1) Prolonged duration of coma (20 hours) has been reported in one case.
2) Ataxia has also been reported.

a) The most frequent cardiovascular side effect during therapy is postural hypotension, which may be accompanied by syncope, especially in patients taking concomitant antihypertensive therapy (Rakel, 1984) (Spivak et al, 1987).

a) SUMMARY
b) PERSISTENT HYPOTENSION

a) CASE REPORT: One case of first-degree atrioventricular block has been described following ingestion of an unknown amount of trazodone along with oxazepam in a 65-year-old woman, which did not require treatment (Lippmann et al, 1982).
b) CASE SERIES: One case of first-degree atrioventricular block (coingestants alprazolam and ibuprofen) and 2 cases of right bundle branch block (coingestants amphetamines in one case and quinidine plus lorazepam in the other) were reported to the manufacturer in 88 cases reviewed (Gamble & Peterson, 1986).
c) Reports of cardiovascular/electrocardiographic toxicity of trazodone have not always ruled out coingestants or underlying cardiac disease.

a) In a retrospective study of 40 patients who had ECGs after trazodone overdose, a significant percentage of patients were found to have ECG abnormalities and/or dysrhythmias. Patients with underlying cardiac disease, an abnormal baseline ECG, or ingestion of other agents known to alter cardiac conduction were excluded. Eleven of the 40 patients (32%) developed dysrhythmias, including torsade de pointes (2), ventricular bigeminy (2), supraventricular tachycardia (2), atrial fibrillation (1), first-degree atrioventricular block (2), and intraventricular conduction delay (2). Prolongation of the QTc interval developed in 77% of patients and all patients with dysrhythmias had prolonged QTc (Tibbles et al, 1997).

a) Trazodone does not appear to produce tachycardia, even in patients with hypotension, and consistently lowers baseline heart rate in therapeutic doses (Himmelhoch et al, 1984).

a) CASE REPORT: Severe bradycardia and hypotension were reported in a 32-year-old woman who ingested 1000 mg of trazodone (20 mg/kg). Bradycardia developed about 4 hours postingestion and persisted for 32 hours (Dubot et al, 1986).
b) Reports of cardiovascular/electrocardiographic toxicity of trazodone have not always ruled out coingestants or underlying cardiac disease.

a) ECG changes are uncommon after overdose. In a review of 88 cases spontaneously reported to the manufacturer, 5 developed ECG changes.
b) CASE SERIES: Two patients with coingestants developed right bundle-branch block, one had T-wave inversion after trazodone alone, and the other had transient first-degree atrioventricular block (Gamble & Peterson, 1986).
c) CASE REPORT: One elderly patient developed torsades de pointes following a trazodone overdose (Augenstein et al, 1987).
d) CASE REPORT: Nonspecific ST-T wave changes along with up to 5 ventricular premature beats per minute were reported in a 58-year-old woman who ingested 6 g of trazodone, along with lithium, theophylline, and aspirin (Gamble & Peterson, 1986).
e) In 23 adult overdoses with trazodone alone, no cardiovascular abnormalities were reported, but ECGs were not examined (Ali & Henry, 1986).
f) In one case of a 3 g overdose, sinus tachycardia was reported which resolved quickly (Roberge et al, 2001).
g) Reports of cardiovascular/electrocardiographic toxicity of trazodone have not always ruled out coingestants or underlying cardiac disease.

a) CASE REPORT: There is one report of complete heart block with an idio-junction rhythm (rate 36 beats/minute), requiring pacemaker insertion, in a 77-year-old man who received a single dose of 50 mg 40 minutes previously. This patient appeared to have an underlying conduction defect (Rausch et al, 1984).
b) CASE REPORT: First-degree heart block was reported in a 74-year-old man after increasing the trazodone dose to 125 mg twice a day. The P-R interval normalized after dose reduction (Irwin & Spar, 1983).

a) CASE REPORTS: In 3 patients, aged 26, 61 and 41 years, with preexisting cardiac disease, therapeutic use of trazodone appears to have exacerbated premature ventricular contractions in 2 cases and ventricular tachycardia in one case (Janowsky et al, 1983; Vlay & Friedling, 1983).
b) CASE REPORT: In a hospitalized patient who developed ventricular fibrillation following surgery, administration of trazodone 75 mg for 3 days was associated with sinus tachycardia alternating with bradycardia and sinus arrest, hypotension, and premature ventricular contractions (Pellettier & Bartolucci, 1984).
c) CASE REPORT: Exercise-induced nonsustained ventricular tachycardia was described in a 79-year-old woman with no underlying heart disease who was receiving trazodone 50 mg twice daily. The relationship to trazodone was confirmed by treadmill testing initially, following discontinuation, and after rechallenge with trazodone (Vitullo et al, 1990).

a) CASE SERIES: Trazodone 150 mg, administered in a single dose to 8 healthy volunteers, was found to significantly prolong the QTc interval and decrease T wave height at 30 minutes postingestion (Burgess et al, 1982).

a) QTc prolongation can be expected to be part of the clinical picture of overdose. The QTc interval was prolonged on day 1 but not on day 15 in another study (Van de Merwe et al, 1984).
b) CASE SERIES: In a retrospective review of 40 patients with trazodone ingestion, 77% developed prolonged QTc and 11 patients developed dysrhythmias (Tibbles et al, 1997). All patients who developed dysrhythmias had prolonged QTc intervals.
c) CASE REPORT: A 36-year-old man reported that he had intentionally ingested 80 tablets of a combination of trazodone and another agent thought to be buspirone. An initial ECG showed normal sinus rhythm with a QT interval of 440 msec in lead II to 580 msec in leads V1 and V4 (QTc 491 to 646 msec); the ECG normalized within 13 hours. Serum trazodone was greater than 3000 mcg/L (reference range: 750 to 1600 mcg/L) at the time of admission and was 0 within 36 hours. A toxicology screen was negative; buspirone was not detected (Dattilo & Nordin, 2007).
d) CASE REPORT: A 20-year-old woman intentionally ingested 1.5 g of trazodone. An initial ECG showed significant QT prolongation of 510 msec (QTc 490 msec). Laboratory analysis was normal along with a negative toxicology screen. The QT returned to normal within 12 hours; however, the PR progressively increased in the first 12 hours postingestion. The ECG normalized and the patient was clinically improved within 24 hours and was discharged to home (Service & Waring, 2008).
e) CASE REPORT: Prolonged corrected QT interval (607 msec), sinus bradycardia (57 beats/min) and nonspecific T-wave changes without dysrhythmia or other significant adverse effects, were reported in a 29-year-old woman 12 hours following an overdose of 3000 mg trazodone. ECG 26 hours postingestion showed a less prolonged, corrected QT interval (486 msec) and the same nonspecific T wave changes. No baseline ECG was available. Complete recovery ensued (Levenson, 1999).
f) CASE REPORT: A case of torsades de pointes related to a prolonged QT interval (QT/QTc: 520/370 msec) has been reported in a 37-year-old woman following an overdose of 20 trazodone tablets in conjunction with ethanol. Severe hypotension (blood pressure 70/40 mmHg) and a relative bradycardia were noted on admission. Marked hypokalemia (2.7 mmol/L) was noted during the first episode of torsades de pointes but not with the second episode. Inotropic support was required for 6 days as was correction of the QT/QTc interval (Wittebole et al, 2007).

a) CASE REPORT: A 30-year-old woman presented with significant drowsiness 2 hours after ingesting approximately 2000 mg of trazodone. An initial ECG showed sinus dysrhythmia with one ventricular premature complex, nonspecific ST-T wave abnormality, prolonged QR interval 554 msec with corrected QR interval 631 msec. Approximately 30 minutes after the first ECG, she collapsed and another ECG revealed polymorphic ventricular dysrhythmias (torsades de pointes). Following successful defibrillation and infusion of magnesium sulfate, she recovered and was discharged 13 hours after admission (Chung et al, 2008).

a) CASE REPORT: Brief intubation and ventilation were required in a 65-year-old woman who overdosed on an unknown amount of trazodone (Lippmann et al, 1982).
b) CASE SERIES: Respiratory arrest, requiring intubation and ventilatory assistance, was reported in a 40-year-old woman who ingested 2200 mg of trazodone alone and in a woman who ingested 3000 mg of trazodone alone (Gamble & Peterson, 1986).

1) Prolonged duration of coma (20 hours) has been reported in one case.
2) Ataxia has also been reported.

a) CASE REPORT: Generalized seizures have been described in a 50-year-old patient with a preexisting abnormal EEG, but no history of seizures following trazodone therapy with 50 mg/day for 18 days (Lefkowitz et al, 1985).
b) The manufacturer had received approximately 30 reports of seizures, the majority in patients with a history of seizures, focal CNS lesions, or concomitant use of other medications.
c) CASE REPORT: Another report described a 47-year-old man who developed complex partial seizures after treatment with trazodone 150 mg/day for 3 weeks. EEG findings were abnormal after discontinuation of trazodone and it was speculated that trazodone unmasked an underlying seizure disorder (Tasini, 1986).

a) CASE REPORT: Respiratory arrest and seizures were reported in a patient who took 2 to 3 g in an overdose (Flomenbaum & Price, 1986).
b) CASE REPORT: Two brief tonic-clonic seizures and hyponatremia (sodium 118 mmol/L) developed in a 72-year-old woman approximately 30 hours following an overdose of 350 mg trazodone. The patient had also concurrently been on oxazepam and propranolol at the time of the overdose. Treatment consisted of intravenous diazepam and fluid restriction. She was discharged 9 days after her overdose with no further seizures (Balestrieri et al, 1992).
c) CASE REPORT: Seizures and hyponatremia (sodium 106 mmol/L) were reported about 40 hours following a 1200-mg overdose in a 60-year-old woman. CT of the brain was normal. Following clonazepam therapy and fluid restriction, the seizures and hyponatremia resolved over a 3-day period (Vanpee et al, 1999).
d) CASE SERIES: In a review of 88 unpublished overdoses reported to the manufacturer, seizures were seen in 2 cases (trazodone alone 3 grams in one case and trazodone 750 mg plus alprazolam 13 mg in the other) (Gamble & Peterson, 1986).

a) CASE REPORT: Myoclonus was reported in a 38-year-old woman receiving 300 mg/day (Patel et al, 1988). This may be related to serotonergic activity.

a) The most common manifestation of overdose is CNS depression. Lethargy, drowsiness, and ataxia are the most frequent symptoms (Chung et al, 2008; Roberge et al, 2001; Henry et al, 1984).
b) In one case, Roberge et al (2001) reported intermittent somnolence from which the patient could easily be aroused following a 3 g overdose (Roberge et al, 2001).
c) CASE SERIES: Drowsiness was reported in 11 of 22 adult patients who overdosed on trazodone alone (Henry et al, 1984).

a) The prolonged duration of coma (20 hours) in one case may indicate involvement of an active metabolite, possibly m-chlorophenylpiperazine (Caccia et al, 1982).

a) CASE SERIES: The most common manifestation of overdose is CNS depression, ranging from lethargy to coma. In 22 adult patients with sole ingestions of trazodone, 2 were comatose (grade 2 to 3 on the Edinburgh scale) (mean dose 1.4 grams) (Henry et al, 1984).

a) CASE SERIES: Ataxia was reported in 5 of 22 adults who overdosed on trazodone alone (Henry et al, 1984).

a) Seizures were not reported in a series of 44 adult patients who overdosed on trazodone (Ali & Henry, 1986). Seizures were also not found in a series of 26 trazodone overdoses (Wedin et al, 1986).

a) Nausea and vomiting are relatively common after overdose.

a) CASE REPORT: Anorexia and hypomania were reported in a patient given 100 mg trazodone and 500 mg of tryptophan 3 times a week. Appetite returned when trazodone was discontinued (Patterson & Srisopark, 1989).

a) Cholestasis has resulted from the therapeutic use of trazodone.
b) CASE REPORT: A 75-year-old woman presented to ED with jaundice, dark urine, pale stools, nausea, and anorexia. Liver function and serologic tests revealed a chronic active hepatitis. The patient was taking no other medication and had no history of alcohol or intravenous drug use or blood transfusions. Prothrombin and thromboplastin times were elevated and remained elevated despite 3 days of vitamin K therapy (Beck et al, 1993).
c) CASE REPORT: Acute reversible hepatic damage after 18 months of trazodone and corticosteroid therapy was reported in a 38-year-old woman. Liver biopsy revealed a cholestatic process. All medications were stopped and her liver enzyme tests started to improve. Following an inadvertent rechallenge with trazodone, liver enzyme levels immediately began to increase. Trazodone was again stopped and the patient's liver function returned to normal (Fernandes et al, 2000).

a) Priapism has been seen as an adverse effect from therapeutic doses (Prod Info Desyrel(R),, 2003) (Scher et al, 1983) (Hanno et al, 1988; Carson et al, 1988).
b) CASE SERIES: Surgery was required in 26 of 84 cases reported to the manufacturer, and permanent impotence has been a sequela (Hayes & Kristoff, 1986).
c) CASE REPORT: A 34-year-old woman presented with priapism of the clitoris after taking trazodone for 5 days while withdrawing from fluoxetine. Both medications were discontinued and an alpha-adrenergic agonist (phenylpropanolamine) was administered. Within 24 hours the clitoral priapism had resolved (Pescatori et al, 1993).
d) Prolonged or inappropriate erections should be referred to a physician after immediately discontinuing the drug.

a) Priapism has been seen rarely after overdose.
b) CASE REPORT: A 24-year-old man who took 3.5 g of trazodone developed priapism (Gamble & Peterson, 1986).

a) CASE REPORT: A 40-year-old man had been using trazodone for one month prior to admission, with no history of any other concurrent drug or chemical use. He was admitted for perianal furuncles. Hematology laboratory values were normal with the exception of an elevated erythrocyte sedimentation rate (ESR) and decreased leukocyte count of 3.7 x 10(9) (normal range of 4 to 10). Differential cell count was reported to be 74% lymphocytes, 25% monocytes, and 1% eosinophils (absolute neutrophil count 0). Pus from his furuncles yielded Staphylococcus aureus. Treatment was instituted with flucloxacillin. Trazodone therapy was discontinued. Four days later, his leukocyte count had increased and ESR had decreased. Eleven days after admission, laboratory values had returned to normal (Van der Klauw et al, 1993).

a) Muscle weakness has been reported in overdose (Lesar et al, 1983).

a) Although cardiovascular toxicity has been minimal in reports of overdose, ECG monitoring is recommended since reports of cardiotoxicity have occurred. There are insufficient data to determine the duration of monitoring required.

a) Monitor vital signs. Hypotension and bradycardia have been reported rarely following overdoses. Hypotension requiring prolonged (6 days) inotropic support has been reported in overdose (Wittebole X, Jacquet L & Wallemacq P et al, 2000).
b) Monitor for signs of CNS depression. In rare cases, prolonged coma has resulted following overdose.

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) 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) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

a) Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
b) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or treat with intravenous dextrose ADULT: 100 mg IV, CHILD: 2 mL/kg 25% 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) Priapism is an emergency requiring immediate consult with a urologist.
b) It has been suggested that administration of anticholinergics (ie, benztropine) or beta-blockers may be effective in reversing trazodone-induced priapism, but clinical studies are needed to verify efficacy (Fishbain, 1989).

a) The following American Urological Association Guideline has been developed to evaluate and treat priapism (Montague et al, 2003):

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, 1992a). 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) CASE REPORTS: Levels as high as 15,000 and 19,000 ng/mL have been described after overdoses of 4 to 5 g. Blood levels as high as 28 mcg/mL (28,000 ng/mL) have been reported to the manufacturer. In these 2 patients, drowsiness and ataxia were the only manifestations of toxicity (Personal Communication, 1987).
b) CASE REPORT: A 36-year-old man reported that he had intentionally ingested 80 tablets of a combination of trazodone and another agent thought to be buspirone. He was alert and oriented at the time of admission with a prolonged QT interval. Upon admission, serum trazodone was greater than 3000 mcg/L (reference range: 750 to 1600 mcg/L) and was 0 within 36 hours. A toxicology screen was negative; an ethanol level was 41 mg/dL. Buspirone was not detected (Dattilo & Nordin, 2007).
c) CASE REPORT: Coma was described in a patient with a level of 4200 ng/mL 18 hours after admission and in a patient with a level of 8200 ng/mL 20 hours after admission. Both of these patients had coingestants which may have contributed to coma (Henry et al, 1984).

a) A postmortem blood level of 32.91 mg/L of trazodone has been reported in an acute trazodone, fluoxetine, and ethanol overdose in a 32-year-old which resulted in death (Goeringer et al, 2000).
b) The postmortem blood concentrations of trazodone and its metabolite, m-chlorophenyl-piperazine, were 4.9 mg/L and 0.6 mg/L, respectively, in an 86-year-old man who died following an intentional ingestion of an unknown amount of trazodone (Martinez et al, 2005).

a) 475 mg/kg (RTECS, 2001)

a) 210 mg/kg (RTECS, 2001)

a) 610 mg/kg (RTECS, 2001)

a) greater than 1 g/kg (RTECS, 2001)

a) 178 mg/kg (RTECS, 2001)

a) 690 mg/kg (RTECS, 2001)