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Neuroleptic Poisoning, Emergency Medicine

Basics

Description

- Neuroleptics (antipsychotics) used for management of: - Psychotic disorders - Agitation - Dementia in the elderly - Autism and behavioral problems in children - Eating disorders - Antiemetic - Migraine headaches

- Acute overdose: - Symptom onset within 6 hr, 9 hr with aripiprazole, up to 24 hr with extended-release formulations (paliperidone) - Can be delayed if anticholinergic symptoms predominate - CNS: - Ranges from mild sedation to coma - Anticholinergic delirium possible - Extrapyramidal symptoms (dystonia, akathisia) - Seizures

- Respiratory: - Respiratory depression - Loss of airway reflexes

- Dystonic reactions: - Involuntary muscle spasms of face, neck, back, and limbs - Dramatic appearance is frightening to patient and family - Laryngeal dystonia is a rare form that may cause stridor and dyspnea.

- Electrolytes, BUN, creatinine, glucose, LFTs - CBC for clozapine overdose, WBC can be elevated in NMS - Creatine phosphokinase (CPK) levels if NMS suspected, agitation, or prolonged immobilization - Serum drug screen with drug levels for possible coingestions based on history: - Aspirin - Acetaminophen - Lithium - Valproate - Phenytoin - Phenobarbital

- Supportive care is the mainstay of treatment - Decontamination: - Administer single dose of activated charcoal if ingestion within 1 hr - Do not give charcoal to patient with unprotected airway - Use NG tube for charcoal only if pt is intubated - Consider whole bowel irrigation if large amounts of extended-release formulation ingested (paliperidone) - Hemodialysis unlikely to be helpful due to high degree of protein binding - Consider lipid emulsion therapy for cardiovascular collapse

- Ventricular dysrhythmias: - Class IA, IB, and III antidysrhythmics can potentiate cardiotoxicity. Lidocaine can be used in refractory cases - Magnesium for prolonged QT - Cardioversion if hemodynamically unstable - Consider intralipid (20% lipid emulsion) for cardiovascular collapse - For asymptomatic QTc prolongation, replete potassium, calcium, and magnesium to normal levels - QRS prolongation (>120 msec) should be treated with sodium bicarbonate therapy

- Anticholinergic delirium: - Benzodiazepines are 1st-line agents - Physostigmine can be used with caution - Physostigmine is contraindicated in a patient with dysrhythmias, heart block, or interval prolongation on EKG

  • Neuroleptics (antipsychotics) used for management of:Psychotic disordersAgitationDementia in the elderlyAutism and behavioral problems in childrenEating disordersAntiemeticMigraine headaches
  • Acute overdose:Symptoms usually mild to moderateCNS and cardiovascular symptoms predominateCNS depression, seizure, and coma possible
  • Dystonic reactions (dystonia):Most common adverse effectCan occur at any time, often within 48 hr of starting medication
  • Akathisia:Patient has motor restlessness and feels a need to pace or move constantlyOccurs within hours to weeks of starting medication
  • Neuroleptic malignant syndrome (NMS):Idiosyncratic, life-threatening eventCan occur at any time but most commonly in overdose, dose increase, and during the 1st wk of usage
  • Tardive dyskinesia:Movement disorder usually affecting patients after years of taking neurolepticsTreated by decreasing, discontinuing, or changing the drug

Etiology

  • Typical neuroleptics (phenothiazines, butyrophenones) strongly antagonize dopaminergic receptors, these include:Haloperidol (Haldol)Chlorpromazine (Thorazine)Prochlorperazine (Compazine)Thioridazine (Mellaril)Fluphenazine (Prolixin)Promethazine (Phenergan)Droperidol (Inapsine)Hydroxyzine (Atarax)
  • Typical neuroleptics also have varying degrees of antagonism for histamine, muscarinic, andα-adrenergic receptors.
  • Atypical neuroleptics have weaker dopaminergic antagonism and moderate serotonergic antagonism, these include:Asenapine (Saphris)Aripiprazole (Abilify)Clozapine (Clozaril)Paliperidone (Invega)Risperidone (Risperdal)Olanzapine (Zyprexa)Quetiapine (Seroquel)Ziprasidone (Geodon)

Diagnosis

Signs and Symptoms

  • Acute overdose:Symptom onset within 6 hr, 9 hr with aripiprazole, up to 24 hr with extended-release formulations (paliperidone)Can be delayed if anticholinergic symptoms predominateCNS:Ranges from mild sedation to comaAnticholinergic delirium possibleExtrapyramidal symptoms (dystonia, akathisia)SeizuresCardiovascular:Tachycardia (anticholinergic)Hypotension (antiadrenergic)QT prolongationTorsade de pointes (rare)Respiratory:Respiratory depressionLoss of airway reflexesGI:Genitourinary:
  • Dystonic reactions:Involuntary muscle spasms of face, neck, back, and limbsDramatic appearance is frightening to patient and familyLaryngeal dystonia is a rare form that may cause stridor and dyspnea.
  • NMS:Occurs in <1% of patients, 30% mortalitySevere hyperthermiaSkeletal muscle rigidityAltered mental statusAutonomic dysfunctionElectrolyte disturbanceRhabdomyolysis
  • Agranulocytosis:Seen with clozapine and olanzapineOccurs with chronic treatment
  • Diabetes:Hyperglycemia, new-onset diabetes, and DKA have all been reported with initiation of neuroleptics.

Essential Workup

  • Monitor vital signs with significant ingestions.
  • Cardiac monitor
  • Pulse oximetry
  • Core body temperature for hyperthermia

Diagnosis Tests & Interpretation

Lab

  • Electrolytes, BUN, creatinine, glucose, LFTs
  • CBC for clozapine overdose, WBC can be elevated in NMS
  • Creatine phosphokinase (CPK) levels if NMS suspected, agitation, or prolonged immobilization
  • Serum drug screen with drug levels for possible coingestions based on history:AspirinAcetaminophenLithiumValproatePhenytoinPhenobarbital
  • Urine toxicologic screens are rarely helpfulFalse-negatives and false-positives can be misleading
  • Quantitative levels are rarely available and not helpful in acute management

Imaging

  • ECG:QT prolongationQRS prolongation (rare)
  • Head CT:Indicated for significant mental status change

Differential Diagnosis

  • Serotonin syndrome
  • Malignant hyperthermia (if recent anesthesia)
  • Antidepressant overdose
  • Anticholinergic crisis
  • Sympathomimetic overdose
  • Opioid overdose
  • Occult head injury
  • Endocrine disorder
  • Sepsis
  • Heat stroke

Treatment

Pre-Hospital

Bring medication bottles when transporting patient to hospital.

Initial Stabilization/Therapy

Airway, breathing, and circulation management (ABCs):

  • Administer supplemental oxygen.
  • Consider naloxone, thiamine, D50 (or check blood glucose) for altered mental status
  • Intubate if respiratory depression

Ed Treatment/Procedures

  • Supportive care is the mainstay of treatment
  • Decontamination:Administer single dose of activated charcoal if ingestion within 1 hrDo not give charcoal to patient with unprotected airwayUse NG tube for charcoal only if pt is intubatedConsider whole bowel irrigation if large amounts of extended-release formulation ingested (paliperidone)Hemodialysis unlikely to be helpful due to high degree of protein bindingConsider lipid emulsion therapy for cardiovascular collapse
  • Hypotension:0.9% normal saline (NS) IV fluid bolusTreat resistant hypotension with norepinephrine or phenylephrineDopamine may be ineffective
  • Ventricular dysrhythmias:Class IA, IB, and III antidysrhythmics can potentiate cardiotoxicity. Lidocaine can be used in refractory casesMagnesium for prolonged QTCardioversion if hemodynamically unstableConsider intralipid (20% lipid emulsion) for cardiovascular collapseFor asymptomatic QTc prolongation, replete potassium, calcium, and magnesium to normal levelsQRS prolongation (>120 msec) should be treated with sodium bicarbonate therapy
  • Dystonic reactions:Administer diphenhydramine or benztropine mesylate.Treatment should be continued for 3 days to prevent recurrence.
  • NMS:Recognition and cessation of neuroleptics is critical.Active cooling for hyperthermiaAggressive benzodiazepines for agitationSevere cases may require bromocriptine (dopamine agonist) or dantrolene (a direct-acting muscle relaxant)Consider intubation and neuromuscular blockade
  • Seizures:Treat initially with diazepam or lorazepam.Phenobarbital for persistent seizuresThere is no role for phenytoin in toxin-induced seizures
  • Anticholinergic delirium:Benzodiazepines are 1st-line agentsPhysostigmine can be used with cautionPhysostigmine is contraindicated in a patient with dysrhythmias, heart block, or interval prolongation on EKG

Medication

  • Activated charcoal: 1 " 2 g/kg PO
  • Benztropine mesylate: 1 " 2 mg IV or PO
  • Bromocriptine: 2.5 " 10 mg q8h PO
  • Dantrolene: 2 " 3 mg/kg/d as continuous infusion (10 mg/kg max.)
  • Diazepam: 5 " 10 mg IV q10 " 15min
  • Diphenhydramine: 25 " 50 mg IV (1 mg/kg)
  • Lidocaine 1 " 2 mg/kg followed by infusion
  • Lipid emulsion (20%) 1.5 mL/kg bolus followed by 0.25 mL/kg/min infusion for 30 " 60 min, may repeat bolus for persistent hemodynamic compromise
  • Lorazepam: 2 " 4 mg (peds: 0.03 " 0.05 mg/kg) IV q10 " 15min
  • Magnesium sulfate: 1 " 2 g IV over 5 " 15 min
  • Norepinephrine: 1 " 2 Όg/kg/min IV titrate to BP
  • Phenobarbital: 10 " 20 mg/kg IV (loading dose); monitor for respiratory depression
  • Physostigmine 0.5 mg IV q3 " 5min

Follow-Up

Disposition

Admission Criteria

  • Overdose with CNS sedation, agitation, dysrhythmias, or vital sign abnormalities to monitored bed or ICU
  • NMS require ICU care
  • New-onset diabetes (secondary to neuroleptic use) with severe hyperglycemia and/or ketoacidosis.

Discharge Criteria

  • Asymptomatic after 6 hr of observation
  • Longer observation required for aripiprazole and paliperidone ingestion as well as ingestion of extended release formulations

Issues for Referral

  • Patients with unintentional (accidental) poisoning require poison prevention counseling.
  • Patients with intentional (e.g., suicide) poisoning require psychiatric evaluation.
  • New-onset diabetes requires primary care/endocrine follow-up.

Follow-Up Recommendations

  • Psychiatric referral for intentional overdoses
  • Primary care follow-up for accidental ingestions or medication side effect follow-up

Pearls and Pitfalls

  • Neuroleptics represent a group of drugs with diverse indications and a wide range of toxicity.
  • Most overdoses are mild, and CNS depression predominates.
  • Dystonic reactions are the most common side effect of neuroleptics. These reactions are dramatic in appearance but easily treatable.
  • NMS is a potentially fatal reaction that can be seen in acute or chronic usage of neuroleptics.
  • Newer antipsychotics can have delayed onset up to 24 hr.
  • Contact the poison control center for further guidance

Additional Reading

  • Levine M, Ruha AM. Overdose of atypical antipsychotics: Clinical presentation, mechanisms of toxicity and management. CNS Drugs. 2012;26:601 " 611.
  • Lipscombe LL, Levesque L, Gruneir A, et al. Antipsychotic drugs and hyperglycemia in older patients with diabetes. Arch Intern Med. 2009;169:1282 " 1289.
  • Minns AB, Clark RF. Toxicology and overdose of atypical antipsychotics. J Emerg Med. 2012;43:906 " 913.
  • Ngo A, Ciranni M, Olson KR. Acute quetiapine overdose in adults: A 5-year retrospective case series. Ann Emerg Med. 2008;52:541 " 547.
  • Reulbach U, D Όtsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11:R4.
  • Wittler MA. Antipsychotics. In: Marx, ed. Rosens Emergency Medicine. 7th ed. St. Louis, MO: Mosby; 2009.
  • www.lipidrescue.org.

Codes

ICD9

  • 969.1 Poisoning by phenothiazine-based tranquilizers
  • 969.2 Poisoning by butyrophenone-based tranquilizers
  • 969.3 Poisoning by other antipsychotics, neuroleptics, and major tranquilizers
  • 333.92 Neuroleptic malignant syndrome

ICD10

  • T43.501A Poisoning by unsp antipsychot/neurolept, accidental, init
  • T43.3X1A Poisoning by phenothiaz antipsychot/neurolept, acc, init
  • T43.4X1A Poisoning by butyrophen/thiothixen neuroleptc, acc, init
  • G21.0 Malignant neuroleptic syndrome

SNOMED

  • 291121009 Poisoning by anti-psychotic agent
  • 48534006 Poisoning by phenothiazine-based tranquilizer (disorder)
  • 16248006 Poisoning by butyrophenone-based tranquilizer (disorder)
  • 15244003 Neuroleptic malignant syndrome (disorder)