SEROTONIN SYNDROME

• TREATMENT
  • MONITORING
    • B. Serum electrolytes, glucose, renal function tests, CK and an ECG are recommended in all patients with suspected serotonin syndrome.
    • C. Obtain liver function tests, PT/PTT or INR, platelets, and arterial blood gases in patients with severe hyperthermia, hypotension or other severe effects.
  • 6.5 ORAL EXPOSURE
    • 6.5.2 PREVENTION OF ABSORPTION
      • A. SUMMARY
        • 1. Gastric decontamination may be useful if serotonin syndrome develops in the setting of recent overdose. Decontamination is generally not indicated if serotonin syndrome develops after therapeutic dosing.
  • B. GASTRIC LAVAGE
    • 1. INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
      • a. Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
  • 2. PRECAUTIONS:
    • a. SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    • b. AIRWAY PROTECTION: Alert patients - place in Trendelenburg and left lateral decubitus position, with suction available. Obtunded or unconscious patients - cuffed endotracheal intubation.
  • 3. LAVAGE FLUID:
    • a. Use small aliquots of liquid. Lavage with 150 to 200 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in children over 5 or adults) and 10 milliliters/kilogram body weight of normal saline in young children. Continue 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.
  • 4. COMPLICATIONS:
    • 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.
    • b. Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
  • 5. CONTRAINDICATIONS:
    • 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.
  • C. ACTIVATED CHARCOAL
    • 1. CHARCOAL ADMINISTRATION
      • a. Consider administration of activated charcoal after a potentially toxic ingestion (Chyka & Seger, 1997). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
  • 2. CHARCOAL DOSE
    • 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; and 1 gram/kilogram in infants up to 1 year old (USP DI, 2000; Chyka & Seger, 1997).
      • (1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (Barceloux et al, 1997).
  • b. ADVERSE EFFECTS/CONTRAINDICATIONS
    • (1) Complications: emesis, aspiration (Chyka & Seger, 1997). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    • (2) Contraindications: unprotected airway, gastrointestinal tract not anatomically intact, therapy may increase the risk or severity of aspiration; ingestion of most hydrocarbons (Chyka & Seger, 1997).
  • 6.5.3 TREATMENT
    • A. HYPERTHERMIA
      • 1. Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
      • 2. MUSCLE ACTIVITY - Benzodiazepines may be useful. 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.
      • 3. Non-depolarizing paralytics may be used in severe cases.
  • B. HYPERTENSION
    • 1. Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention may not be necessary. For hypertensive emergencies (emergent need to lower mean BP 30 percent within 30 minutes and achieve diastolic BP of 100 mmHg or less within one hour), nitroprusside is preferred.
    • 2. NITROPRUSSIDE
      • a. NITROPRUSSIDE/INDICATIONS
        • (1) Nitroprusside is preferred for hypertensive emergencies (emergent need to lower mean arterial pressure by 20 to 25 percent within one hour, or evidence of end organ (CNS, cardiac, renal) damage).
  • b. NITROPRUSSIDE/DOSE
    • (1) Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required. Frequent hemodynamic monitoring and administration by an infusion system that ensures a precise flow rate is mandatory.
  • c. NITROPRUSSIDE/SOLUTION PREPARATION
    • (1) Dilute a 50-milligram vial in 500 milliliters of dextrose 5 percent in water (100 micrograms/milliliter). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution.
  • d. NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    • (1) Severe hypotension; thiocyanate or cyanide toxicity; methemoglobinemia; lactic acidosis; chest pain or dysrhythymias (high doses). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions.
  • e. NITROPRUSSIDE/MONITORING PARAMETERS
    • (1) Monitor blood pressure every 30 to 60 seconds at onset of drip; once stabilized, monitor every 5 minutes.
  • 3. NITROGLYCERIN
    • a. In theory, nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin.
    • b. ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
    • c. CHILD - Begin infusion at 0.25 to 0.5 micrograms/kilogram/minute and titrate to desired effect.
  • C. HYPOTENSION
    • 1. Administer 10 to 20 milliliters/kilogram 0.9% saline bolus and place patient in Trendelenburg position. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    • 2. Control hyperthermia.
    • 3. Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution.
    • 4. DOPAMINE
      • a. PREPARATION: Add 200 or 400 milligrams to 250 milliliters of normal saline or dextrose 5% in water to produce 800 or 1600 micrograms per milliliter or add 400 milligrams to 500 milliliters of normal saline or dextrose 5% in water to produce 800 micrograms per milliliter.
      • b. DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed. Norepinephrine should be added if more than 20 micrograms/kilogram/minute of dopamine is needed.
      • c. CAUTION: If VENTRICULAR DYSRHYTHMIAS occur, decrease rate of administration. Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred.
  • 5. NOREPINEPHRINE
    • a. PREPARATION: Add one milligram norepinephrine to 250 milliliters of dextrose 5% in water to produce 4 micrograms/milliliter.
    • b. DOSE
      • (1) ADULT: 2 to 3 milliliters (8 to 12 micrograms)/minute
      • (2) ADULT AND CHILD: 0.1 to 0.2 microgram/kilogram/minute. Titrate to maintain adequate blood pressure.
      • (3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised.
  • D. SEIZURES
    • 1. SUMMARY
      • a. Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbital. Benzodiazepines and barbiturates are generally preferred over phenytoin for the control of overdose or withdrawal related seizures.
      • b. Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
      • c. Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or treat with intravenous dextrose ADULT: 50 milliliters IV, CHILD: 2 milliliters/kilogram 25% dextrose).
  • 2. DIAZEPAM
    • a. MAXIMUM RATE: Administer diazepam intravenously over 2 to 3 minutes (maximum rate = 5 milligrams/minute).
    • b. ADULT DIAZEPAM DOSE: 5 to 10 milligrams initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    • c. PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 milligram per kilogram repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    • d. RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (generally use twice the usual initial dose because of decreased absorption), or lorazepam may be given intramuscularly.
    • e. MIDAZOLAM: has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. PEDIATRIC MIDAZOLAM DOSE: INTRAMUSCULAR: 0.2 milligram/kilogram (maximum 7 milligrams) (Chamberlain et al, 1997); INTRANASAL: 0.2 milligram/kilogram (Lahat et al, 2000). Buccal midazolam, 10 milligrams, 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).
  • 3. LORAZEPAM
    • a. MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 milligrams/minute (Prod Info Ativan(R), 1999).
    • b. ADULT LORAZEPAM DOSE: 2 to 8 milligrams intravenously. Initial doses may be repeated in 10 to 15 minutes if seizures persist (Prod Info, Ativan(R), 1999; AMA, 1991).
    • c. PEDIATRIC LORAZEPAM DOSE: 0.05 to 0.1 milligram/kilogram intravenously, (maximum 4 milligrams/dose) repeated twice at intervals of 10 to 15 minutes (Benitz & Tatro, 1995).
  • 4. PHENOBARBITAL
    • a. ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 milligrams of phenobarbital intravenously initially (10 to 20 milligrams per kilogram) diluted in 60 milliliters of 0.9 percent saline given at 25 to 50 milligrams per minute.
    • b. ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 milligrams may be given every 20 minutes.
    • c. MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 milligrams/minute until seizure control was achieved.
    • d. PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 milligrams per kilogram of phenobarbital intravenously at a rate of 25 to 50 milligrams per minute.
    • e. PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 milligrams per kilogram may be given every 20 minutes.
    • f. MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 milligrams/kilogram within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    • g. MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation.
    • h. NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 milligrams/kilogram intravenously at a rate of no more than 1 milligram/kilogram per minute in patients with no preexisting phenobarbital serum levels.
    • i. NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 milligrams/kilogram every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 micrograms/milliliter.
    • j. MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 milligrams/kilogram/minute up to a total of 30 milligrams/kilogram have been tolerated in neonates.
    • k. CAUTIONS: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    • l. SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (20 to 40 micrograms per milliliter).
  • 5. PHENYTOIN/FOSPHENYTOIN
    • a. Benzodiazepines and/or barbiturates are generally preferred to phenytoin or fosphenytoin in the treatment of drug or withdrawal induced seizures.
    • b. PHENYTOIN
      • (1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION: Manufacturer does not recommend intravenous infusions due to lack of solubility and resultant precipitation, however infusions are commonly used.
        • (a) Administer phenytoin undiluted, by very slow intravenous push or dilute 50 milligrams per milliliter solution in 50 to 100 milliliters of 0.9 percent saline.
  • (2) PHENYTOIN ADMINISTRATION RATE: Rate of administration by either method should not exceed 0.5 milligram per kilogram per minute or 50 milligrams per minute.
  • (3) ADULT PHENYTOIN LOADING DOSE: 15 to 18 milligrams per kilogram of phenytoin initially. Rate of administration by very slow intravenous push or diluted to 50 milligrams per milliliter should not exceed 0.5 milligram per kilogram per minute or 50 milligrams per minute.
  • (4) ADULT PHENYTOIN MAINTENANCE DOSE: Manufacturers recommend a maintenance dose of 100 milligrams orally or intravenously every 6 to 8 hours. The goal is to maintain a serum concentration between 10 to 20 micrograms/milliliter.
  • (5) PEDIATRIC PHENYTOIN LOADING DOSE: 15 to 20 milligrams per kilogram or 250 milligrams/square meter of phenytoin. Rate of intravenous administration should not exceed 0.5 to 1.5 milligrams per kilogram per minute.
  • (6) PEDIATRIC PHENYTOIN MAINTENANCE DOSE: Repeat doses of 1.5 milligrams per kilogram may be given every 30 minutes to a maximum daily dose of 20 milligrams per kilogram.
  • (7) CAUTIONS: Administer phenytoin while monitoring ECG. Stop or slow infusion if arrhythmias or hypotension occur. Be careful not to extravasate. Follow each injection with injection of sterile saline through the same needle.
  • (8) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (10 to 20 micrograms per milliliter).
  • c. FOSPHENYTOIN
    • (1) ADULT DOSAGE AND ADMINISTRATION: The dose, concentration in dosing solutions, and infusion rate of fosphenytoin are expressed as phenytoin sodium equivalents.
    • (2) ADULT LOADING DOSE FOSPHENYTOIN: 15 to 20 milligrams/kilogram of phenytoin sodium equivalents at a rate of 100 to 150 milligrams phenytoin equivalent/minute.
    • (3) Fosphenytoin should not be infused at rates greater than 150 milligrams phenytoin equivalent/minute because of the risk of hypotension.
    • (4) CAUTIONS: Perform continuous monitoring of respiratory function, cardiac rhythm, and blood pressure throughout infusion and for at least 30 minutes thereafter.
    • (5) ADULT MAINTENANCE DOSING: 4 to 6 milligrams phenytoin equivalents/kilogram/day. Rate of administration should not exceed 150 milligrams phenytoin equivalent/minute.
    • (6) SERUM LEVEL MONITORING: Monitor serum phenytoin levels over the next 12 to 24 hours; therapeutic levels 10 to 20 microgram/milliliter. Do not obtain serum phenytoin concentrations until at least 2 hours after infusion is complete to allow for conversion of fosphenytoin to phenytoin.
  • E. PULMONARY EDEMA/NON-CARDIOGENIC
    • 1. ONSET: Respiratory tract irritation or injury can progress to pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    • 2. NON-PHARMACOLOGIC TREATMENT: Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 milliliters/kilogram) is preferred if ARDS develops.
      • a. To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 milliliters/kilogram) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000).
  • 3. FLUIDS: Crystalloid solutions must be administered cautiously, AVOIDING a net positive fluid balance. Monitor fluid status through a central line or Swan Ganz(R) catheter.
  • 4. DIURETICS: May be needed to avoid a net positive fluid balance.
  • 5. ANTIBIOTICS: Indicated only when there is evidence of infection.
  • 6. EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
  • F. CYPROHEPTADINE
    • 1. 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; Graudins et al, 1997). There are no controlled human trials substantiating its efficacy.
    • 2. Of 5 probable or definite cases of serotonin syndrome treated with cyproheptadine, most cases had either a poor response or no response, with only one case having a good response. The authors suggested that the doses of cyproheptadine administered may have been too low to be beneficial, since blockade of brain serotonin receptors occurs at doses between 20 to 30 mg; the cases reported used doses of 4 to 16 mg (Gillman, 1999).
    • 3. ADULT - 4 to 8 milligrams orally repeated every 1 to 4 hours until therapeutic response is observed or maximum of 32 milligrams administered (Mills, 1997).
    • 4. CHILD - 0.25 milligrams/kilogram/day divided every 6 hours, maximum dose 12 milligrams/day (Mills, 1997).
  • G. NITROGLYCERIN
    • 1. In theory nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin. It has been used in human cases with apparent benefit (Brown et al, 1996). There are no human trials substantiating its efficacy.
    • 2. ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
    • 3. CHILD - Begin infusion at 0.25 to 0.5 micrograms/kilogram/minute and titrate to desired effect.
  • H. PROPRANOLOL
    • 1. Propranolol is a 5-HT1A receptor antagonist (Sternbach, 1991). Propranolol has been used in human cases of serotonin syndrome with apparent benefit (Guze & Baxter, 1986; Dursun et al, 1997). There are no controlled human trials substantiating its efficacy.
      • a. PROPRANOLOL/ADULT DOSE
        • (1) 1 milligram/dose intravenously, administered no faster than 1 milligram/minute repeated every 2 to 5 minutes until desired response is seen or a maximum of 5 milligrams has been given.
  • b. PROPRANOLOL/PEDIATRIC DOSE
    • (1) 0.1 milligram/kilogram/dose over 10 minutes. Maximum 1 milligram/dose (Benitz & Tatro, 1995). Repeat at 6 to 8 hour intervals if needed.
  • I. CHLORPROMAZINE -
    • 1. Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). In a review of 13 patients, chlorpromazine was relatively efficacious. Of 7 severe cases, 3 patients had a good response, 1 patient had a moderate response, and 3 patients had poor responses; of 4 moderate cases, 3 had a good response and 1 had a moderate response (Gillman, 1999). Doses used ranged from 50 to 200 milligrams IM, 10 to 50 milligrams IV, and 50 milligrams orally.
      • 2. ADULT - 25 to 100 milligrams intramuscularly repeated in one hour if necessary.
      • 3. CHILD - 0.5 to 1 milligram/kilogram repeated as needed every 6 to 12 hours not to exceed 2 milligrams/kilogram/day.
  • J. Other agents which have been used to treat serotonin syndrome include methysergide and mirtazapine (Mills, 1997; Hoes, 1996).
  • K. NOT RECOMMENDED
    • 1. BROMOCRIPTINE - Is 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).
  • 6.11 ENHANCED ELIMINATION
    • A. SUMMARY
      • 1. Most agents which have been implicated in serotonin syndrome have large volumes of distribution and/or high degrees of protein binding and are not amenable to extracorporeal methods of enhanced elimination.
  • B. HEMODIALYSIS
    • 1. Hemodialysis may be useful if serotonin syndrome develops in the setting of lithium toxicity.
• 7.0 RANGE OF TOXICITY
  • 7.1 SUMMARY
    • A. Serotonin syndrome may develop after overdose or therapeutic use of substances which increase serotonin activity in the brain.
• 9.0 PHARMACOLOGY/TOXICOLOGY
  • 9.2 TOXICOLOGIC MECHANISM
    • A. Animal experiments suggest that stimulation of postsynaptic 5-HT1A receptors is primarily responsible for the serotonin syndrome. Stimulation of postsynaptic 5-HT2 receptors is probably also involved.
    • B. Serotonin syndrome most commonly develops when a patient is receiving two or more drugs that increase brain serotonin levels by different mechanisms.
    • C. Pharmacokinetic interactions may also be involved in some cases. Paroxetine is a potent inhibitor of the hepatic P450 isoenzyme CYP2D6, fluoxetine is to a lesser extent while sertraline and fluvoxamine have minimal effects. Dextromethorphan is metabolized by CYP2D6, predisposing patients taking paroxetine and dextromethorphan to serotonin syndrome (Harvey & Burke, 1995).
• 12.0 REFERENCES
  • 12.2 GENERAL BIBLIOGRAPHY
  • 1. Alderman CP: Comment: serotonin syndrome associated with combined sertraline-amitriptyline treatment (letter). Ann Pharmacother 1996; 30:1499-1500.
  • 2. AMA Department of Drugs: Drug Evaluation Subscription. American Medical Association, Chicago, IL, 1991.
  • 3. Baetz M: Serotonin syndrome from fluvoxamine and buspirone. Can J Psych 1995; 40:428-429.
  • 4. Barceloux D, McGuigan M, Hartigan-Go K: Position statement: cathartics. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Clin Toxicol 1997; 35:743-752.
  • 5. Bastani JB, Troester MM & Bastani AJ: "Serotonin syndrome and fluvoxamine: a case study". Nebraska Med J 1996; 107-109.
  • 6. Benazzi F: Serotonin syndrome with moclobemide-fluoxetine combination (letter). Pharmacopsychiatry 1996; 29:162.
  • 7. Benitz WE & Tatro DS: The Pediatric Drug Handbook, 3rd ed. Mosby-Year Book Inc, Chicago, IL, 1995.
  • 8. Benitz WE & Tatro DS: The Pediatric Drug Handbook, 3rd ed. Mosby-Year Book, Inc., St Louis, MO, 1995.
  • 9. Bertorini TE: Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome. Neurologic Clin 1997; 15:649-671.
  • 10. Bhatara VS, Magnus RD, Paul KL et al: Serotonin syndrome induced by venlafaxine and fluoxetine: a case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms. Ann Pharmacother 1998; 32:432-436.
  • 11. Bodner RA, Lynch T, Lewis L et al: Serotonin syndrome. Neurology 1995; 45:219-223.
  • 12. Brazelton T, Blanc PD, Olson KR et al: Toxic effects of nefazodone (letter). Ann Emerg Med 1997; 30:550-551.
  • 13. Brower RG, Matthay AM, Morris A and the Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Eng J Med 2000; 342:1301-1308.
  • 14. Brown TM, Skop BP & Mareth TR: Pathophysiology and management of the serotonin syndrome. Ann Pharmacother 1996; 30:527-533.
  • 15. Brown TM: Nitroglycerin in the treatment of the serotonin syndrome (letter). Ann Pharmacother 1996; 30:191-192.
  • 16. Brubacher JR, Hoffman RS & Lurin MJ: Serotonin syndrome from venlafaxine-tranylcypromine interaction. Vet Human Toxicol 1996; 38:358-361.
  • 17. Cano-Munoz JL, Montejo-Iglesias ML, Yanez-Saez RM et al: Possible serotonin syndrome following the combined administration of clomipramine and alprazolam. J Clin Psychiatr 1995; 56:122.
  • 18. Chamberlain JM, Altieri MA, Futterman C et al; A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care, 1997; 13:92-94.
  • 19. Chan BSH, Graudins A, Whyte IM et al: Serotonin syndrome resulting from drug interactions. MJA 1998; 169:523-525.
  • 20. Chyka PA & Seger D: Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Clin Toxicol 1997; 35:721-736.
  • 21. Corkeron MA: Serotonin syndrome - a potentially fatal complication of antidepressant therapy. Med J Aust 1995; 163:481-482.