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BUTYROPHENONES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Haloperidol is the first drug of the butyrophenone series of major tranquilizers. Drugs in this class have been used to treat schizophrenia and acute psychosis; schizoaffective disorders; paranoid syndrome; and Tourette's syndrome. Haloperidol is frequently used for agitation or aggressive behavior, especially in elderly patients.

Specific Substances

    A) DROPERIDOL (SYNONYM)
    1) McN-JR-4749
    2) R-4749
    3) CAS 548-73-2
    HALOPERIDOL (SYNONYM)
    1) McN-JR-1625
    2) R-1625
    3) CAS 52-86-8
    BENPERIDOL (SYNONYM)
    1) CB-8089
    2) McN-JR-4584
    3) R-4584
    4) CAS 2062-84-2

    1.2.1) MOLECULAR FORMULA
    1) DROPERIDOL: C22H22FN3O2 (Prod Info INAPSINE(R) injection, 2006)
    2) HALOPERIDOL: C21H23ClFNO2 (Prod Info haloperidol oral tablets, 2008)
    3) HALOPERIDOL DECANOATE: C31H41ClFNO3 (Prod Info haloperidol decanoate injection, 2005)

Available Forms Sources

    A) FORMS
    1) HALOPERIDOL: Haloperidol is available 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, and 20 mg tablets, 2 mg/mL oral solution, and 50 mg/mL and 100 mg/mL intramuscular oil and suspension (Prod Info HALDOL(R) Decanoate 100 intramuscular injection, 2013; Prod Info haloperidol oral tablets, 2012; Prod Info HALOPERIDOL oral solution concentrate, 2010).
    2) DROPERIDOL: Droperidol is available as 2.5 mg/mL injection solution (Prod Info INAPSINE(R) intravenous, intramuscular injection, 2011).
    B) USES
    1) Haloperidol is used to treat schizophrenia and psychotic disorders, hyperactive behavior, and Tourette's syndrome (Prod Info HALDOL(R) Decanoate 100 intramuscular injection, 2013; Prod Info haloperidol oral tablets, 2012; Prod Info HALOPERIDOL oral solution concentrate, 2010).
    2) Droperidol, a neuroleptic (tranquilizer) agent, is used to reduced the incidence of nausea and vomiting associated with surgical and diagnostic procedures (Prod Info INAPSINE(R) intravenous, intramuscular injection, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Butyrophenones include the typical antipsychotics, droperidol and haloperidol. They are primarily used for treatment of schizophrenia and mood disorders. They are also used as an adjunct in migraines, states of acute psychosis and agitation, and nausea and vomiting.
    B) PHARMACOLOGY: In therapeutic doses, butyrophenones are D2 receptor antagonists. Antagonizing D2 neurotransmission is thought to treat the positive symptoms of schizophrenia. It also interferes with other receptors, such as acetylcholine muscarinic receptors (M1 and M2), histamine receptor (H1), and alpha adrenergic receptors.
    C) TOXICOLOGY: In overdose, butyrophenones cause CNS depression and sedation. Hypotension can develop from alpha adrenergic blockade. These agents are also antagonists of the delayed rectifier potassium current blockade which can lead to QTc prolongation and possibly torsades de pointes.
    D) EPIDEMIOLOGY: With increasing use of atypical antipsychotics, exposure to butyrophenones is less common. Severe toxicity is uncommon and deaths have rarely been reported.
    E) WITH THERAPEUTIC USE
    1) Common adverse effects with therapeutic dosing include hypotension, constipation, xerostomia, extrapyramidal symptoms, somnolence, and blurred vision.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate toxicity typically consists of CNS depression and sedation. Dystonia may also occur.
    2) SEVERE TOXICITY: Severe toxicity includes more profound CNS depression that can lead to coma. However, significant respiratory depression is uncommon in single agent exposures. Other CNS symptoms can develop, such as delirium and agitation, psychosis, and hallucinations; severe agitation can lead to hyperthermia. Seizures and hypotension can also develop. Torsades de pointes may occur. Neuroleptic malignant syndrome (NMS) can occur, characterized by hyperthermia and autonomic dysfunction, muscle rigidity, and altered mental status.
    0.2.3) VITAL SIGNS
    A) HALOPERIDOL: Hypotension may develop in adults and children who have ingested an overdose of haloperidol. One pediatric case of hypertension following overdose has been reported. Hyperthermia has both been associated with haloperidol therapy and may occur with overdose. Respiratory depression may occur.
    0.2.20) REPRODUCTIVE
    A) Droperidol and haloperidol are classified as FDA pregnancy category C. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. The manufacturer does not recommend breastfeeding infants during maternal ingestion of haloperidol.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Initiate continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes.
    D) Other laboratory tests should be obtained to evaluate for other co-ingestants as needed.
    E) Concentrations can be measured, but are typically done at reference laboratories and are not useful in acute care management.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive care is the mainstay of treatment for butyrophenone toxicity. Evaluate for co-ingestants, intravenous fluids for volume expansion, and benzodiazepines for agitation or delirium. Benztropine or diphenhydramine for acute dystonia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) If CNS depression is severe, intubation and ventilation may be required to protect the airway. Intravenous fluid expansion is initial therapy for hypotension, and vasopressors may also be used if hypotension persists. For agitation and delirium, benzodiazepines should be given. If severe psychomotor agitation and hyperthermia develop, or other signs of NMS, sedation, intubation, and external cooling should be initiated. For QTc prolongation, ensure electrolytes are corrected and monitor for torsades de pointes.
    C) DECONTAMINATION
    1) PREHOSPITAL: Charcoal can be considered if a large or polypharmacy overdose has occurred. However, the patient should have an alert mental status and be able to take it voluntarily.
    2) HOSPITAL: Typically there is no role for lavage. Charcoal can be considered if a large or polypharmacy overdose has occurred. However, the patient should have an alert mental status and be able to take it voluntarily.
    D) AIRWAY MANAGEMENT
    1) Intubation and ventilation may be needed in a large or polypharmacy overdose when severe CNS depression and coma develop and the patient is unable to protect the airway.
    E) ANTIDOTE
    1) None
    F) DRUG-INDUCED DYSTONIA
    1) DYSTONIC REACTION: ADULT: BENZTROPINE: 1 to 4 mg once or twice daily IV or IM (max, 6 mg/day); 1 to 2 mg of the injection will usually provide quick relief in emergency situations, OR DIPHENHYDRAMINE: ADULT: 10 to 50 mg IV at a rate not exceeding 25 mg/minute or deep IM (max, 100 mg/dose; 400 mg/day). CHILDREN: Diphenhydramine: 5 mg/kg/day or 150 mg/m(2)/day IV divided into 4 doses at a rate not to exceed 25 mg/min, or deep IM (max,, 300 mg/day). Not recommended in premature infants and neonates.
    G) ENHANCED ELIMINATION
    1) There is no role for enhanced elimination, including multidose activated charcoal, hemodialysis, and hemoperfusion, due to large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with low dose supratherapeutic ingestions who are asymptomatic or with mild sedation can be watched at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, or who are symptomatic, should be observed in the emergency department for 6 to 8 hours, or until symptoms have resolved.
    3) ADMISSION CRITERIA: Patients who have severe toxicity or prolonged toxicity should be admitted until symptoms have resolved.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity.
    I) PITFALLS
    1) Most antipsychotics are taken as polypharmacy self-harm attempts. Pitfalls include not evaluating for other co-ingestants. Dystonic reactions are likely to recur; patients should be provided with several days of medication to prevent recurrence.
    J) PHARMACOKINETICS
    1) Absorption when given IV or IM is rapid, and oral dosing peak levels occur by 3 to 6 hours. Volume of distribution is 18 L/kg and 2 L/kg for haloperidol and droperidol, respectively. Butyrophenones are mainly metabolized by the liver, and excreted mostly by the kidney, also by feces. Haloperidol half-life is 13 to 35 hours; droperidol half-life is 2 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other typical and atypical antipsychotics can cause similar toxicity.

Range Of Toxicity

    A) TOXICITY: Adults who have ingested 300 mg haloperidol have experienced life-threatening symptoms, but some have had severe reactions with therapeutic dosing. Toxic concentrations have not been established.
    B) THERAPEUTIC DOSE: DROPERIDOL: ADULT: Initial maximum dose is 2.5 mg IM/IV, may repeat 1.25 mg dose based on patient response, caution is advised. CHILD (2 to 12 years): 0.1 mg/kg IV. HALOPERIDOL: ADULT: 0.5 to 5 mg orally 2 or 3 times daily. CHILD (3 to 12 years, 15 to 40 kg): 0.05 to 0.15 mg/kg/day in divided doses, 2 or 3 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: Butyrophenones include the typical antipsychotics, droperidol and haloperidol. They are primarily used for treatment of schizophrenia and mood disorders. They are also used as an adjunct in migraines, states of acute psychosis and agitation, and nausea and vomiting.
    B) PHARMACOLOGY: In therapeutic doses, butyrophenones are D2 receptor antagonists. Antagonizing D2 neurotransmission is thought to treat the positive symptoms of schizophrenia. It also interferes with other receptors, such as acetylcholine muscarinic receptors (M1 and M2), histamine receptor (H1), and alpha adrenergic receptors.
    C) TOXICOLOGY: In overdose, butyrophenones cause CNS depression and sedation. Hypotension can develop from alpha adrenergic blockade. These agents are also antagonists of the delayed rectifier potassium current blockade which can lead to QTc prolongation and possibly torsades de pointes.
    D) EPIDEMIOLOGY: With increasing use of atypical antipsychotics, exposure to butyrophenones is less common. Severe toxicity is uncommon and deaths have rarely been reported.
    E) WITH THERAPEUTIC USE
    1) Common adverse effects with therapeutic dosing include hypotension, constipation, xerostomia, extrapyramidal symptoms, somnolence, and blurred vision.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate toxicity typically consists of CNS depression and sedation. Dystonia may also occur.
    2) SEVERE TOXICITY: Severe toxicity includes more profound CNS depression that can lead to coma. However, significant respiratory depression is uncommon in single agent exposures. Other CNS symptoms can develop, such as delirium and agitation, psychosis, and hallucinations; severe agitation can lead to hyperthermia. Seizures and hypotension can also develop. Torsades de pointes may occur. Neuroleptic malignant syndrome (NMS) can occur, characterized by hyperthermia and autonomic dysfunction, muscle rigidity, and altered mental status.

Vital Signs

    3.3.1) SUMMARY
    A) HALOPERIDOL: Hypotension may develop in adults and children who have ingested an overdose of haloperidol. One pediatric case of hypertension following overdose has been reported. Hyperthermia has both been associated with haloperidol therapy and may occur with overdose. Respiratory depression may occur.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) HALOPERIDOL: Respiratory depression may occur with overdose (Prod Info HALDOL intramuscular injection, 2011).
    3.3.3) TEMPERATURE
    A) HYPERTHERMIA has both been associated with haloperidol therapy (Westlake & Rastegar, 1973; Harder, 1971; Greenblatt et al, 1978) and following overdose (Gajre et al, 2012).
    B) HYPOTHERMIA has been reported in very young children and adolescents who ingested an overdose of haloperidol (James et al, 2000; Scialli & Thronton, 1978).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTENSION: In haloperidol overdosage, patients usually remain normotensive; however, hypertension may occur.
    a) PEDIATRIC CASE REPORT: A 22-month-old girl who ingested 15 to 20 mg haloperidol developed blood pressure of 146/100 at 8 hours and 164/134 at 10 hours after a baseline level of 136/66 on admission (Cummingham & Challapalli, 1979).
    1) IV hydralazine was required to reduce pressures reaching as high as 180 systolic over the subsequent 5 days.
    2) HYPOTENSION has been reported in very young (2 years or less) children who have ingested overdoses of haloperidol (Scialli & Thronton, 1978). Adults and children who have ingested overdoses of haloperidol may experience hypotension (Gajre et al, 2012; Prod Info haloperidol oral tablets, 2008).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision has been reported with haloperidol use (Prod Info haloperidol oral tablets, 2008).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ECTOPIC BEATS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A patient who received therapeutic haloperidol doses developed multifocal PVCs after three days. After 4 days off haloperidol, the ECG was normal (Mehta et al, 1979).
    B) TORSADES DE POINTES
    1) HALOPERIDOL
    a) HALOPERIDOL: Torsades de pointes has been reported in adults who overdosed on oral haloperidol (Henderson et al, 1991; Zee-Cheng et al, 1985; Fayer, 1986) as well as adults treated with high-dose intravenous haloperidol (Wilt et al, 1993) O'Brien et al, 1999; (Perrault et al, 2000)and low-dose oral haloperidol therapy (Jackson et al, 1997).
    b) CASE REPORT: A case of haloperidol-induced torsades de pointes was reported in a 41-year-old woman with no predisposing factors. The patient developed torsades de pointes 55 minutes after receiving 80 milligrams (mg) of intravenous haloperidol. The patient was treated and the dysrhythmia was controlled. She received one more 80-mg dose of haloperidol without incident and then it was discontinued. The patient experienced no further dysrhythmias (O'Brien et al, 1999).
    c) A total of 7 patients developed torsade de pointes after therapeutic use of haloperidol in high doses (Metzger & Friedman, 1993; Wilt et al, 1993). Three patients developed the dysrhythmia after administration of 211 to 825 mg haloperidol over 1 to 2 days for agitated delirium. These 3 patients recovered from the initial episodes, but 1 patient subsequently died of cardiac arrest upon readministration of haloperidol. Four patients developed the dysrhythmia after administration of 170 to 580 mg over 1 to 4 days for delirium associated with bacterial meningitis (1), status asthmaticus (2) or respiratory insufficiency (1). All 4 patients recovered with no adverse sequelae.
    d) CASE REPORT: A case of torsades de pointes was reported in a 48-year-old woman who ingested 210 mg of haloperidol and 1400 mg of orphenadrine. It was concluded that the haloperidol caused this reaction. The patient was given gastric lavage, 50 g of activated charcoal and a constant infusion of lidocaine. Later, lidocaine was stopped and replaced by a pacing electrode. The patient was released eight days later in normal condition (Henderson et al, 1991).
    e) CASE REPORT: A case of torsades de pointes caused by haloperidol was reported in a 36-year-old male chronic schizophrenic patient. The patient had been treated with oral haloperidol 20 mg/day for five days, and then 50 mg/day for two more days during hospitalization in a closed psychiatric department. The torsades de pointes was treated with an isoproterenol infusion (Kriwisky et al, 1990).
    f) In another report, the incidence of torsades de pointes was substantial, developing in 8 of 223 critically ill patients in intensive care units (Sharma et al, 1998). Patients who received intravenous haloperidol greater than 35 mg/day or had a QTc interval prolongation of greater than 500 ms were at greatest risk.
    g) The incidence of long QTc interval syndrome or torsades de pointes with haloperidol is small (Lawrence & Nasraway, 1997). The majority of cases occurred in critically ill patients with a history of cardiovascular disease prescribed more than 50 mg/day. It is recommended that before initiating therapy with haloperidol in critically ill patients that a baseline QTc interval and serum magnesium and potassium concentrations be measured. In cases where the baseline QTc interval is 440 milliseconds or longer and they are receiving other drugs that may prolong the QTc interval, or they have an electrolyte disturbance, haloperidol or similar drugs should be used with caution. Electrocardiogram monitoring should be done in critically ill patients once haloperidol is initiated. If the QTc interval lengthens by 25% or more, the haloperidol should be discontinued or the dosage should be reduced.
    2) DROPERIDOL
    a) CASE REPORT: Pre-operative administration of droperidol 0.625 milligrams in a 59-year-old woman was associated with development of torsades de pointes progressing to ventricular fibrillation. She was on long-term fluoxetine and cyclobenzaprine therapy, and an ECG obtained several days prior to surgery showed a prolonged QTc of 497 msec. She recovered following successful cardioversion and treatment with lidocaine, atropine, magnesium, and isoproterenol. It is speculated that a drug interaction between fluoxetine and cyclobenzaprine, causing significant QT interval prolongation, progressed to torsades de pointes following droperidol administration (Michalets et al, 1998).
    b) Cases of QT prolongation and/or torsades de pointes have been reported in patients receiving Inapsine(R) at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal (FDA, 2001).
    3) PIPAMPERONE
    a) CASE REPORT: A 16-year-old girl was admitted to the emergency department drowsy after ingesting pipamperone (serum level 3.2 mg/L {normal range 0.1 to 0.4 mg/L}) , fluoxetine and oxazepam (serum levels within therapeutic range) . Six hours after admission, the patient's QT interval was prolonged to 513 ms, and the patient developed torsades de pointes which converted to sinus rhythm after one minute. A temporary pacemaker was transvenously implanted, and no further dysrhythmias occurred (Bont et al, 1998).
    C) PROLONGED QT INTERVAL
    1) CASE REPORT: Prolonged Q-T interval (0.71 seconds) was observed in one adult 12 hours after she ingested 300 mg haloperidol (Aunsholt, 1989).
    2) PEDIATRIC: Yoshida et al (1993) reported prolonged QT intervals in 2 of 8 children who ingested large doses of haloperidol and whose rhythms were subsequently observed (Yoshida et al, 1993).
    3) DROPERIDOL: Cases of QT prolongation and/or torsades de pointes have been reported in patients receiving Inapsine(R) at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal (FDA, 2001).
    4) RISK FACTORS: In a study of 495 psychiatric patients in various inpatient and community treatment programs, the risk factors for QTc lengthening (defined as a QT interval greater than 456 ms) was studied. Age greater than 65 (odds ratio 3.0, CI 1.1-8.3) and therapeutic use of droperidol (odd ratio 6.7 {1.8 to 24.8}) were both associated with QTc lengthening in a logistic regression model (Reilly et al, 2000).
    D) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Bradycardia has been reported in very young (2 years or less) children who have ingested overdoses of haloperidol (Scialli & Thronton, 1978).
    E) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) HALOPERIDOL: Hypotension has been reported in very young (2 years or less) children who have ingested overdoses of haloperidol (Scialli & Thronton, 1978). Adults and children who have ingested overdoses of haloperidol may experience hypotension (Gajre et al, 2012; Prod Info haloperidol oral tablets, 2008).
    F) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) HALOPERIDOL: In haloperidol overdosage, patients usually remain normotensive; however, hypertension may occur.
    1) PEDIATRIC CASE REPORT: A 22-month-old girl who ingested 15 to 20 mg haloperidol developed blood pressure of 146/100 at 8 hours and 164/134 at 10 hours after a baseline level of 136/66 on admission (Cummingham & Challapalli, 1979).
    a) IV hydralazine was required to reduce pressures reaching as high as 180 systolic over the subsequent 5 days.
    G) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) HALOPERIDOL/CASE REPORT: A 6-year-old girl experienced a heart rate of 104 bpm after ingesting an unknown amount of 5-mg haloperidol tablets (Gajre et al, 2012).
    H) DEAD - SUDDEN DEATH
    1) WITH POISONING/EXPOSURE
    a) HALOPERIDOL
    1) Sudden death has been reported in three young otherwise healthy adults given large therapeutic doses of haloperidol (Mahutte et al, 1982; Ketai et al, 1979; Modestin et al, 1981).
    a) Pathophysiology of these fatalities is unclear. One patient died of fulminant pulmonary edema, the others of cardiorespiratory arrest following cyanosis and extrapyramidal signs. Neurogenic etiology is likely in all three patients. No indicators are available to identify patients who may react in this way to haloperidol administration.
    2) CASE REPORT: A 49-year-old woman sustained a cardiopulmonary arrest after receiving 25 milligrams of haloperidol IM along with 3 milligrams lorazepam and 50 milligrams diphenhydramine over about 24 hours. Initial ECG had been normal with a normal QTc interval. She had a history of "serious reactions" to neuroleptic agents in the past (Johri et al, 2000).
    b) DROPERIDOL
    1) Prehospital droperidol was given to two adult men who were extremely agitated after taking cocaine and phencyclidine, respectively. The patients received 5 to 10 mg of droperidol intramuscularly. Both became pulseless shortly after drug administration. Despite aggressive care, both patients died less than an hour after droperidol administration. Although the authors could not determine the exact cause of death, the safe use of droperidol for drug induced agitation in the prehospital setting appears uncertain and caution was suggested (Cox et al, 2004).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CONDUCTION DELAY
    a) In perfused isolated rat hearts, haloperidol alone increased the atrioventricular refractory period and the heart rate, while the combination of haloperidol and ethanol increased His-ventricular conduction time, heart rate and atrioventricular effective refractory period, and decreased left ventricular peak systolic pressure. Lorazepam had no effect on conduction alone or in combination with ethanol (Medlin et al, 1995).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) HALOPERIDOL: Respiratory depression may occur with a haloperidol overdose (Prod Info HALDOL intramuscular injection, 2011).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A case of fatal pulmonary edema was attributed to therapeutic doses of haloperidol (Mahutte et al, 1982).
    C) APNEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 24-year-old man, who ingested LSD, was given 5 mg of IV droperidol for treatment of agitation. Within 5 minutes, the patient developed rigidity and apnea, and was mechanically ventilated. Following supportive care, the rigidity resolved and the patient was successfully extubated 16 hours later (Heard et al, 1999). It is speculated that the patient was exhibiting signs of serotonin syndrome due to LSD ingestion, which was exacerbated by the administration of droperidol, leading to increased muscle rigidity and respiratory distress.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) Seizures, in association with parkinsonism symptoms, have occurred in pediatric patients following haloperidol overdose (Debray & Galland, 1970).
    2) CASE REPORT: Nonconvulsive status epilepticus developed in a 62-year-old woman with neuroleptic malignant syndrome secondary to haloperidol. Manifestations included unresponsiveness, myoclonus, diaphoresis and periodic synchronous discharges on EEG. She improved after administration of 20 mg diazepam (Yoshino & Yoshimasu, 2000).
    B) EXTRAPYRAMIDAL DISEASE
    1) HALOPERIDOL
    a) Therapeutic use and overdose of haloperidol can cause extrapyramidal effects in children and adults (Prod Info haloperidol oral tablets, 2006; Yoshida et al, 1993).
    b) ADULT
    1) Doenecke & Heuermann (1980) reported the cases of five adults who had taken haloperidol for recreational purposes and were subsequently treated for haloperidol toxicity. All experienced severe extrapyramidal side effects (Doenecke & Heuermann, 1980).
    2) TARDIVE DYSKINESIA: Potentially irreversible, involuntary dyskinetic movements may develop in some patients treated therapeutically with haloperidol. Elderly women appear at greatest risk (Prod Info HALDOL intramuscular injection, 2011). These signs may also occur with overdose (James et al, 2000).
    3) DYSTONIA: Relatively small doses of haloperidol (5 milligrams) may cause dystonic reactions when combined with amphetamine (Capstick et al, 1994).
    c) PEDIATRIC
    1) Yoshida et al (1993) studied 24 children who ingested large amounts of haloperidol and recorded the following clinical signs, in decreasing order of frequency: consciousness disturbance (often drowsiness); tremors in the limbs; abnormal eye movements; dystonic movements; difficulty in swallowing; dysarthria; drooling; akathisia; increased plantar reflexes; and opisthotonus.
    a) Eleven of the 24 children showed behavioral disorders when examined one month following the episode; 3 of these still showed abnormalities at the 6-month follow up examination, prompting the authors to warn that pediatric haloperidol overdose may induce long term behavioral sequelae (Yoshida et al, 1993).
    2) Rigidity of the extremities, restlessness, aphonia, tongue deviation, locked jaw, and torticollis have also been reported in children (Tsujimoto et al, 1982; Boyer et al, 1987; Sinaniotis et al, 1978). Extrapyramidal reactions may be accompanied by hyperthermia (Geller & Greydanus, 1979).
    3) CASE REPORTS: Dystonia with opisthotonus, hyperreflexia, and clonus was reported in a 6-year-old girl following ingestion of an unknown amount of 5-mg haloperidol tablets. Her 4-year-old brother also experienced generalized dystonia with perioral tremors, intention tremors, tongue fasciculations, hyperreflexia, and nystagmus after ingesting an unknown amount of the same medication. Both patients recovered within 72 hours post-admission (approximately 79 hours post-ingestion) following treatment with promethazine and trihexyphenidyl (Gajre et al, 2012).
    2) DROPERIDOL
    a) Low-dose droperidol has also been rarely associated with extrapyramidal reactions (Melnick, 1988; Merridew & Keefe, 1994). A 1% incidence of droperidol-induced extrapyramidal effects is reported by Merridew & Keefe (1994) (Merridew & Keefe, 1994).
    b) ADULT
    1) AKATHISIA is reported following chronic use (2 months) of epidural infusions of droperidol added to morphine therapy in a cancer patient. The akathisia disappeared within 72 hours of discontinuation of droperidol (Athanassiadis & Karamanis, 1992). Akathisia is very common after single therapeutic doses of droperidol and is usually well controlled with benzodiazepines, diphenhydramine or benztropine.
    2) DYSTONIA: A 41-year-old woman experienced facial dystonia within minutes after receiving droperidol intravenously. Despite administration of antihistamines, benzodiazepines, muscle relaxants, and anticholinergic medications, her dystonia continued to persist. A review of the patient's past medical history revealed that she had experienced brief dystonic reactions following single-dose administration of prochlorperazine and metoclopramide. With each episode, the dystonia resolved following administration of diphenhydramine (Walker & Samii, 2006).
    C) NEUROLEPTIC MALIGNANT SYNDROME
    1) GENERAL/ADULT: Neuroleptic malignant syndrome (NMS) is a rare, but a potentially fatal complication of neuroleptic therapy (ie, haloperidol or droperidol) and overdose. Cases in adults taking therapeutic doses of haloperidol have also been reported (Kostic et al, 2002; Hermesh et al, 1989; van Harten & Kemperman, 1991; Osser & Steward, 1988; Keck et al, 1987; Gaitini et al, 1997). Agitated, exhausted, and dehydrated patients may be more at risk to develop NMS (Keck et al, 1989; Caroff & Mann, 1993).
    2) INCIDENCE: Keck et al (1987) conducted a prospective assessment of 679 neuroleptic-treated patients and found that the incidence of NMS was only 0.9%; however, 4 of the 5 patients affected were taking haloperidol (Keck et al, 1987a). Caroff & Mann (1993) state that haloperidol has been implicated in half of all NMS cases; this may be due to increased use of haloperidol or to use of high dosages (Caroff & Mann, 1993).
    3) ADULT: Neuroleptic malignant syndrome associated with droperidol therapy is reported in a 76-year-old woman. No other neuroleptics were administered, and other potential causative agents, e.g., carbamazepine were continued after droperidol was stopped. The NMS resolved several days later (Ratan & Smith, 1993).
    4) ADULT: An 86-year-old man developed NMS after receiving droperidol 5 mg for agitation post-surgically. He became hypertensive (160/60 mmHg), tachycardic (170 bpm), drowsy, and confused, and he demonstrated muscle tremor and rigidity, and hyperpyrexia (38.6 degrees C). With supportive care, the patient gradually recovered (So, 2001).
    5) ADULT: A 33-year-old man, with a history of schizophrenia, was hospitalized after exhibiting abnormal behavior, including insomnia, loud shouting, running outside, and destruction of property. Vital signs showed tachycardia (120 beats/min); neurological exam was normal. Because of continued agitation and combativeness, the patient was administered a total of 5 IM injections of haloperidol 5 mg and scopolamine 0.3 mg and 3 IM injections of clonazepam 1 mg. On hospital day 2, approximately 15 hours post-admission, the patient developed loss of consciousness, tachypnea, rigidity in all extremities, and seizures. Monitoring of vital signs indicated a pulse rate of 158 beats/min, blood pressure ranging from 90/47 to 120/60 mmHg, a respiratory rate of 52 bpm, and a temperature of 42 degrees C. ECG revealed tachycardia and ventricular extrasystole with Wolff-Parkinson-White syndrome. Despite resuscitative efforts, the patient died. Autopsy revealed cerebral and pulmonary edema, and the cause of death was determined to be NMS due to haloperidol administration (Zou et al, 2014).
    6) PEDIATRIC: Rigidity with hyperthermia has also been reported in children given therapeutic doses of haloperidol (Geller & Greydanus, 1979).
    7) PEDIATRIC: NMS developed in a 6-year-old child following pre-operative medication with droperidol and post-operative medication with metoclopramide. Hyponatremia may have been a contributing factor (Shaw & Matthews, 1995).
    8) SIGNS: May include rigidity, hyperthermia, elevated creatinine phosphokinase, tachycardia, tachypnea, hypertension, sweating, and leukocytosis.
    a) Sequelae to an episode of NMS may include rhabdomyolysis and disseminated intravascular coagulation (Hosford et al, 1988).
    D) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Increasing agitation and deteriorating mental status was reported in a 54-year-old man following high-dose intravenous haloperidol administration. The encephalopathy gradually resolved following discontinuation of haloperidol (Maxa et al, 1997).
    E) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression is common after haloperidol overdose (Gajre et al, 2012; Hansen et al, 1997; Satar et al, 2001). In a series of 83 patients with phenothiazine or butyrophenone overdose (haloperidol was the most common ingestant, in 35 (40%) of patients) CNS depression developed in 78 patients (91%). Other effects included dystonia (51%), parkinsonian signs (40%), anticholinergic effects (20%), miosis (15%), dysarthria (11%), hyperreflexia (8%), and seizures (2%) (James et al, 2000).
    F) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness has been reported with haloperidol use (Prod Info haloperidol oral tablets, 2008).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported with haloperidol use (Prod Info haloperidol oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) HALOPERIDOL/CASE REPORT: Persistent vomiting occurred in a 6-year-old girl who ingested an unknown amount of 5-mg haloperidol tablets. In addition to the vomiting, the child also developed tachycardia, diaphoresis, dystonia, hyperreflexia, opisthotonus, and clonus. The patient completely recovered with symptomatic and supportive therapy (Gajre et al, 2012).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has been reported with haloperidol use (Prod Info haloperidol oral tablets, 2008).
    C) PARALYTIC ILEUS
    1) WITH THERAPEUTIC USE
    a) HALOPERIDOL: A case of ileus was reported in a 52-year-old woman who received a mean dose of 41.4 mg haloperidol/day, raised to a mean dose of 53 mg/day the 5 days prior to onset. The resulting fecal impaction resolved over 6 days with discontinuation of haloperidol, IV fluids, and continuous nasogastric suction (Maltbie et al, 1981).
    D) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth has been reported with haloperidol use (Prod Info haloperidol oral tablets, 2008).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) HALOPERIDOL: Acute renal insufficiency may occur secondary to dehydration and rhabdomyolysis (Hosford et al, 1988).
    2) ADVERSE EFFECTS: Therapeutic use of haloperidol has been associated with the following adverse effects: urinary incontinence and enuresis; urinary hesitation; hyperprolactinemia leading to menstrual irregularities and decreased libido; erectile dysfunction; and ejaculatory dysfunction (Pollack et al, 1992).
    B) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) HALOPERIDOL/CASE REPORT: Urinary retention was reported in a 4-year-old child following inadvertent ingestion of an unknown amount of 5-mg haloperidol tablets (Gajre et al, 2012).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) HALOPERIDOL: Metabolic acidosis occurs in 75% of patients with neuroleptic malignant syndrome (Caroff & Mann, 1993).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) Moderate doses of haloperidol have been associated with the development of mild and usually transient leukopenia (Prod Info HALDOL intramuscular injection, 2011).
    B) DISSEMINATED INTRAVASCULAR COAGULATION
    1) Sequelae to an episode of neuroleptic malignant syndrome may include disseminated intravascular coagulation (Hosford et al, 1988).
    C) LEUKOCYTOSIS
    1) Nonspecific leukocytosis occurs in 98% of all cases of neuroleptic malignant syndrome (Caroff & Mann, 1993).
    D) THROMBOCYTOSIS
    1) PEDIATRIC: Transient thrombocytosis has been reported in children who ingested large amounts of haloperidol; thrombocytosis developed 16 days postingestion (Yoshida et al, 1993).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) HALOPERIDOL/CASE REPORTS: Diaphoresis was reported in two children (a 6-year-old girl and her 4-year-old brother) who ingested an unknown amount of 5-mg haloperidol tablets (Gajre et al, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) Sequelae to an episode of neuroleptic malignant syndrome may include rhabdomyolysis (Hosford et al, 1988).
    2) Patients being treated with therapeutic doses of haloperidol may be asymptomatic but have elevated CPK levels (Pearlman et al, 1988).
    3) CASE REPORT: A 62-year-old man presented to the hospital with epigastric pain. Current medications included famotidine, aspirin, haloperidol, nitroglycerin patch, benztropine, and clorazepate. The patient's CPK concentrations were elevated, peaking on hospital day 2 at 4800 IU/L, with normal MB fractions, indicating that the elevated CPK concentrations was likely of skeletal muscle origin. The CPK concentrations decreased following discontinuation of haloperidol therapy (Marinella, 1997). There was no clinical evidence of neuroleptic malignant syndrome in the patient.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) Allergic reactions may occasionally occur following therapeutic as well as overdoses of droperidol. Angioedema with difficult breathing was reported in a 21-year-old woman following a 10 mg dose of droperidol (Corke & Murray, 1993), and Clark (1993) reports 4 patients out of 3000 who experienced allergic reactions involving droperidol (Clark, 1993).
    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNE SYSTEM DISORDER
    a) HALOPERIDOL is an immunosuppressant in laboratory mice (Surman, 1993).

Reproductive

    3.20.1) SUMMARY
    A) Droperidol and haloperidol are classified as FDA pregnancy category C. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. The manufacturer does not recommend breastfeeding infants during maternal ingestion of haloperidol.
    3.20.2) TERATOGENICITY
    A) SKELETAL MALFORMATION
    1) HALOPERIDOL: No well-controlled studies of haloperidol use by pregnant women exist. However, a few cases of limb malformations following maternal use of haloperidol along with other medications during the first trimester of pregnancy have been reported, although causal relationship was not established (Prod Info HALDOL(R) Decanoate IM injection, 2010).
    B) ANIMAL STUDIES
    1) RATS: Midpregnancy subcutaneous haloperidol injections (5 mg/kg twice daily) in rats produced permanently stunted brain growth in the offspring (Holson et al, 1994).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Droperidol and haloperidol are classified as FDA pregnancy category C (Prod Info HALDOL(R) Decanoate IM injection, 2010; Prod Info INAPSINE(R) injection, 2006).
    B) EXTRAPYRAMIDAL AND/OR WITHDRAWAL SYMPTOMS
    1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info HALDOL(R) Decanoate IM injection, 2010).
    C) PLACENTAL BARRIER
    1) A prospective, observational study of 54 women (mean age, 30.7 years), recruited from the Emory Women’s Mental Health program exposed to antipsychotic medication during pregnancy, showed permeability of the placental barrier. Outcomes were determined by maternal and umbilical cord blood samples taken at delivery and through data collected from maternal reports and medical records. Placental passage ratios (defined as the ratio of umbilical cord to maternal plasma concentrations) showed a significant difference between antipsychotic medications, with olanzapine 72.1% (95% confidence interval (CI), 46.8% to 97.5%) being the highest, followed by haloperidol 65.5% (95% CI, 40.3% to 90.7%), risperidone 49.2% (95% CI, 13.6% to 84.8%), and quetiapine 24.1% (95% CI, 18.7% to 29.5%), showing the lowest placental passage ratio (Newport et al, 2007).
    D) CASE/CONTROL STUDY
    1) In a multicenter prospective case-control study of 215 pregnant women exposed to haloperidol (n=188) or penfluridol (n=27) during their first trimester, no increase in the rate of congenital anomalies was reported, as compared to 631 non-exposed pregnant women (6/179 = 3.4% vs 22/581 = 3.8%; p=0.787, respectively). The median daily oral dose of haloperidol was 5 mg (2.25 to 10 mg) and 100 mg/4 weeks (50 to 100 mg) for the parenteral dose; median oral dose for penfluridol was 20 mg/week (20 to 40 mg). Various psychotic disorders were the primary reason for drug therapy, with 0.5% used for hyperemesis gravidarum. In general, women in the butyrophenone group were slightly older and more likely to smoke than the control group (Diav-Citrin et al, 2005).
    E) MATERNAL ADVERSE REACTION
    1) A 34-year-old pregnant woman ingested 300 mg haloperidol at 34 weeks gestation and presented with CNS depression, hypotonia, and involuntary spasms of the extremities. A biophysical profile of the fetus on admission was 2 of 10 (two points for amniotic fluid, no evidence of fetal movement, flexion-extension or fetal breathing, fetal heart rate 150 beats/minute, nonreactive with minimal long-term and short-term variability). The mother appeared fully recovered by 48 hours after admission, but a biophysical profile of 10 was not achieved for the fetus until 5 days after admission. A healthy girl was delivered at 39 weeks gestation and she had normal developmental milestones and growth at 18 months of age (Hansen et al, 1997).
    F) DYSKINESIA
    1) CASE REPORT: A healthy full-term 3880 g female was exposed in utero to haloperidol. The mother had schizoaffective disorder and was treated with haloperidol decanoate 200 mg every 2 weeks throughout the pregnancy. Haloperidol was stopped 3 weeks prior to delivery and the mother had an acute psychotic episode at which time labor was induced. The newborn was noted to be "jittery" at the time of birth and developed diarrhea and metabolic acidosis. During the first week of life she was treated for electrolyte imbalance (Na 137 mEq/L) and was advanced to normal feeds. By day 8, the newborn experienced recurring episodes of tonic-clonic movements in all extremities (an EEG was negative for seizures), which were treated with clonazepam for approximately 10 days. The newborn was discharged to foster care by day 21 with no further tremulous movements observed.
    a) The authors concluded that the symptoms noted in the newborn could not clearly be attributable to tardive dyskinesia or withdrawal dyskinesia (ie, due to neuroleptic withdrawal), but the events responded well to clonazepam with no adverse effects observed. The authors suggested that neuroleptics should be continued in a patient who becomes pregnant, and to educate parents about potential extrapyramidal symptoms that may occur after the newborn is discharged to home (Collins & Comer, 2003).
    G) NEPHROGENIC DIABETES INSIPIDUS
    1) CASE REPORT: Transient nephrogenic diabetes insipidus was reported in a neonate due to fetal haloperidol exposure. The 31-year-old mother had taken a daily dose of haloperidol 20 mg for psychosis. The mother received no prenatal care but discontinued haloperidol use after a vaginal delivery. The infant was referred to the hospital 3 days after discharge due to fever, irritability, and feeding difficulties. The infant was hypoactive, hypotonic, dehydrated and experienced weight loss and increased urine output. Spontaneous resolution occurred after 6 days of hospitalization and the infant was discharged with no further issues (Akar et al, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) HALOPERIDOL: The American Academy of Pediatrics (Anon, 1983), in addition to other authors (Ayd, 1978), reports no adverse reactions in nursing infants whose mothers are taking haloperidol. The manufacturer does not recommend breastfeeding infants during maternal ingestion of haloperidol (Prod Info HALDOL(R) Decanoate IM injection, 2010).
    a) The milk/plasma ratio of haloperidol when calculated assuming nonionic passive diffusion was 7.2 and when assuming ion partitioning was 2.1 (Wilson, 1981).
    2) CASE REPORT: One study reported that a woman receiving 30 mg/day haloperidol for 6 days secreted the drug into breast milk to a level of 5 nanograms (ng)/mL. When the dose was lowered to 12 mg/day, the milk level fell to 2 ng/mL (Stewart et al, 1980).
    3) CASE REPORT: In a single case study, a puerperal psychotic patient treated with haloperidol 5 mg twice a day secreted 23.5 nanograms (ng)/mL haloperidol into the milk. She continued to breastfeed under hospital supervision without adverse effect to the infant (Whalley, 1981).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Initiate continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes.
    D) Other laboratory tests should be obtained to evaluate for other co-ingestants as needed.
    E) Concentrations can be measured, but are typically done at reference laboratories and are not useful in acute care management.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Correlation of therapeutic haloperidol dose with blood levels and clinical signs is controversial. Shvartsburd et al (1983) did not find a correlation between therapeutic dose and blood haloperidol level (Shvartsburd et al, 1983). Many reports failed to find a correlation between plasma or blood haloperidol levels and clinical response (Cressman, 1974) Vaisanen et al, 1981; (Itoh et al, 1984; Bigelow et al, 1985; Moulin et al, 1982).
    2) Concentrations can be measured, but are typically done at reference laboratories and are not useful in acute care management.
    3) Monitor the following with haloperidol overdose: acid-base status, fluid and electrolyte balance, and renal function. Patients with clinical signs of neuroleptic malignant syndrome should be monitored for rising serum CPK levels.
    B) OTHER
    1) Yamazumi & Muira (1981) compared serum and saliva levels of haloperidol by radioimmunoassay in 98 subjects who received the same dose for at least one month prior to sampling. Saliva levels were higher than serum levels and there was a significant correlation between dose and saliva level (Yamazumi & Miura, 1981).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Institute continuous cardiac monitoring and follow serial ECGs to detect dysrhythmias and QT prolongation.
    2) MONITORING
    a) Monitor vital signs and mental status.

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid chromatography-mass spectrometry (HPLC-MS) was used to analyze haloperidol and its two metabolites (reduced haloperidol and 4-(4-chlorphenyl)-4-hydroxypiperidine (CPHP) in human plasma and urine. The authors noted that this method was both rapid and sensitive enough to detect and determine both high therapeutic and toxic levels (Arinobu et al, 2002).
    2) Plasma samples may be analyzed using reverse-phase high-performance liquid chromatography (Nayak et al, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who have severe toxicity or prolonged toxicity should be admitted until symptoms have resolved.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with low dose supratherapeutic ingestions who are asymptomatic or with mild sedation can be watched at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, or who are symptomatic, should be observed in the emergency department for 6 to 8 hours, or until symptoms have resolved.

Monitoring

    A) Monitor vital signs and mental status.
    B) Initiate continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes.
    D) Other laboratory tests should be obtained to evaluate for other co-ingestants as needed.
    E) Concentrations can be measured, but are typically done at reference laboratories and are not useful in acute care management.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) Charcoal can be considered if a large or polypharmacy overdose has occurred. However, the patient should have an alert mental status and be able to take it voluntarily.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    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).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) 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 (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).
    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 (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    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.
    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 (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).
    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 (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Initiate continuous cardiac monitoring and obtain an ECG.
    3) Monitor serum electrolytes.
    4) Other laboratory tests should be obtained to evaluate for other co-ingestants as needed.
    5) Concentrations can be measured, but are typically done at reference laboratories and are not useful in acute care management.
    B) CONDUCTION DISORDER OF THE HEART
    1) SUMMARY: Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) ATRIOVENTRICULAR BLOCK: If a high grade atrioventricular block is evident, insert a transvenous (preferred) or use a transcutaneous pacemaker.
    C) TORSADES DE POINTES
    1) SUMMARY
    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).
    2) MAGNESIUM SULFATE
    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).
    3) OVERDRIVE PACING
    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).
    4) POTASSIUM REPLETION
    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).
    5) ISOPROTERENOL
    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).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (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).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    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.
    D) HYPOTENSIVE EPISODE
    1) CHOICE OF VASOPRESSORS: Fluid challenge is sufficient for correction of hypotension in most patients. Some reviews recommend avoidance of mixed alpha/beta agonists (epinephrine, dopamine) due to theoretical production of unopposed beta vasodilation, resulting in worsened hypotension (Benowitz et al, 1979); norepinephrine or metaraminol may be preferred. No primary research or case reports in either humans or animals could be found to substantiate this theory.
    a) Dopamine is expected to be effective for agents with less alpha blockade activity (piperazines, haloperidol, loxapine, molindone, thioxanthenes). In theory, exacerbation of hypotension is more likely with overdose of agents with high alpha activity (chlorpromazine, mesoridazine, thioridazine).
    2) SUMMARY
    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.
    3) DOPAMINE
    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).
    4) NOREPINEPHRINE
    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
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    3) When the dystonia resolves, patient should be put on maintenance doses of diphenhydramine or benztropine for two days.
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    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 .
    3) NO INTRAVENOUS ACCESS
    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).
    4) LORAZEPAM
    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).
    5) PHENOBARBITAL
    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).
    6) OTHER AGENTS
    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):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    G) PSYCHOMOTOR AGITATION
    1) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    2) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 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).
    3) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    H) NEUROLEPTIC MALIGNANT SYNDROME
    1) NMS may be successfully managed with intravenous or oral dantrolene sodium, diphenhydramine, or oral bromocriptine, in conjunction with cooling and other supportive care (May et al, 1983) (Mueller et al, 1983) (Leikin et al, 1987) (Schneider, 1991) (Barkin, 1992).
    a) DANTROLENE LOADING DOSE: 2.5 milligrams/kilogram, to a maximum of 10 milligrams/kilogram intravenously (Barkin, 1992).
    b) DANTROLENE MAINTENANCE DOSE: 2.5 milligrams/kilogram intravenously every 6 hours (Barkin, 1992); 1 milligram/kilogram orally every 12 hours, up to 50 milligrams/dose has also been successful (May et al, 1983).
    c) BROMOCRIPTINE DOSE: 5 milligrams 3 times a day orally (Mueller et al, 1983).
    d) NONPHARMACOLOGIC METHODS: Rapid cooling, hydration, and serial assessment of respiratory, cardiovascular, renal and neurologic function, and fluid status are used in conjunction with drug therapy and discontinuation of the neuroleptic agent (Knight & Roberts, 1986).
    2) In a review of 67 case reports of neuroleptic malignant syndrome, the onset of clinical response was shorter after treatment with DANTROLENE (mean 1.15 days) or BROMOCRIPTINE (1.03 days) than with supportive measures alone (6.8 days).
    a) The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).
    3) RETROSPECTIVE STUDY: A study comparing 438 untreated patients with neuroleptic malignant syndrome and 196 treated cases found that administration of dantrolene, bromocriptine, or amantadine significantly reduced the death rate in these cases (Sakkas et al, 1991).
    a) Death rate of untreated cases was 21%; administration of dantrolene alone (no dosage reported) decreased death rate to 8.6% (n=58); with bromocriptine alone death rate was 7.8% (n=51); and with amantadine alone death rate was 5.9% (n=17).
    b) In combination with other drugs, each of these drugs significantly decreased the NMS-related death rate, although the decrease was slightly less than for single administrations.
    4) ANECDOTAL REPORTS
    a) The intravenous administration of dopamine has also been reported to be effective in two case reports (Ungvari, 1987; Ryken & Merrell, 1989).
    b) PLASMAPHERESIS: A 36-year-old man developed neuroleptic malignant syndrome 3 days after beginning oral haloperidol therapy, 25 mg daily. Initial treatment consisted of respiratory support, cooling blankets, and pharmacologic therapy, including dantrolene, bromocriptine, and amantadine, with no improvement in signs and symptoms.
    1) A daily course of plasmaphereses was then given to the patient 3 times, using a FENWAL PS-400 module. Each course exchanged 55 mL/kg of plasma with albumin, fresh frozen plasma and cryoprecipitate. Two days later, the patient was awake and responsive with a subsequent improvement in vital signs, CPK values, and psychiatric, neurological, and cardiovascular systems (Gaitini et al, 1997). The patient, however, developed a large duodenal ulcer, became septic with multi-organ failure and died 2 months later.
    I) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

    A) DIALYSIS
    1) HALOPERIDOL: Its large volume of distribution and low plasma levels suggest that little drug would be removed by dialysis (Anderson et al, 1976; Bennett et al, 1987).

Abstracts

Case Reports

    A) ADULT
    1) TORSADES DE POINTES: Henderson et al (1991) reported a case of torsades de pointes in a 48-year-old woman who ingested 210 mg of haloperidol and 1400 mg of orphenadrine. The authors attributed this reaction to the haloperidol.
    a) The patient was treated with gastric lavage, 50 g of activated charcoal and a constant infusion of lidocaine administered at a rate of 4 mg per minute. Lidocaine infusion was later replaced by a pacing electrode.
    b) The patient was released eight days after admission in normal condition (Henderson et al, 1991).
    2) NEUROLEPTIC MALIGNANT SYNDROME/AMNESTIC DISORDER: Van Harten and Kemperman (1991) report a case of a 30-year-old woman who experienced NMS after receiving haloperidol (20 mg twice daily).
    a) The patient began suffering from organic amnestic disorder some months after the NMS episode.
    b) She also displayed intellectual deterioration, emotional blunting and depression, and irregular theta waves on EEG for three years after the NMS episode (van Harten & Kemperman, 1991).
    3) NEUROLEPTIC MALIGNANT SYNDROME/PNEUMONIA: Osser and Stewart (1988) report a fatal case of NMS with complications of pneumonia in an elderly man who was given extra doses of haloperidol at home by his family (Osser & Steward, 1988).
    B) PEDIATRIC
    1) HYPERTENSION: A 22-month-old girl who ingested 15 to 20 mg haloperidol developed blood pressure of 146/100 at 8 hours and 164/134 at 10 hours after a baseline level of 136/66 taken on admission (Cummingham & Challapalli, 1979).
    a) IV hydralazine was required to reduce pressures reaching as high as 180 systolic over the subsequent 5 days.

Range Of Toxicity

Summary

    A) TOXICITY: Adults who have ingested 300 mg haloperidol have experienced life-threatening symptoms, but some have had severe reactions with therapeutic dosing. Toxic concentrations have not been established.
    B) THERAPEUTIC DOSE: DROPERIDOL: ADULT: Initial maximum dose is 2.5 mg IM/IV, may repeat 1.25 mg dose based on patient response, caution is advised. CHILD (2 to 12 years): 0.1 mg/kg IV. HALOPERIDOL: ADULT: 0.5 to 5 mg orally 2 or 3 times daily. CHILD (3 to 12 years, 15 to 40 kg): 0.05 to 0.15 mg/kg/day in divided doses, 2 or 3 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) DROPERIDOL
    a) For prevention of nausea and vomiting related to surgical or diagnostic procedures, the maximum recommended initial dose is 2.5 mg IM or slow IV. Additional 1.25 mg doses may be given with caution and only if the benefit outweighs the potential risk (Prod Info INAPSINE(R) intravenous, intramuscular injection, 2011).
    2) HALOPERIDOL
    a) ORAL
    1) 0.5 to 2 mg (moderate symptoms) or 3 to 5 mg (severely symptomatic, chronic or resistant patients) orally 2 to 3 times daily (Prod Info haloperidol oral tablets, 2008; Prod Info haloperidol oral solution, 2008).
    b) INTRAMUSCULAR INJECTION
    1) 2 to 5 mg IM; subsequent doses based on patient response dosed every 1 hour, although every 4 to 8 hours may suffice. MAX DOSE: 20 mg/day (Prod Info HALDOL(R) intramuscular injection, 2015)
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) DROPERIDOL
    a) 2 TO 12 YEARS: For prevention of nausea and vomiting related to surgical or diagnostic procedures, the maximum recommended dose is 0.1 mg/kg IV (Prod Info INAPSINE(R) intravenous, intramuscular injection, 2011).
    b) 13 YEARS AND OLDER: The maximum recommended initial dose is 2.5 mg IM or slow IV. Additional 1.25 mg doses may be given with caution and only if the benefit outweighs the potential risk (Prod Info INAPSINE(R) intravenous, intramuscular injection, 2011).
    2) HALOPERIDOL
    a) The safety and effectiveness of the IM route has not been established in pediatric patients (Prod Info HALDOL(R) intramuscular injection, 2015).
    b) NON-PSYCHOTIC BEHAVIOR DISORDERS/TOURETTE'S DISORDER
    1) ORAL: 3 TO 12 YEARS (15 to 40 kg): 0.05 mg/kg/day to 0.075 mg/kg/day, administered in divided doses, two or three times daily. Therapy should be initiated at the lowest possible dose (0.5 mg/day) and can be increased incrementally at 0.5 mg every 5 to 7 days until the desired response is obtained, up to a maximum dose of 0.075 mg/kg/day (Prod Info haloperidol oral tablets, 2008; Prod Info haloperidol oral solution, 2008).
    2) ORAL: 12 YEARS AND OLDER: 0.5 to 2 mg (moderate symptoms) or 3 to 5 mg (severe symptoms) orally 2 to 3 times daily (Prod Info haloperidol oral tablets, 2008; Prod Info haloperidol oral solution, 2008).
    c) PSYCHOTIC DISORDERS
    1) ORAL: 3 TO 12 YEARS (15 to 40 kg): 0.05 mg/kg/day to 0.15 mg/kg/day, administered in divided doses, two or three times daily. Therapy should be initiated at the lowest possible dose (0.5 mg/day) and can be increased incrementally at 0.5 mg every 5 to 7 days until the desired response is obtained, up to a maximum dose of 0.15 mg/kg/day (Prod Info haloperidol oral tablets, 2008; Prod Info haloperidol oral solution, 2008).
    2) ORAL: 12 YEARS AND OLDER: 0.5 to 2 mg (moderate symptoms) or 3 to 5 mg (severe symptoms) orally 2 to 3 times daily (Prod Info haloperidol oral tablets, 2008; Prod Info haloperidol oral solution, 2008).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) HALOPERIDOL: Adults who have ingested as little as 300 mg have experienced life-threatening symptoms. With treatment for these effects, such as cardiovascular abnormalities, adults can survive ingestion of large doses (greater than 1 gram). Some individuals have had fatal reactions to even therapeutic doses of haloperidol (Aunsholt, 1989; Zee-Cheng et al, 1985).(Mahutte et al, 1982; Modestin et al, 1981; Ketai et al, 1979) .
    2) DROPERIDOL: Prehospital droperidol was given to two adult men who were extremely agitated after taking cocaine and phencyclidine, respectively. The patients received 5 to 10 mg of droperidol intramuscularly. Both became pulseless shortly after drug administration. Despite aggressive care, both patients died less than an hour after droperidol administration. Although the authors could not determine the exact cause of death, the safe use of droperidol for drug induced agitation in the prehospital setting appears uncertain and caution was suggested (Cox et al, 2004).

Maximum Tolerated Exposure

    A) ADULT
    1) HALOPERIDOL: Adults who have ingested 300 to 1000 milligrams haloperidol have experienced serious cardiovascular effects but have survived (Aunsholt, 1989; Zee-Cheng et al, 1985).
    2) DROPERIDOL: An 86-year-old man developed NMS after receiving droperidol 5 mg for agitation post-surgically. He became hypertensive (160/60 mmHg), tachycardic (170 bpm), drowsy, and confused, and he demonstrated muscle tremor and rigidity, and hyperpyrexia (38.6 degrees C). With supportive care, the patient gradually recovered (So, 2001).
    B) PEDIATRIC
    1) HALOPERIDOL: Acute dystonic reactions, altered mental status, and other extrapyramidal symptoms were reported (Tsujimoto et al, 1982) in 2 children following ingestion of 0.26 and 0.1 milligram haloperidol/kilogram over 24 hours.
    2) HALOPERIDOL: A 22-month-old girl who ingested 15 to 20 mg haloperidol developed blood pressure of 146/100 at 8 hours and 164/134 at 10 hours after a baseline level of 136/66 on admission (Cummingham & Challapalli, 1979).
    a) IV hydralazine was required to reduce pressures reaching as high as 180 systolic over the subsequent 5 days.

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) HALOPERIDOL
    1) Although controversial, therapeutic antipsychotic plasma levels of haloperidol reported are 5 to 15 ng/mL (Magliozzi, 1981; Morselli, 1982; Extein et al, 1983) Mavroidis et al, 1983); with 100 to 175 ng/mL reported following daily therapy with 3 to 9 mg (Marcucci et al, 1971).
    2) Serum haloperidol levels were examined in patients of various ages (adults and the elderly) receiving long-term treatment with haloperidol. In the elderly, it was noted that the free fraction of haloperidol (per daily dose) in serum increased with age. The authors concluded that the therapeutic levels in the elderly should be based on the concentration of free haloperidol rather than the total level, which is influenced by serum protein binding of the drug (Koyama et al, 2003).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) HALOPERIDOL
    1) Toxic blood levels have not been definitively established.
    2) PEDIATRIC: One study of 24 children who ingested large doses of haloperidol concluded that clinical signs increased in incidence if plasma haloperidol concentration 12 to 14 hours postingestion exceeded 6 nanograms/milliliter (Yoshida et al, 1993).
    a) The serum haloperidol concentration of 2 children who ingested 0.26 and 0.1 milligram haloperidol/kilogram over 24 hours was 23.3 and 5.5 nanograms/milliliter, respectively (Tsujimoto et al, 1982).
    3) ADULT: An 84-year-old man developed NMS-like symptoms (ie, fever, delirium, dyskinesia, garbled speech, only minimal CK increase {peak 179 units/L}) following an inadvertent intravenous haloperidol dose of 25 mg (intended dose 0.5 mg IV). Serum concentrations were 5.9 ng/mL at 6 hours and 1.2 ng/mL at 41 hours (serum half-life = 15 hours) and CSF levels at 43 hours were 0.8 ng/mL (therapeutic range for both serum and CSF is 0.8 to 33 ng/mL). The patient returned to baseline at 72 hours (Kostic et al, 2002).
    4) ADULTS (FATALITIES): Autopsy blood and tissue samples were tested in an adult who died of a haloperidol overdose of unspecified amount. Blood concentration of haloperidol was 1.9 milligrams/liter; bile concentration was 3.4 milligrams/liter; urine, 6.6 milligrams/liter. Liver tissue haloperidol concentration was 44 milligrams/kilogram (Levine et al, 1991).
    b) MALPERONE
    1) ADULT: Post mortem malperone levels in a fatality attributed to melperone overdose were: venous blood: 17.1 mg/L; heart blood 23.2 mg/L; CSF 18.6 mg/L; urine 346 mg/L (Stein et al, 2000).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) DROPERIDOL
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 72 mg/kg ((RTECS, 2000))
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 125 mg/kg ((RTECS, 2000))
    3) LD50- (ORAL)RAT:
    a) 750 mg/kg ((RTECS, 2000))
    4) LD50- (SUBCUTANEOUS)RAT:
    a) greater than 100 mg/kg ((RTECS, 2000))
    B) HALOPERIDOL
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 30 mg/kg ((RTECS, 2000))
    2) LD50- (ORAL)MOUSE:
    a) 71 mg/kg ((RTECS, 2000))
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 41 mg/kg ((RTECS, 2000))
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 27 mg/kg ((RTECS, 2000))
    5) LD50- (ORAL)RAT:
    a) 128 mg/kg ((RTECS, 2000))
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 60 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) HALOPERIDOL is pharmacologically related to the piperazine phenothiazines (Ayd, 1978). Similar to other neuroleptics, haloperidol centrally blocks the action of dopamine by binding previously to DA-2 receptors, and to a lesser extent, DA-1 receptors. The potency of all antipsychotic drugs correlates well with their affinity for DA-2 receptors (AMA Department of Drugs, 1983; Snyder, 1981).

Physicochemical

Physical Characteristics

    1) DROPERIDOL has a pKa of 7.46 (Prod Info INAPSINE(R) injection, 2006).
    2) HALOPERIDOL DECANOATE is almost insoluble in water (0.01 mg/mL) but soluble in most organic solvents (Prod Info haloperidol decanoate injection, 2005).

Ph

    1) DROPERIDOL: 3 to 3.8 (Prod Info INAPSINE(R) injection, 2006)
    2) HALOPERIDOL LACTATE: 3 to 3.6 (Prod Info HALDOL(R) immediate release IM injection, 2008)

Molecular Weight

    1) DROPERIDOL: 379.43 (Prod Info INAPSINE(R) injection, 2006)
    2) HALOPERIDOL: 375.87 (Prod Info haloperidol oral tablets, 2008)
    3) HALOPERIDOL DECANOATE: 530.13 (Prod Info haloperidol decanoate injection, 2005)

References

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    127) Product Information: HALDOL(R) DECANOATE intramuscular injection, haloperidol decanoate intramuscular injection. Ortho-McNeil Neurologics (per DailyMed), Titusville, NJ, 2011.
    128) Product Information: HALDOL(R) Decanoate 100 intramuscular injection, haloperidol decanoate intramuscular injection. Janssen Pharmaceuticals, Inc. (per DailyMed), Titusville, NJ, 2013.
    129) Product Information: HALDOL(R) Decanoate IM injection, haloperidol IM injection. Ortho-McNeil Neurologics, Titusville, NJ, 2010.
    130) Product Information: HALDOL(R) immediate release IM injection, haloperidol immediate release IM injection. Janssen Pharmaceutica NV, Beerse, Belgium, 2008.
    131) Product Information: HALDOL(R) intramuscular injection, haloperidol intramuscular injection. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2015.
    132) Product Information: HALOPERIDOL oral solution concentrate, haloperidol lactate oral solution concentrate. Teva Pharmaceuticals USA (per DailyMed), Sellersville, PA, 2010.
    133) Product Information: Haldol(R), haloperidol. McNeil Laboratories, Fort Washington, PA, 1994.
    134) Product Information: INAPSINE(R) injection, droperidol injection. Taylor Pharmaceuticals, Decatur, IL, 2006.
    135) Product Information: INAPSINE(R) intravenous, intramuscular injection, droperidol intravenous, intramuscular injection. Akorn, Inc. (per DailyMed), Lake Forest, IL, 2011.
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    141) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    142) Product Information: haloperidol decanoate injection, haloperidol decanoate injection. Bedford Laboratories, Bedford, OH, 2005.
    143) Product Information: haloperidol oral solution, haloperidol oral solution. Teva Pharmaceuticals USA, Sellersville, PA, 2008.
    144) Product Information: haloperidol oral tablets, haloperidol oral tablets. Sandoz Inc, Princeton, NJ, 2008.
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    149) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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