SEROTONIN SYNDROME

• 0.0 OVERVIEW
  • 0.1 LIFE SUPPORT
    • A. This overview assumes that basic life support measures have been instituted.
  • 0.2 CLINICAL EFFECTS
    • 0.2.1 SUMMARY OF EXPOSURE
      • A. Sternbach's diagnostic criteria for serotonin syndrome include at least three of the following features: mental status changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and fever.
        • 1. Other etiologies must be ruled out and the patient must not have recently started or increased the dose of a neuroleptic prior to the onset of effects.
  • B. Other manifestations may include:
    • 1. Cognitive and behavioral effects: disorientation, coma, drowsiness, lethargy, seizures, insomnia, hallucinations, and dizziness;
    • 2. Autonomic dysfunction: tachycardia, hypertension, tachypnea, mydriasis, unreactive pupils, flushing, hypotension, abdominal pain, and salivation;
    • 3. Neuromuscular effects: muscle rigidity, hyperactivity, restlessness, ataxia, chills, nystagmus, teeth chattering, opisthotonos, and trismus.
  • C. In severe cases disseminated intravascular coagulation, acidosis, respiratory failure, rhabdomyolysis, renal failure, and ARDS may develop.
  • 0.2.3 VITAL SIGNS
    • A. Hyperthermia is characteristic; tachycardia, hypertension and tachypnea are common. Hypotension and respiratory failure may develop in severe cases.
  • 0.2.4 HEENT
    • A. Nystagmus, mydriasis and hypersalivation are common.
  • 0.2.5 CARDIOVASCULAR
    • A. Hypertension and tachycardia are common. Hypotension, dysrhythmias, and ECG changes may develop in severe cases.
  • 0.2.6 RESPIRATORY
    • A. Tachypnea is common. Respiratory failure, trismus and ARDS may develop in severe cases.
  • 0.2.7 NEUROLOGIC
    • A. CNS effects are common and include confusion, disorientation, agitation, CNS depression, coma and hallucinations. Seizures may develop in severe cases.
    • B. Neuromuscular effects include myoclonus, tremor, hyperreflexia, rigidity, hyperactivity, ataxia, shivering, teeth chattering, opisthotonus and abnormal Babinski reflexes.
  • 0.2.8 GASTROINTESTINAL
    • A. Diarrhea is common, abdominal pain may also develop.
  • 0.2.9 HEPATIC
    • A. Hepatocellular injury may develop in severe cases.
  • 0.2.10 GENITOURINARY
    • A. Acute renal failure may develop in severe cases.
  • 0.2.11 ACID-BASE
    • A. Mild metabolic acidosis is common; respiratory acidosis may develop in severe cases.
  • 0.2.13 HEMATOLOGIC
    • A. Leukocytosis is common. DIC may develop in severe cases.
  • 0.2.14 DERMATOLOGIC
    • A. Diaphoresis is common and skin may be flushed.
  • 0.2.15 MUSCULOSKELETAL
    • A. Rhabdomyolysis may develop in severe cases.
  • 0.3 LABORATORY/MONITORING
    • A. There is no test that confirms the diagnosis of serotonin syndrome.
    • 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.
  • 0.4 TREATMENT OVERVIEW
    • 0.4.2 ORAL/PARENTERAL EXPOSURE
      • A. Gastric decontamination may be useful if serotonin syndrome develops in the setting of recent overdose.
      • B. EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
      • C. ACTIVATED CHARCOAL: Administer charcoal as slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
      • D. AGITATION - Benzodiazepines may be useful. Diazepam: Adult: 5 to 10 mg IV every 5-10 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. Non-depolarizing paralytics may be used in severe cases.
      • E. HYPERTHERMIA - Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
      • F. SEIZURES: Administer a benzodiazepine IV; DIAZEPAM (ADULT: 5 to 10 mg, repeat every 10 to 15 min as needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05 to 0.1 mg/kg).
        • 1. Consider phenobarbital if seizures recur after diazepam 30 mg (adults) or 10 mg (children > 5 years).
        • 2. Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, hypoxia.
  • G. HYPOTENSION - Administer 10 to 20 ml/kg 0.9% saline and control hyperthermia. Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution.
  • H. HYPERTENSION - Monitor vital signs regularly. For severe hypertension nitroprusside or nitroglycerin may be necessary.
  • I. CYPROHEPTADINE has been used in the treatment of serotonin syndrome. Adult: 4 to 8 milligrams orally repeated every 1 to 4 hours until therapeutic response is observed or maximum of 32 milligrams administered. Child: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day.
  • J. Other agents which have been used include propranolol, chlorpromazine, nitroglycerin, methylsergide, mirtazapine.
  • 0.5 RANGE OF TOXICITY
    • A. Serotonin syndrome may develop after overdose or therapeutic use of substances which increase serotonin activity in the brain.
• 1.0 SUBSTANCES INCLUDED/SYNONYMS
  • 1.1 THERAPEUTIC/TOXIC CLASS
    • A. The serotonin syndrome is a disorder that can be caused by use of drugs or combinations of drugs which increase serotonin availability. It most often occurs when two or more drugs which increase serotonin availability by different mechanisms are used simultaneously. It may develop after therapeutic use or overdose.
  • 1.2 SPECIFIC SUBSTANCES
    • A. CONSTITUENTS OF THE GROUP
      • 1. DRUGS THAT INCREASE SEROTONIN SYNTHESIS

               L-tryptophan 
        

      • 2. DRUGS THAT DECREASE SEROTONIN METABOLISM

               Meclobemide 
               Monoamine oxidase inhibitors 
               Isocarboxazid 
               Phenelzine 
               Selegeline 
               Tranylcypromine 
        

      • 3. DRUGS THAT INCREASE SEROTONIN RELEASE

               Amphetamine 
               Cocaine 
               Fenfluramine 
               Methylenedioxymethamphetamine (MDMA) 
               Reserpine 
        

      • 4. DRUGS THAT INHIBIT SEROTONIN REUPTAKE
        • a. SELECTIVE SEROTONIN REUPTAKE INHIBITORS

                  Fluvoxamine 
                  Fluoxetine 
                  Paroxetine 
                  Nefazodone 
                  Sertraline 
                  Trazodone 
          

        • b. TRICYCLIC ANTIDEPRESSANTS

                  Amitriptyline 
                  Clomipramine 
                  Desipramine 
                  Doxepin 
                  Imipramine 
                  Nortriptyline 
                  Protriptyline 
          

        • c. OTHER SEROTONIN UPTAKE INHIBITORS

                  Amphetamine 
                  Cocaine 
                  Dextromethorphan 
                  Meperidine 
                  Methylenedioxymethamphetamine (MDMA) 
                  Venlafaxine 
          

  • 5. DIRECT SEROTONIN RECEPTION AGONISTS

           Buspirone 
           Lysergic acid diethylamide 
           Sumatriptan 
    

  • 6. NONSPECIFIC INCREASE IN SEROTONIN ACTIVITY

           Electroconvulsive Therapy 
           Lithium 
    

  • 7. DOPAMINE AGONISTS

           Amantadine 
           Bromocriptine 
           Bupropion 
           Levodopa 
    

  • 8. REFERENCES - Mills, 1995; Reynolds, 1996; Einfeld & Looi, 1996; Price et al, 1992; Fischer, 1995; Sandyk, 1986; Bastani et al, 1996; Richard et al, 1997; Kudo et al, 1997; Benazzi, 1996; Chan et al, 1998; Roxanas & Machado, 1998; Mueller & Korey, 1998
  • 9. OTHER DRUGS WHICH HAVE BEEN IMPLICATED IN SEROTONIN SYNDROME

           Admetionine 
           Carbamazepine 
           Dextropropoxyphene 
           Dihydroergotamine 
           Fentanyl 
           Nefazodone 
           Pentazocine 
           Pethidine 
           Sumatriptan 
           Tramadol 
           Trazodone 
    

    • a. REFERENCES - Sporer, 1995; Mathew et al, 1996; Mason & Blackburn, 1997; John et al, 1997; Rao, 1997; Brazelton et al, 1997; Gillman, 1995; Reeves & Bullen, 1995
  • 1.6 AVAILABLE FORMS/SOURCES
    • A. Drugs that are implicated in the serotonin syndrome are widely used in the treatment of major depression, bipolar affective disorder, obsessive-compulsive disorder, anxiety disorders, eating disorders, attention-deficit disorders, migraines, and Parkinson's disease. Some are common agents of recreational abuse.
• 3.0 CLINICAL EFFECTS
  • 3.1 SUMMARY OF EXPOSURE
    • A. Sternbach's diagnostic criteria for serotonin syndrome include at least three of the following features: mental status changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and fever.
      • 1. Other etiologies must be ruled out and the patient must not have recently started or increased the dose of a neuroleptic prior to the onset of effects.
  • B. Other manifestations may include:
    • 1. Cognitive and behavioral effects: disorientation, coma, drowsiness, lethargy, seizures, insomnia, hallucinations, and dizziness;
    • 2. Autonomic dysfunction: tachycardia, hypertension, tachypnea, mydriasis, unreactive pupils, flushing, hypotension, abdominal pain, and salivation;
    • 3. Neuromuscular effects: muscle rigidity, hyperactivity, restlessness, ataxia, chills, nystagmus, teeth chattering, opisthotonos, and trismus.
  • C. In severe cases disseminated intravascular coagulation, acidosis, respiratory failure, rhabdomyolysis, renal failure, and ARDS may develop.
  • 3.3 VITAL SIGNS
    • 3.3.1 SUMMARY
      • A. Hyperthermia is characteristic; tachycardia, hypertension and tachypnea are common. Hypotension and respiratory failure may develop in severe cases.
  • 3.3.2 RESPIRATIONS
    • A. TACHYPNEA is common in patients with serotonin syndrome (Power et al, 1995; Price et al, 1986; Weiss, 1995; Nijhawan et al, 1996; Roxanas & Machado, 1998; Pao & Tipnis, 1997).
      • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, tachypnea was reported in 35 (28%) patients (Mills, 1997).
  • B. RESPIRATORY FAILURE may develop in severe cases (Power et al, 1995; Ruiz, 1994; Brubacher et al, 1996).
  • 3.3.3 TEMPERATURE
    • A. HYPERTHERMIA is characteristic of serotonin syndrome. In severe cases core temperature may exceed 42 degrees centigrade (Power et al, 1995; Kline et al, 1989; Weiss, 1995; Hodgman et al, 1997; Keltner, 1994).
      • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, hyperthermia was reported in 59 (46%) patients (Mills, 1997).
  • 3.3.4 BLOOD PRESSURE
    • A. HYPERTENSION - Mild to moderate hypertension is common in patients with serotonin syndrome (Weiss, 1995; Sandyk, 1996).
      • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, hypertension was reported in 42 (33%) patients (Mills, 1997).
  • B. HYPOTENSION may develop in severe cases (Kline et al, 1989; Power et al, 1995; Heisler et al, 1996; Francois et al, 1997).
    • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, hypotension was reported in 18 (14%) patients (Mills, 1997).
  • 3.3.5 PULSE
    • A. TACHYCARDIA is common with serotonin syndrome (Mason & Blackburn, 1997; Mathew et al, 1996).
      • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, tachycardia was reported in 52 (41%) patients (Mills, 1997).
  • 3.4 HEENT
    • 3.4.1 SUMMARY
      • A. Nystagmus, mydriasis and hypersalivation are common.
  • 3.4.3 EYES
    • A. MYDRIASIS - Dilated sluggishly reactive pupils are common (Brubacher et al, 1996; John et al 1997; Mathew et al, 1996).
      • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, dilated pupils were reported in 33 (26%) patients and unreactive pupils were reported in 23 (18%) patients (Mills, 1997).
  • B. NYSTAGMUS has been reported (Ruiz, 1994).
    • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, nystagmus was reported in 16 (13%) patients (Mills, 1997).
  • 3.4.6 THROAT
    • A. HYPERSALIVATION may occur (Brubacher et al, 1996; Mathew et al, 1996).
      • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, hypersalivation was reported in 6 (5%) patients (Mills, 1997).
  • B. TRISMUS has been reported and may significantly complicate airway management (Kuisma, 1995; Brubacher et al, 1996; Ruiz, 1994; Chan et al, 1998).
    • 1. INCIDENCE - In a review of 127 reports of serotonin syndrome, trismus was reported in 8 (6%) patients (Mills, 1997).
  • 3.5 CARDIOVASCULAR
    • 3.5.1 SUMMARY
      • A. Hypertension and tachycardia are common. Hypotension, dysrhythmias, and ECG changes may develop in severe cases.
  • 3.5.2 CLINICAL EFFECTS
    • A. HYPERTENSION
      • 1. Mild to moderate hypertension is common in patients with serotonin syndrome (Weiss, 1995; Sandyk, 1996).
      • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, hypertension was reported in 42 (33%) patients (Mills, 1997).
  • B. HYPOTENSION
    • 1. Hypotension may develop in severe cases (Kline et al, 1989; Power et al, 1995; Heisler et al, 1996; Francois et al, 1997).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, hypotension was reported in 18 (14%) patients (Mills, 1997).
  • C. TACHYCARDIA
    • 1. Tachycardia is common with serotonin syndrome (Mason & Blackburn, 1997; Mathew et al, 1996).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, tachycardia was reported in 52 (41%) patients (Mills, 1997).
  • D. DYSRHYTHMIA
    • 1. CASE REPORT - A 35-year-old woman developed unifocal ventricular bigeminy during an episode of suspected serotonin syndrome (Insel et al, 1982). Her bigeminy began to abate two hours after the onset of her syndrome.
  • E. ECG ABNORMAL
    • 1. CASE REPORT - A 42-year-old woman developed sinus tachycardia to 140 beats/minute and questionable anterolateral ST depression during an episode of suspected serotonin syndrome (Mason & Blackburn, 1997).
  • 3.6 RESPIRATORY
    • 3.6.1 SUMMARY
      • A. Tachypnea is common. Respiratory failure, trismus and ARDS may develop in severe cases.
  • 3.6.2 CLINICAL EFFECTS
    • A. HYPERVENTILATION
      • 1. Tachypnea is common in patients with serotonin syndrome (Power et al, 1995; Price et al, 1986; Weiss, 1995; Nijhawan et al, 1996; Roxanas & Machado, 1998; Pao & Tipnis, 1997).
      • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, tachypnea was reported in 35 (28%) patients (Mills, 1997).
  • B. RESPIRATORY INSUFFICIENCY
    • 1. Respiratory failure may develop in severe cases (Power et al, 1995; Ruiz, 1994; Brubacher et al, 1996).
    • 2. Trismus has been reported and may significantly complicate airway management (Kuisma, 1995; Brubacher et al, 1996; Ruiz, 1994).
  • C. PULMONARY EDEMA
    • 1. Non-cardiogenic pulmonary edema may develop in severe cases (Kline et al, 1989; Power et al, 1995).
  • 3.7 NEUROLOGIC
    • 3.7.1 SUMMARY
      • A. CNS effects are common and include confusion, disorientation, agitation, CNS depression, coma and hallucinations. Seizures may develop in severe cases.
      • B. Neuromuscular effects include myoclonus, tremor, hyperreflexia, rigidity, hyperactivity, ataxia, shivering, teeth chattering, opisthotonus and abnormal Babinski reflexes.
  • 3.7.2 CLINICAL EFFECTS
    • A. CONFUSION
      • 1. Some degree of confusion is common in patients with serotonin syndrome (Ruiz, 1994; Brubacher et al, 1996; Heisler et al, 1996; Baetz & Malcom, 1995;).
      • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, confusion and disorientation were reported in 69 (54%) patients (Mills, 1997).
  • B. CNS STIMULATION
    • 1. Agitation and hyperactivity are common; hypomania is also reported (Ruiz, 1994; Alderman & Lee, 1996; Baetz & Malcom, 1995;).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, agitation was reported in 44 (35%) patients and hypomania developed in 19 (15%) patients (Mills, 1997). Insomnia developed in 13 (10%) of the patients in the same review.
  • C. CNS DEPRESSION
    • 1. Lethargy is fairly common and coma may develop in severe cases (John et al, 1997;Baetz & Malcom, 1995; Power et al, 1995; Roxanas & Machado, 1998).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, coma or unresponsiveness were reported in 36 (28%) patients and drowsiness or lethargy developed in 19 (15%) patients (Mills, 1997).
  • D. SEIZURES
    • 1. Seizures may develop in severe cases (Francois et al, 1997).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, seizures were reported in 18 (14%) patients (Mills, 1997).
  • E. HALLUCINATION
    • 1. Hallucinations have been reported (Heisler et al, 1996;).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, hallucinations were reported in 8 (6%) patients (Mills, 1997).
  • F. MYOCLONUS
    • 1. Myoclonus is common (Bodner et al, 1995; Brubacher et al, 1996; Heisler et al, 1996; Baetz & Malcom, 1995).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, myoclonus was reported in 73 (57%) patients (Mills, 1997).
  • G. HYPERREFLEXIA
    • 1. Hyperreflexia is common (Alderman & Lee, 1996; Power et al, 1995; Cano-Munoz et al, 1995; Chan et al, 1998). In severe cases clonus man develop (Weiner et al, 1998).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, hyperreflexia was reported in 70 (55%) patients (Mills, 1997).
  • H. TREMOR
    • 1. Extremity tremors and muscle rigidity are very common in patients with serotonin syndrome (Brubacher et al, 1996; Heisler et al, 1996; John et al, 1997; Baetz & Malcom, 1995; Cano-Munoz et al, 1995).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, tremor was reported in 62 (49%) patients, muscle rigidity was reported in 62 (49%) patients, and shivering and chills were reported in 32 (25%) patients (Mills, 1997).
  • I. ATAXIA
    • 1. Ataxia and loss of coordination are common (Mills, 1997).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, ataxia and loss of coordination were reported in 48 (38%) patients (Mills, 1997).
  • J. OPISTHOTONOS
    • 1. Opisthotonos has been reported (Power et al, 1995).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, opisthotonos was reported in 7 (6%) patients (Mills, 1997).
  • K. EEG ABNORMAL
    • 1. EEG abnormalities that have been reported in patients with serotonin syndrome include slow waves, spikes and waves in the delta range, generalized slowing of background activity, and triphasic waves (Dike, 1997; Miyaoka & Kamijima, 1995; Lejoyeux et al, 1992).
  • L. ABNORMAL REFLEXES
    • 1. Babinski reflexes may be abnormal (Ruiz, 1994; Roxanas & Machado, 1998).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome 18 (14%) patients had extensor Babinski reflexes (Mills, 1997).
  • 3.8 GASTROINTESTINAL
    • 3.8.1 SUMMARY
      • A. Diarrhea is common, abdominal pain may also develop.
  • 3.8.2 CLINICAL EFFECTS
    • A. DIARRHEA
      • 1. Diarrhea is a common finding (George & Godleski, 1996; Gitlin, 1997).
      • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, diarrhea was reported in 15 (12%) patients (Mills, 1997).
  • B. ABDOMINAL PAIN
    • 1. Abdominal pain develops in some patients.
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome abdominal cramps were reported in 6 (5%) patients (Mills, 1997).
  • 3.9 HEPATIC
    • 3.9.1 SUMMARY
      • A. Hepatocellular injury may develop in severe cases.
  • 3.9.2 CLINICAL EFFECTS
    • A. HEPATOCELLULAR DAMAGE
      • 1. Hepatocellular injury may develop in patients with severe hyperthermia (Kline et al, 1989; Francois et al, 1997; Power et al, 1995; Keltner, 1994).
      • 2. CASE REPORT - Serum liver enzyme elevation, with an AST of 3,560 U/L and ALT of 2,680 U/L, was reported in a 60-year-old female who developed serotonin syndrome after taking clomipramine for 8 months (Rosebush et al, 1999).
  • 3.10 GENITOURINARY
    • 3.10.1 SUMMARY
      • A. Acute renal failure may develop in severe cases.
  • 3.10.2 CLINICAL EFFECTS
    • A. RENAL FAILURE ACUTE
      • 1. Acute tubular necrosis and renal failure may develop in patients with prolonged hypotension or severe rhabdomyolysis (Kline et al, 1989; Power et al, 1995; Francois et al, 1997; Rosebush et al, 1999).
  • 3.11 ACID-BASE
    • 3.11.1 SUMMARY
      • A. Mild metabolic acidosis is common; respiratory acidosis may develop in severe cases.
  • 3.11.2 CLINICAL EFFECTS
    • A. ACIDOSIS
      • 1. Mild metabolic acidosis is fairly common (Nijawan et al, 1996; Keltner, 1994).
      • 2. Respiratory acidosis may develop in severe cases (Hodgman et al, 1997; Ruiz, 1994, Brubacher et al, 1996).
  • 3.13 HEMATOLOGIC
    • 3.13.1 SUMMARY
      • A. Leukocytosis is common. DIC may develop in severe cases.
  • 3.13.2 CLINICAL EFFECTS
    • A. LEUKOCYTOSIS
      • 1. Leukocytosis is a common finding (Cano-Munoz, 1995; Nisijima et al, 1996).
  • B. DISSEMINATED INTRAVASCULAR COAGULATION
    • 1. Disseminated intravascular coagulation may develop in severe cases (Francois et al, 1997; Power et al, 1995; Kline et al, 1989).
  • C. THROMBOCYTOPENIA
    • 1. CASE REPORT - A 60-year-old woman with serotonin syndrome due to clomipramine monotherapy developed thrombocytopenia, with platelets decreasing from 269,000 on admission to 44,000 within 24 hours. She also developed evidence of disseminated intravascular coagulation (Rosebush et al, 1999).
  • 3.14 DERMATOLOGIC
    • 3.14.1 SUMMARY
      • A. Diaphoresis is common and skin may be flushed.
  • 3.14.2 CLINICAL EFFECTS
    • A. SWEATING INCREASED
      • 1. Diaphoresis is a common finding (George & Godleski, 1996; Gitlin, 1997).
      • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, diaphoresis was reported in 59 (46%) patients (Mills, 1997).
  • B. FLUSHING
    • 1. Flushing is common (Corkeron, 1995).
    • 2. INCIDENCE - In a review of 127 reports of serotonin syndrome, flushed skin was reported in 18 (14%) patients (Mills, 1997).
  • 3.15 MUSCULOSKELETAL
    • 3.15.1 SUMMARY
      • A. Rhabdomyolysis may develop in severe cases.
  • 3.15.2 CLINICAL EFFECTS
    • A. RHABDOMYOLYSIS
      • 1. Rhabdomyolysis may develop in patients with prolonged tremors or rigidity (John et al, 1997; Roxanas & Machado, 1998; Weiner et al, 1998).
      • 2. CASE REPORT - A 60-year-old woman developed serotonin syndrome and rhabdomyolysis after clomipramine monotherapy. The patient presented with a creatine phosphokinase of 4,300 U/L which rose to 39,900 U/L over the next 72 hours. Rhabdomyolysis led to acute renal failure requiring dialysis; the patient died 4 weeks after admission due to infection (Rosebush et al, 1999).
  • 3.23 OTHER
    • 3.23.2 CLINICAL EFFECTS
      • A. DRUG INTERACTION
        • 1. Serotonin syndrome most commonly develops when a patient is receiving two or more drugs that increase brain serotonin levels by different mechanisms. Possible precipitants of the serotonin syndrome include:

                   Drugs that increase serotonin synthesis: 
                   L-tryptophan 
                   Drugs that decrease serotonin metabolism: 
                   Monoamine oxidase inhibitors 
                   Isocarboxazid 
                   Phenelzine 
                   Selegeline 
                   Tranylcypromine 
                   Meclobemide 
                   Drugs that increase serotonin release: 
                   Amphetamine 
                   Cocaine 
                   Fenfluramine 
                   Methylenedioxymethamphetamine (MDMA) 
                   Reserpine 
                   Drugs that inhibit serotonin reuptake: 
                   Selective serotonin reuptake inhibitors - 
                   Fluvoxamine 
                   Fluoxetine 
                   Paroxetine 
                   Nefazodone 
                   Sertraline 
                   Trazodone 
                   Tricyclic antidepressants - 
                   Amitriptyline 
                   Clomipramine 
                   Desipramine 
                   Doxepin 
                   Imipramine 
                   Nortriptyline 
                   Protriptyline 
                   Other serotonin uptake inhibitors - 
                   Amphetamine 
                   Cocaine 
                   Dextromethorphan 
                   Meperidine 
                   Methylenedioxymethamphetamine (MDMA) 
                   Venlafaxine 
                   Direct serotonin reception agonists: 
                   Buspirone 
                   Lysergic acid diethylamide 
                   Sumatriptan 
                   Nonspecific increase in serotonin activity 
                   Electroconvulsive therapy 
                   Lithium 
                   Dopamine agonists: 
                   Amantadine 
                   Bromocriptine 
                   Bupropion 
                   Levodopa 
          

          • References: Mills, 1995; Reynolds, 1996; Einfeld & Looi, 1996; Price et al, 1992; Fischer, 1995; Sandyk, 1986; Bastani et al, 1996; Richard et al, 1997; Kudo et al, 1997; Benazzi, 1996; Sporer, 1995; Roxanas & Machado, 1998; Chan et al, 1998; Mueller & Korey, 1998; Weiner et al, 1998; Bhatara et al, 1998; Gillman, 1997; Skop et al, 1994).
  • 2. Other drugs which have been implicated include fentanyl, pentazocine, carbamazepine, dextropropoxyphene, admetionine, sumatriptan, pethidine, dihydroergotamine, tramadol, nefazodone, trazodone (Sporer, 1995; Mathew et al, 1996; Mason & Blackburn, 1997; John et al, 1997; Rao, 1997; Brazelton et al, 1997; Gillman, 1995; Reeves & Bullen, 1995).
  • 3. Monoamine oxidase inhibitors appear to be particularly likely to produce serotonin syndrome. Patients have developed serotonin syndrome when a second serotonergic agent was begun more than two weeks after discontinuation of a monoamine oxidase inhibitor (Gitlin, 1997; Kolecki, 1997).
• 4.0 LABORATORY/MONITORING
  • 4.1 MONITORING PARAMETERS/LEVELS
    • 4.1.1 SUMMARY
      • A. There is no test that confirms the diagnosis of serotonin syndrome.
      • 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.
  • 4.1.2 SERUM/BLOOD
    • A. BLOOD/SERUM CHEMISTRY
      • 1. Monitor serum electrolytes, glucose, renal function and CK in all patients with suspected serotonin syndrome.
      • 2. Monitor hepatic function tests in patients with severe hyperthermia or other serious effects.
  • B. ACID/BASE
    • 1. Monitor arterial blood gases in patients with pulmonary symptoms, severe hyperthermia or hypotension, or other serious effects.
  • C. COAGULATION STUDIES
    • 1. Monitor PT/PTT or INR and platelet count in patients with severe hyperthermia, hypotension, or other severe effects.
  • 4.1.3 URINE
    • A. URINALYSIS
      • 1. Monitor urinalysis and urine output in patient with rhabdomyolysis.
  • 4.1.4 OTHER
    • A. ECG
      • 1. Obtain an ECG and institute continuous cardiac monitoring in all patients with suspected serotonin syndrome.
  • 4.2 RADIOGRAPHIC STUDIES
    • A. CHEST RADIOGRAPH
      • 1. Obtain a chest radiograph in patients with CNS depression or hypoxia.
• 5.0 ABSTRACTS
  • 5.1 CASE REPORTS
    • A. PEDIATRIC
      • 1. An 11-year-old boy developed symptoms of serotonin syndrome, including rapidly progessive agitation, unresponsiveness, erratic blood pressure and heart rate changes, myoclonus of the jaw and ankles, diaphoresis, shivering, and hyperreflexia. The symptoms occurred approximately 1 hour after a single dose of fluvoxamine 50 mg given for attention-deficit disorder. Progressive hyperthermia and rhabdomyolysis developed.
        • a. The patient was paralyzed with rocuronium and sedated for 24 hours. The patient recovered and physical exam was normal 48 hours after admission (Gill et al, 1999).
• 6.0 TREATMENT
  • 6.1 LIFE SUPPORT
    • A. Support respiratory and cardiovascular function.
  • 6.3 PATIENT DISPOSITION
    • 6.3.1 DISPOSITION/ORAL EXPOSURE
      • 6.3.1.1 ADMISSION CRITERIA/ORAL
        • A. Admit patients with hyperthermia, hypotension, mental status changes, dysrhythmias, muscle hyperactivity, seizures or persistent tachycardia to an intensive care setting.
  • 6.4 MONITORING
    • A. There is no test that confirms the diagnosis of serotonin syndrome.