without experiencing toxicity.
e) Seizures were only reported in patients with serum levels of 1000 nanograms/milliliter or greater in a study of 187 cases (Lavoie et al, 1990).

a) A 6-year-old girl developed seizures and ECG abnormalities after taking 300 mg (15 mg/kg) of amitriptyline every night for 1 month instead of the prescribed 30 mg nightly for treatment of insomnia secondary to ADHD. Her total amitriptyline/nortriptyline concentration, obtained at hospital admission, was 1676 ng/mL (normal therapeutic, 50 to 300 ng/mL). With supportive treatment, the patient gradually recovered and was discharged, without apparent sequelae, approximately 7 days post-admission (Clement et al, 2012)
b) FATALITIES/POSTMORTEM -

a) BURNS: Patients with severe burns may have unusually high therapeutic levels of tricyclics without experiencing toxicity. One patient had a plasma amitriptyline level of 480 micrograms/liter without clinical evidence of toxicity (Crompton et al, 1991).

a) 305 mg/kg

a) 464 mg/kg

a) 320 mg/kg

a) 450 mg/kg

a) 660 mg/kg

a) 518 mg/kg

a) >2500 mg/kg

a) 5580 mg/kg