Antipsychotics for the treatment of sympathomimetic toxicity: A systematic review ^q

Nicholas J. Connors, MD ^a,?, Ahmed Alsakha, MD ^b,h, Alexandre Larocque, MD ^c,d, Robert S. Hoffman, MD ^e,

Tara Landry, MLIS ^f, Sophie Gosselin, MD ^b,c,g

^a Department of Emergency Medicine, Medical University of South Carolina, Charleston, SC, USA

^b Department of Emergency Medicine, McGill University Health Centre, Montreal, Quebec, Canada

^c Centre Antipoison Du Quebec, Montreal, Quebec, Canada

^d Department of Emergency Medicine, Centre Hospitalier de l’Universite de Montreal, Montreal, Quebec, Canada

^e Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University School of Medicine, New York, NY, USA

^f McGill University Library, Montreal, Quebec, Canada

^g Departement d’urgence, Hopital Charles-Lemoyne, Greenfield Park, Qc, Canada

^h Department of Emergency Medicine, Cornwall Community Hospital, Cornwall, Ontario, Canada

a r t i c l e i n f o

Article history:

Received 15 August 2018

Received in revised form 19 December 2018 Accepted 2 January 2019

Keywords:

Cocaine Amphetamine Antipsychotic Benzodiazepine

Sympathomimetic toxicity

a b s t r a c t

Objective: Benzodiazepines are often recommended first-line for management of cocaine and ampheta- mine toxicity while antipsychotic treatment is discouraged due to the potential for lowering seizure threshold, prolonging the QT interval, and decreasing heat dissipation. We performed a systematic review including animal and human studies to elucidate the efficacy and safety of antipsychotics in managing sympathomimetic toxicity specifically evaluating the effect of treatment on mortality, seizures, hyper- thermia, and Cardiovascular effects.

Methods: We searched MEDLINE, Embase, BIOSIS Previews, Web of Science, Scopus, CENTRAL and gray literature from inception to 31 May 2017 to answer: Can antipsychotics be used safely and effectively to treat cocaine or amphetamine toxicity? Citations were screened by title and abstract. Additional cita- tions were identified with citation tracking. Data were extracted from full-texts.

Results: 6539 citations were identified; 250 full-text articles were assessed. Citation tracking identified 2336 citations; 155 full texts were reviewed. Seventy-three papers were included in this review. In 96 subjects with cocaine toxicity treated with an antipsychotic, there were three deaths, two cardiac arrests, two seizures, and one episode of hyperthermia. In 330 subjects with amphetamine toxicity treated with an antipsychotic, there were two episodes of coma and QT prolongation and one episode of each: hypotension, NMS, cardiac arrest, and death.

Conclusion: This systematic review represents an exhaustive compilation of the available evidence. There is neither a clear benefit of antipsychotics over benzodiazepines nor a definitive signal of harm noted. We encourage clinicians to adapt treatment based on specific circumstances and characteristics of their individual patients.

(C) 2019

Introduction

Cocaine is one of the most common recreational substances used in the United States. According to the U.S. Substance Abuse and Mental Health Services Administration’s 2015 National Survey

^q There was no grant support for this work. The results presented in this paper have not been presented or published previously in whole or part.

* Corresponding author at: Department of Emergency Medicine, 169 Ashley Ave,

MSC 300, Charleston, SC 29425, USA.

E-mail address: [email protected] (N.J. Connors).

on Drug Use and Health, there were 1.8 million active cocaine users, 1.6 million users of nonmedical stimulants, and 897,000 users of methamphetamine [1]. Of the 1,252,500 emergency department (ED) visits due to illicit drugs in 2011, 505,224 ED vis- its were due to cocaine alone (40.3%). Similarly, 182,338 ED visits (14.6%) were related to amphetamines and derivatives, including methamphetamine and MDMA [2]. Adverse effects of sympath- omimetic drugs include: agitation, seizures, hypertension, tachy- cardia, hyperthermia, dysrhythmias, and sudden death [3-6].

The management of patients with sympathomimetic toxicity is challenging. Rapid sedation, hemodynamic stabilization, and

https://doi.org/10.1016/j.ajem.2019.01.001

0735-6757/(C) 2019

cooling are crucial early interventions in the management of these patients [7]. Pharmacological sedation options are limited to ben- zodiazepines, ketamine, and antipsychotic medications, though central alpha adrenergic antagonists and NMDA receptor antago- nists are in the early stages of evaluation. It is sometimes difficult to know if an ED patient with acute agitation has sympath- omimetic toxicity or an acute psychiatric illness.

Antipsychotics are used frequently for undifferentiated agita- tion. While quantifying use is nearly impossible, it is extremely common to see the use of haloperidol 5-10 mg IV or IM used for rapid sedation, among others. Paralytics and mechanical ventila- tion are generally considered a last resort and are usually reserved for severe symptoms such as hyperthermia or failure to control agitation. Benzodiazepines are considered by many to be the safest choice to treat sympathomimetic toxicity and, thus are often rec- ommended as the first-line agent [8]. Some authors discourage using antipsychotics owing to the hypothesis that these medica- tions lower seizure threshold, predispose to cardiac dysrhythmias, and decrease heat dissipation [9-11]. If true, these effects could worsen the clinical course of sympathomimetic toxicity and poten- tially increase mortality.

As sympathomimetic toxicity is a frequent clinical problem and as the optimal way to treat these patients remains partly based on expert opinion, we undertook this systematic review to evaluate the efficacy and safety of antipsychotics in managing sympath- omimetic toxicity. We did not aim to address the use of ketamine or dexmedetomidine due to the significant lack of research into the use of these agents to treat sympathomimetic toxicity.

Methods

Search strategy

The following databases were searched from inception to 31 May, 2017 for relevant citations by an experienced librarian (T. L.): MEDLINE (via OvidSP; via PubMed); Embase Classic + Embase (via OvidSP); BIOSIS Previews (via OvidSP); Web of Science (via ThomsonReuters); Scopus (via Elsevier); CENTRAL (via Cochrane Library). The search strategy (Appendix 1) used key text words and relevant indexing to answer the following question: Can antipsychotics be used safely to treat cocaine or amphetamine tox- icity? The full MEDLINE strategy was applied to all databases, with modifications to search terms as necessary. No language restric- tions were applied. Further citations were identified in Web of Science and Scopus by carrying out searches for citations referenc- ing the already included studies, as well as by examining their ref- erence lists. Proceedings of the North American Congress of Clinical Toxicology were hand-searched from 2009 to 2017. Additionally, the gray literature was reviewed for references to relevant publications.

Outcomes measures

Significant clinical Safety outcomes occurring as a result of treatment with antipsychotics in subjects with sympathomimetic toxicity were considered. The outcomes included in the present work were mortality, seizures, hyperthermia, and cardiovascular effects such as dysrhythmias, tachycardia and hypertension, as defined and reported by each study’s authors. The reviewers also catalogued apparent adverse effects from treatment.

Study eligibility

Two investigators (A.A. and N.C.) initially evaluated the eligibil- ity of citations and full-text articles; one author (AL) reviewed

excluded citations. All authors reviewed and agreed on full-text article inclusions. Full text articles were included if they respected the following criteria:

Study types: randomized controlled trials, non-randomized controlled trials, observational studies, case series, case reports, Animal experimental studies, and data presented as abstracts in scientific meetings.

Study subjects: humans or animals poisoned with cocaine or amphetamines.

Intervention: antipsychotics used to mitigate the toxic effects of sympathomimetic drugs. Investigations utilizing chemicals without regulatory approval (investigative drugs) for humans use in the United States or Canada were excluded.

There was no restriction on language. All materials without original data were excluded. However, their references were reviewed to identify citations potentially missed by the previously described search strategy. In-vitro experiments or studies with clinically irrelevant outcomes in the ED such as place preference conditioning, behavioral changes, neuronal toxicity or cell death without clinical endpoints were also excluded.

Data extraction

One of two investigators (A.A. and N.C.) extracted data from each study on a standardized form agreed upon by all authors. For each of the included studies, the following data were collected: species of subjects and their numbers if available, study type, sym- pathomimetic, antipsychotic, benzodiazepine, and other study medications used with doses and routes of administration, out- comes measured including: mortality, seizures, hyperthermia, car- diovascular effects, and other relevant treatment effects. The GRADE approach was applied to the human studies. Two of the authors (S.G. and R.S.H.) reviewed all papers independently and discussed their findings to resolve conflicts, which were minimal. No kappa was calculated.

Results

The search strategy returned 6539 citations, (Medline via Ovid = 892, Embase = 4485, Biosis Previews = 367, Cochrane Library = 16, Medline via PubMed = 7, Scopus = 548, Web of Science = 155, PsycINFO = 69). The gray literature search yielded no additional reports. 5132 citations were screened after removing duplicates, of which 4882 were irrelevant and excluded by title alone. Articles were translated from Japanese, German, French, Bul- garian, Spanish and Dutch. Two hundred and fifty full-text articles were assessed for eligibility, of which 187 articles did not meet the inclusion criteria, leaving 63 studies. Citation tracking provided an additional 2336 citations after duplicates removal. Of these 2181 were excluded based on the title or abstract, 155 full texts were retrieved. A total of 74 papers met all criteria for inclusion, but there was very similar data between two [12,24]. Following a per- sonal communication from one of the authors (N.C.) with the first author of these, it was clarified that the earlier study, published in 1997 is a subgroup of the later, published in 1998. For this analysis, only the later was included and the data were only counted once. Seventy-three papers were ultimately included in this review; 20 are human studies and described in the following text. Fifty- three animal studies are described in Supplemental material. Although all reviewed full text articles were translated, the included articles were all in English. Fig. 1 summarizes the study Selection process.

Fig. 1. Study selection access date May 31, 2017.

Twenty-five articles addressed cocaine alone, 44 articles addressed amphetamines alone, and 4 articles addressed cocaine and amphetamines together. The human data were not universally supported by confirmatory toxicologic confirmation, while the ani- mal studies used pure drugs in precise doses. Heterogeneity was present in the animal amphetamine literature with studies addressing amphetamine (21), methamphetamine (7), methylene- dioxymethamphetamine (MDMA) (4), methylenedioxyam- phetamine (MDA) (3), and paramethoxyamphetamine (PMA) (2). Similar heterogeneity existed in the antipsychotic use for both

cocaine and amphetamine toxicity with several different agents utilized at varying dosages. Haloperidol was the most common antipsychotic studied alone (27), followed by chlorpromazine (18), droperidol (7), ziprasidone (4), pimozide (3), olanzapine (2), clozapine (1) and quetiapine (1). An additional 13 papers studied multiple antipsychotics, with haloperidol most commonly investi- gated in 10 of them. There were 96 human subjects included in the articles dealing with cocaine toxicity and 330 in those with amphe- tamine toxicity. The adverse effects documented after antipsy- chotic administration include: hyperthermia (n = 1), hypotension

Fig. 2. Article results summary with adverse effects.

(n = 1), neuroleptic malignant syndrome (NMS) (n = 1), seizures (n = 2), QT prolongation (n = 2), coma (n = 2), cardiac arrest (n = 3), and death (n = 4) (Fig. 2).

Cocaine

Human data

Seven articles described the treatment of cocaine toxicity in humans (Table 1) [12-18]. In summary, there were several adverse events associated with antipsychotic administration. Droperidol was administered to 1 patient who suffered seizures and cardiac arrest, and another had seizures and hyperthemia. One patient developed asystolic cardiac arrest shortly after EMS-administered droperidol during transport and died. Haloperidol was adminis- tered to a patient who was found dead the next day and haloperi- dol and chlropromazine were given to a patient with unrecognized cocaine toxicity who died in the psychiatric ED. Low cocaine and metabolite concentrations were noted in a cohort of patients at autopsy who also had presence of an antipsychotic than those who had only evidence of cocaine.

• Randomized trials. A randomized controlled trial compared droperidol 2.5 mg IV for subjects <=50 kg or 5 mg IV for subjects

>50 kg to IV lorazepam 2 mg IV for subjects <=50 kg, 4 mg IV for subjects >50 kg in agitated ED patients who used cocaine or methamphetamine. Twelve subjects with urine drug screens posi- tive for cocaine (four of whom also had measurable serum ethanol concentrations) were treated with lorazepam while 16 (seven with concomitant ethanol intoxication) were treated with droperidol. There were no statistically significant differences in sedation 5 min after study drug administration, but those treated with droperidol were more likely to be sedated after 5 min and required less redosing than those treated with lorazepam. At 0 min the mean sedation scores (on a scale created by the authors with a lower score indicating greater sedation) were 5.3 and 5.6 in the lor-

azepam and droperidol groups respectively. At 5 min the mean sedation scores were 4.7 and 4.8, but over time, the differences became statistically significant between the lorazepam and droperidol groups with respective scores of 4.1 vs 2.8 at 10 min;

3.5 vs 2 at 15 min, 2.9 vs 1.6 at 30 min, and 2.5 vs 1.5 at 60 min. When sedation scores versUS time were separated by cause of tox- icity (cocaine vs methamphetamine), there was a similar increase in sedation with more rapid onset in those who had used cocaine and were treated with droperidol compared to lorazepam, but sta- tistical analysis was not performed to determine the significance of these findings. One patient treated with droperidol developed an acute dystonic reaction, though it is not reported whether they had cocaine or amphetamine toxicity [12].

• Uncontrolled observations. A retrospective case series describes 64 patients who either admitted to using cocaine or had a urine drug screen positive for cocaine (20 of whom also had positive breath or serum ethanol concentrations), who were treated with IM or IV droperidol for agitation, anxiety, vomiting, or pain. Among these, a 39-year-old man was brought to the ED after ingesting multiple pieces of crack cocaine. He was treated with droperidol 5 mg IM and lorazepam 2 mg IM for sedation but eleven hours later he suffered a seizure and cardiac arrest. He was treated with cardioversion, antidysrhythmics, antiepileptics, multidose activated charcoal, and naloxone infusion. He was dis- charged seven days after presentation, Neurologically intact. A 28-year-old woman with a urine drug screen positive for cocaine was brought to the ED by police with agitated delirium and a heart rate of 200/min. She was administered lorazepam 2 mg IM and, 12 min later, droperidol 5 mg IM. Nine minutes later she had a sei- zure. She was treated with antibiotics and phenytoin. She was dis- charged five days after presentation [13].

A case series describes five patients with oral ingestions of crack cocaine. The first ingested 28 nuggets and was found convulsing by police. She was given diazepam 10 mg IV, but suffered PEA arrest and was eventually declared brain dead after prolonged status epilepticus. Another adult patient became symptomatic and was treated with lorazepam 16 mg IV and haloperidol 5 mg IV. He was admitted and treated with an esmolol infusion and lorazepam 2-4 mg IV boluses and discharged without sequelae. A patient who was agitated after a cocaine ingestion was treated with a total lor- azepam dose of 12 mg IV followed by labetalol, diphenhydramine, and esmolol and discharged without sequelae. Lorazepam 4 mg IV was used to treat another agitated patient after cocaine ingestion along with labetalol. The patient developed seizures and was trea- ted with lorazepam 2 mg IV and midazolam 5 mg IV. He signed out of the hospital against medical advice and was lost to follow-up. Finally, a patient rapidly ingested poorly packaged cocaine to avoid prosecution and became agitated. He was treated with a total lor- azepam dose of 10 mg IV and propranolol, then discharged home after 48 h [16].

Finally, a retrospective case series of cocaine-related deaths performed by a Medical Examiner reported lower cocaine and ben- zoylecgonine concentrations in patients who also had measurable concentrations of various antipsychotics compared to those with- out any measurable concentrations of antipsychotics, which included one case involving thioridazine [15].

• Case reports. The three case reports are summarized in Table 1 [14,17,18].

  Animal data

  Briefly, chlorpromazine pretreatment of dogs protected against mortality, compared to diazepam pretreatment, which resulted in 33% mortality 48-72 h after cocaine exposure. Chlorpromazine compared to placebo in pretreatment models in rats and guinea

  Table 1

  Human cocaine toxicity treated with antipsychotics

  Citation and GRADE Level of evidence

  Randomized trials

  Subjects Treatment Results Threats to validity

  Richards JR et al., 1998 [12]

  Level LOW

  Case series Merigian KS,

  1994

  [16]

  Level VERY LOW

  Study of general agitated ED patients (n = 202), 28 of

  whom used cocaine.

  Patients with oral cocaine ingestion (n = 5)

  Droperidol 2.5 mg IV for weight <50 kg, 5 mg IV for weight >50 kg

  vs.

  Lorazepam 2 mg IV for weight <50 kg, 4 mg IV for weight >50 kg

  Patient 1: ingested 28 nuggets, convulsion, given diazepam 10 mg IV

  Patient 2: combative, violent, aggressive, given lorazepam 16 mg IV haloperidol 5 mg IV

  Patient 3: agitated, given lorazepam 12 mg IV

  Patient 4: agitation and Seizures. Given lorazepam; lorazepam 2 mg IV and midazolam 5 mg IV

  In 28 subjects with urine drug screen positive for cocaine, 11 of which were also positive for ethanol.

  statistically significant increase in sedation in droperidol group compared to lorazepam after 5 min.

  Patient 1: suffered PEA arrest. Brain dead after prolonged status epilepticus.

  Patient 2: discharged without sequelae.

  Patient 3: discharged without sequelae.

  Patient 4: he signed out of the hospital against medical advice.

  Patient 5: agitation. Discharged home after 48 h.

  Definition of toxicity based on urine drug screen (-1 indirectness)

• Non blinded (-1 lack of allocation concealment)
• Weight ”visually estimated”
• Non validated sedation scale
• Dose equivalency between lorazepam and droperidol not validated
• See discrepancy with dosing below under methamphetamine as reported in Richards JR et al., 1997 [24]
• Confounding of other drugs present (etha- nol for one present in 33.3% of the loraze- pam group vs 44% in the droperidol group)
• Lorazepam not ideal comparator - proven slow onset compared with midazolam
• Uncontrolled data
• Cocaine ingestion uncommon
• Treatment confounded by multiple thera- pies - all patients given beta adrenergic antagonists, some received phenytoin, diphenhydramine and morphine
• No confirmation of ingestion (indir- ectness)

  Chase PB et al., 2002 [13]

  Level VERY LOW

  Molina K et al., 2011 [15]

  Retrospective Review

  Level VERY LOW

  Case reports

  Retrospective review of ED patients treated with droperidol (n = 2468)

  Patients with cocaine-related deaths

  Patient 5: agitation, given lorazepam 10 mg

  Droperidol IM or IV In 44 with cocaine exposures 2 subjects

  suffered seizures, 1 had hyperthermia, and 1 had cardiac arrest. Fourteen percent were admitted.

  In 20 patients with cocaine and alcohol exposures, 55% were admitted.

  The concentration of cocaine and benzoylecgonine was less in those who also had measurable antipsychotic concentrations compared to those with only cocaine or benzoylecgonine.

  Uncontrolled data

• Definition of toxicity unclear; history or urine drug screen positive
• Actual cause of death unclear.
• Definition of ”cocaine-related” is undefined.
• 69% had at least one drug in addition to cocaine but only 12% had an antipsychotic plus cocaine.
• Since percent of ”dead on arrival” patients unknown, for some the antipsychotic was therapeutic prior to the cocaine use and not given as treatment for the toxicity.

  Fishbain D et al., 1981 [14]

  Level VERY LOW

  Klein C et al., 2000

  [17]

  Level VERY LOW

  31 year old man, cocaine body packer

  38 year old woman, cocaine body packer

  Chlorpromazine 50 mg

  IM x 2

  Haloperidol 10 mg IM

  Diazepam 20 mg

  Haloperidol 10 mg

  The patient died 3.5 h after arrival to psychiatric ED, an unknown time from presentation or ingestion.

  A seizure treated with phenytoin, then diazepam 20 mg and haloperidol 10 mg, increasingly paranoia.

  Transferred to psychiatry; found dead the next day.

  Autopsy: multiple intestinal broken packets containing cocaine

  Anecdotal by definition

  Anecdotal by definition

  Cox RD et al., 2004 [18]

  Level VERY LOW

  33 year old man with agitation

  Droperidol 5 mg IM Agitated and EMS gave droperidol. Apneic

  and asystolic after while in transport. Autopsy showed cocaine in blood and metabolites in urine

  Anecdotal by definition

  Table 2

  Human amphetamine toxicity treated with antipsychotics

  Citation Subjects Treatment Results Threats to validity Randomized trials

  Richards JR et al.,

  Study of general agitated ED patients

  Droperidol 2.5 mg IV for weight In 146 subjects with urine drug screen

  Definition of toxicity

  1998 [12]

  Also reported in Richards JR et al., 1997 [24]

  Level LOW

  Case series

  (n = 202), 146 of whom used methamphetamine

  <50 kg, 5 mg IV for weight

  >50 kg vs. lorazepam 2 mg IV for weight <50 kg, 4 mg IV for weight >50 kg

  positive for methamphetamine, 59 of which were also positive for ethanol.

  Statistically significant increase in sedation in droperidol group compared to lorazepam after 5 min.

  based on urine drug screen (-1 indirectness)

  Non blinded (-1 lack of allocation concealment)

• Weight ”visually esti- mated” (indirectness)
• Non validated sedation scale
• Dose equivalency between lorazepam and droperidol not validated
• Dosing listed as ”sugges- tions” but left up to the clinicians decision
• Confounding of other drugs present (ethanol for one)
• Lorazepam not ideal com- parator - proven slow onset compared with midazolam

  Espelin DE et al.,

  Children aged 11-48 month old

  Varying doses (0.4 to 4.0 mg/kg) Sedation occurred in all subjects. Two

  Retrospective

  1968 [19]

  Level VERY LOW

  (n = 22) with toxicity due to: Methamphetamine (n = 2) Amphetamine (n = 5) Methamphetamine/phenobarbital (n = 8) Amphetamine/phenobarbital (n = 1) Phenmetrazine (n = 2) Detroamphetamine/Meprobamate (n = 1)

  Dextroamphetamine (n = 2) Carboxyphen/butabarbital (n = 1)

  of chlorpromazine (n = 22) and 5/22 treated with barbiturates

  serious adverse effects. One child ingested a methamphetamine phenobarbital combination, was agitated and was treated with 1.2 mg/kg chlorpromazine IM. Then became unresponsive, apneic and pulseless which resolved with ”chest pounding.” They were discharged home without sequelae. Another became frankly comatose after 1.1 mg/kg chlorpromazine IM.

  Uncontrolled data

• No confirmation of ingestion
• Chlorpromazine different from many antipsychotics with very potent alpha adrenergic antagonism (antihypertensive effect)

  Derlet RW et al., 1989 [20]

  Level VERY LOW

  127 adults with amphetamine toxicity Haloperidol 6% (n = 8) of Agitated patients were

  treated with haloperidol, 4% (n = 5) were treated with diazepam. Patients responded ”equally well.”

  Retrospective

• Uncontrolled data
• Definition of toxicity is a positive urine drug screen
• 21 cases had other drugs detected
• Drug doses not specified

  Calver L et al.,

  Safety arm of a prospective study of

  41 year old man with

  QT prolongation 522 ms, 11 h post

  Etiology of QT prolonga-

  2013 [21]

  the use of droperidol for agitation in 46 amphetamine toxicity treated

  droperidol

  tion unclear because of

  Level VERY LOW

  Guharoy R et al., 1999 [25]

  Level VERY LOW

  Ruha AM et al., 2006 [26]

  Level VERY LOW

  Case reports

  patients.

  Six adults with methamphetamine toxicity

  Retrospective review of children

  <13 years old with methamphetamine toxicity admitted to one ICU (n = 18)

  with droperidol 20 mg IM

  25 year old man taking methadone presents with amphetamine toxicity and is treated with droperidol 10 mg IM

  Haloperidol, a benzodiazepine or both

  All 18 received a benzodiazepine. Haloperidol (0.02-0.67 mg/kg) was also given in 12.

  QT prolongation 512 ms up to 2.25 h post droperidol

  One treated with haloperidol 6 mg and diazepam 10 mg; one treated with diazepam 50 mg and haloperidol 2 mg; one treated with haloperidol 4 mg; on treated with 40 mg diazepam and 4 mg lorazepam, one treated with 10 mg diazepam; on required no sedation. All did well.

  Clinical improvement without adverse effects reported in all

  time delay (case 1) and co-ingestion (case 2)

  Unclear how the cases were identified Uncon- trolled data

• Unclear rationale for doses of drugs given
• Retrospective
• Uncontrolled data
• Use of benzodiazepines in all patients confounds any assessment

  Ginsberg MD et al., 21 year old man with amphetamine

  Chlorpromazine 100 mg

  Ingestion of about 2 g amphetamine and Anecdotal by definition

  1970 [22]

  Level VERY LOW

  toxicity

  subcutaneously

  became agitated, hyperthermic, tachycardic, and hypertensive. Post treatment became somnolent, obtunded and hypotensive. Blood pressure improved with IVF, Trendelenberg positioning. He developed AKI and

  (continued on next page)

  Table 2 (continued)

  Citation	Subjects	Treatment	Results	Threats to validity
  Soong WJ et al.,	Two children with amphetamine	Case 1: 18 month old boy	required hemodialysis but improved over several days. Slept for 20 h, and improved.	Anecdotal by definition
  1991 [23] Level VERY	toxicity	diazepam 10 mg, haloperidol 20 mg IV, and Chloral hydrate,
  LOW		Case 2: 20 month old boy treated with diazepam 10 mg IV	Improvement in agitation
  Gullatt R, 1957	21 month old boy with	twice and haloperidol 20 mg IV Chlorpromazine 2.5 mg IV (two	The child had Rapid resolution of	Anecdotal by definition
  [27] Level VERY	methamphetamine toxicity	doses 9 h apart)	symptoms and survived without sequalae
  LOW Hall CD et al., 1973	26 year old man with	Chlorpromazine 50 mg IM	The patient presented agitated,	Anecdotal by definition
  [28]	methamphetamine toxicity		hypertensive after complaining of severe
  Level VERY			headache. Post treatment became hemiplegic and evidence of intracranial
  LOW Gary NE et al.,	27 year old man with	Droperidol 2.5 mg/min IV	hemorrhage was found on cerebral arteriography and confirmed on autopsy. Fifteen minutes after initiation of	Anecdotal by definition
  1978 [29] Level VERY	methamphetamine toxicity	infusion, Phenobarbital 120 mg IM initial treatment	droperidol infusion (105 min after phenobarbital) pulse and BP improved.
  LOW Brown C et al.,	32 year old woman with MDMA	Haloperidol	The patient presented with agitation and	1. Anecdotal by definition
  1987 [30] Level VERY	toxicity	gastric lavage, dextrose, diazepam, and naloxone. Drug doses not specified	hallucinations, was hyperthermic, tachycardic, hypotensive. She was intubated, After stabilization she was	2. No dose reported
  LOW			given haloperidol and diazepam for agitation. She was extubated and had no
  Lehmann ED et al.,	36 year old man with MDMA toxicity	Chlorpromazine and diazepam	further complications. The patient presented after seizing at a	1. Anecdotal by definition
  1995 [31] Level VERY		given, dose not specified	nightclub. He became hyperthermic and agitated. Sodium was 115 mmol/L. He developed rhabdomyolysis and	2. No dose reported
  LOW Russell T et al.,	20 year old woman with MDMA	Haloperidol, total 115 mg	recovered. NMS in a patient with ryanodine	Anecdotal by definition
  2012 [32]	toxicity		receptor mutation. Recovered without
  Level VERY			sequelae.
  LOW

  pigs protected against mortality. In a monkey model chlorpro- mazine treatment resulted in no mortality, while diazepam treat- ment resulted in 33% (n = 1). Due to species and model differences with the human clinical scenarios, the applicability of these finding to humans is questionable at best. See Supplemental text and tables for a detailed description of the animal data.

  Amphetamines

  Human data

  In summary, there were several adverse events associated with antipsychotics. Chlorpromazine was associated with two episodes of coma, and one episode each of cardiac arrest, intracranial hem- orrhage, hypotension, and death. Haloperidol, in a very high dose, was associated with NMS. Droperidol administration was associ- ated with two episodes of QT prolongation. These findings are shown in Fig. 2.

  • Amphetamine.

    Randomized trials. There are very few human studies on the effect of antipsychotics in patients with amphetamine toxicity. No randomized trials of the treatment for amphetamine toxicity were found. The data below are summarized in Table 2.

  • Uncontrolled observations. A case series of 22 children, aged from 11 to 48 months, describes exposures to various amphetamines, and amphetamine combination medications. Five of these children were initially treated with barbiturates for sym-

  pathomimetic toxicity. All were administered chlorpromazine at varying doses to control symptoms. There was one case of apnea and pulselessness in a 23-month-old child who had ingested methamphetamine/phenobarbital and was given chlorpromazine

  1.2 mg/kg intramuscularly. The child improved with ”chest pound- ing” and was discharged without noted sequelae. Another child became ”frankly comatose” after ingestion of a metham- phetamine/phenobarbital combination and treatment with chlor- promazine 1.1 mg/kg intramuscularly [19]. Another case series from 1989 describes 127 adult patients with amphetamine toxic- ity. Six percent (n = 8) were treated with haloperidol and 4% (n = 5) were treated with diazepam for agitation. Patients responded ”equally well” to both [20].

  A 2013 case study on the effects of high-dose droperidol (nor- mal dosage 2.5-5 mg IV or IM) for the treatment of aggressive ED patients reported two patients with QT prolongation. The first, a 41-year-old man with hallucinations due to amphetamines, had QT prolongation to 522 ms after 10 mg droperidol IM and a 25- year-old man on methadone with amphetamine toxicity and agita- tion had a QT of 512 ms after 20 mg droperidol IM (customary dos- ing: 2.5-5 mg IV/IM) [21].

  • • Case reports. Two case reports are summarized in Table 2 [22,23].

      Methamphetamine.

      Randomized trials. A randomized controlled trial (previ- ously described above with regards to cocaine-toxicity) compared

    droperidol, 2.5 mg IV for patients <=50 kg or 5 mg IV for patients

    >50 kg to IV lorazepam 2 mg IV for patients <=50 kg or 4 mg IV for patients >50 kg for methamphetamine toxicity. Seventy-four patients with urine drug screens positive for methamphetamine (30 of whom also had serum ethanol concentrations) were treated with lorazepam while 72 (29 with serum ethanol concentrations) were treated with droperidol. There was statistically significant faster onset and greater sedation in all patients treated with droperidol compared to lorazepam. When sedation scores versus time were separated by cause of toxicity, there was similar increased sedation with more rapid onset in those who had used methamphetamine and treated with droperidol compared to lora- zepam, but statistical analysis was not performed to determine the significance of these findings. One patient in the droperidol group developed an acute dystonic reaction. It was not stated whether this patient had evidence of amphetamine or cocaine use [12].

    • • Uncontrolled observations. One case series reports six adults with methamphetamine toxicity, three of whom were trea- ted with haloperidol for agitation and did well [25]. A more recent case series describes children, 4 months to 7 years old, with methamphetamine toxicity treated with benzodiazepines and haloperidol. Twelve children were administered haloperidol after all received a benzodiazepine. The haloperidol Dose ranged from 0.02-0.67 mg/kg. There were no cases of QT prolongation, respira- tory depression, or dystonic reactions [26].

      • Case reports. Three case reports are summarized in Table 2 [27-29].

        Methylenedioxymethamphetamine (MDMA). No randomized trials of antipsychotics in MDMA toxicity were found. Three case reports are summarized in Table 2 [30-32].

        Animal data

        In summary, the animal data show chlorpromazine and haloperidol pretreatment resulted in decreased mortality com- pared to controls. In a rat model, haloperidol pretreatment reduced mortality compared to those pretreated with diazepam. Due to species and model differences with the human clinical scenarios, the applicability of these finding to humans is questionable at best. See Supplemental text and tables for a detailed description of the animal data.

        Discussion

        Abuse of amphetamines and cocaine is common resulting in many ED admissions for sympathomimetic toxicity and agitated delirium worldwide [33]. While EDs encounter a significant number of patients presenting with sympathomimetic toxicity, it is often unclear whether or not cocaine and or amphetamines are responsi- ble due to the fact patients do not always know what they were sup- plied. Additionally, ED physicians encounter a fair number of patients who are agitated, and the differential diagnosis is exten- sive, including both toxicological and non-toxicological causes.

        The ideal management of patients with acute agitation involves treatments that prevent significant complications such as seizures and hyperthermia in order to reduce mortality and morbidity but also, prevent harmful effects of the other possible etiologies. For decades, the notion that antipsychotic use could be detrimental for sympathomimetic toxicity was discussed in many forums yet, clinical experience and published case reports of successful use without harm continues. We undertook this systematic review to quantify the available literature on the topic and tried to gather evi- dence of either safety or harm to better inform clinical management.

        Specifically, droperidol compared to lorazepam in cocaine and methamphetamine toxicity resulted in greater sedation and less frequent redosing, but also was likely responsible for one pub- lished case of dystonia [12]. Two other patients given droperidol exhibited complicated Clinical courses [13]. One is a patient with ingestion of crack cocaine who suffered a cardiac arrest approxi- mately 11 h after treatment with droperidol. While it is impossible to know the proximate cause, given the temporal delay, it seems most likely that this could be the result of chronic use and cocaine toxicity, rather than an adverse effect of the droperidol. The other patient with severe cocaine toxicity had a seizure 9 min after droperidol administration. The shorter delay makes it impossible to adjudicate the cause of the seizure between cocaine toxicity and a droperidol adverse effect. While others [14,17] report cocaine deaths after antipsychotic administration, all are cases of missed body packers and it is unclear if the causes of death are not more related to the massive amount of drug ingested. Finally, the one case that raises concerns describes an agitated patient who became asystolic shortly after treatment with droperidol [18]. It is unknown what underlying dysrhythmias were present pre-treatment. Animal data of cocaine toxicity suggests improved mortality with antipsychotics compared to benzodiazepines though the reported deaths were at least two days after exposure and potentially unrelated to cocaine exposure or treatment.

        The published data for amphetamine toxicity is similarly lim-

        ited; one author [21] reported two cases of QT prolongation after droperidol treatment, another [22] a patient who became obtunded and hypotensive after chlorpromazine 100 mg IV. Finally, one author [32] described a patient with MDMA toxicity, treated with haloperidol (115 mg) who subsequently developed NMS. Of note, this patient was found to possess a ryanodine recep- tor abnormality, raising the question of combined malignant hyperthermia with a massive dose of haloperidol that most clini- cians would not administer.

        Haloperidol, the most commonly used antipsychotic for acute agitation, and the most commonly studied antipyschotic in our sample of studies, has not been evaluated in any randomized con- trolled trial for the management of patients with cocaine or amphetamine toxicity [34]. Only case reports describe safe and effective use, though there are reports of adverse events associated with its use as well. Like droperidol, though, haloperidol is a first generation antipsychotic and has a warning for use due to QT pro- longation. It does have less alpha₁ adrenergic and muscarinic antagonism than other typical antipsychotics though, which may make it somewhat safer for use in cocaine and amphetamine tox- icity than other medications in its class [35].

        Several limitations to our study exist. As with any systematic review, the evidence is prone to publications bias. However, the main findings of our work presented in this article reflect, in our opinion, the most comprehensive evidence collated from all possi- ble sources. As a whole, the body of evidence is very heteroge- neous, with many studies using different Experimental models that cannot be merged into a formal meta-analysis. The choice of sympathomimetic, the dosing regimen, the type of antipsychotic used and the delay between sympathomimetic use and treatment differ greatly. Many animal experiments are also pretreatment models, which, while potentially useful to inform on the risk of individuals therapeutically treated with antipsychotics before using sympathomimetic, are not generalizable for the emergency clinician faced with an agitated patient. The human data are lim- ited to low and very low quality of evidence suggesting a lack of certainty of true effects.

        We were unable to establish a dose response curve for any antipsychotic treatment. The most common medication used was haloperidol followed by chlorpromazine. Doses used ranged from

        0.25 mg/kg to 2 mg/kg in a number of different species. One cannot

        directly extrapolate from doses given to animals to humans due to differences in species’ drug metabolism. The administered dose varied significantly with many experiments done with the IP route, which is not something clinicians would consider in emergency settings.

        Conclusion

        This systematic review on the use of antipsychotics in sympath- omimetic toxicity represents the most exhaustive compilation of the available evidence to date. Although the studies differ in their methodologies and several models are not generalizable to the human clinical poisoning scenarios, we did not identify a signifi- cant signal of harm within the published literature. While several Major adverse events are noted in the literature, there are signifi- cant questions regarding causation for each. Also, while there is no recurrent evidence of safety issues, there is no more evidence of a significant benefit over benzodiazepines, especially at doses used in human medicine. Future studies should focus on establish- ing a benefit or non-inferiority of antipsychotics to benzodi- azepines in the management of sympathomimetic toxicity in an ED population. Awaiting more robust data, we encourage clinicians to adapt their treatment based on the specific circumstances and characteristics of their individual patients rather than using a ”one size fits all” strategy in order to balance the risks and benefits of any chosen therapy.

        Disclosure

        The authors have nothing to disclose.

        Funding

        This study did not receive any funding.

        Author involvement

        All authors contributed to the protocol and study planning. NC, AA and TL performed the search and article citations screen. AL resolved discrepancies. NC, AA, AL, RSH and SG analysed the included full text articles, summarized and wrote the manuscript.

        Appendix 1

        Database: Ovid MEDLINE(R) and Epub Ahead of Print, In- Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily

        <1946 to Present>. Search Strategy:

        —————————————————————————

        exp Antipsychotic Agents/

      • Phenothiazines/
      • Butyrophenones/
      • Indoles/
      • Thioxanthenes/
      • Azepines/
      • Oxepins/
      • Benzamides/
      • Amides/
      • Benzoates/
      • exp Dopamine Antagonists/
      • (major adj3 (tranquilis* or tranquillis* or tranquiliz* or tranquilliz*)).tw,kf.
      • (butyrophen* or butyrofenon* or phenothiazin* or (indole* adj2 derivativ*) or indoles or thioxanthen* or azepin* or oxe- pin* or benzamide*).mp.
      • (antipsychotic* or anti-psychotic* or neuroleptic*).mp.
      • (azaperon* or r-1929 or r1929 or stresnil).mp.
      • (acetophenazin* or acephenazin*).mp.
      • (acepromazin* or acetopromazin* or vetranquil or acetylpro- mazin* or calmivet or acetazin* or plegicil).mp.
      • (aminosultoprid* or amisulprid* or amisulpirid* or dan2163 or dan-2163 or sertol or socian or solian).mp.
      • (benperidol or anquil or benperidolneuraxpharm or frenactil or glianimon).mp.
      • (ay23028 or ay-23028 or butaclamol).mp.
      • (butaperazin* or butyrylperazin* or megalectil or randolectil or randolectyl or repoise or riker-95 or tyrylen or ahr3000 or ahr-3000 or bayer-1362).mp.
      • (chlorpromazin* or thorazin* or largactil or chlorazin* or chlordelazin* or contomin or aminazin* or propaphenin or fenactil).mp.
      • (taractan or chlorprotixen* or chlorprothixen*).mp.
      • (cremin or clospipramin* or mosapramin* or y516 or y-516). mp.
      • (clozapin* or leponex or clozaril).mp.
      • (cyamemazin* or cyamepromazin* or cianactil or kyamepro- mazin* or fi6229 or fi-6229 or rp7204 or rp-7204 or tercian). mp.
      • (chlorproethazin* or neuriplege or rp4909 or rp-4909).mp.
      • (droperidol or dehydrobenzperidol or dehidrobenzperidol or droleptan or inapsin*).mp.
      • (etazolate or sq20009 or sq-20009).mp.
      • (fluanxol or flupentixol or flupenthixol or emergil).mp.
      • (fluphenazin* or lyogen or prolixin* or flufenazin*).mp.
      • (fluspirilen* or redeptin or spirodiflamin* or imap or kivat or fluspi).mp.
      • (haloperidol or Haldol).mp.
      • (flanapt* or hp873 or hp-873 or iloperidone or ilo522 or ilo- 522 or zomaril).mp.
      • lithium.mp.
      • (loxapin* or loxipin* or cl71563 or cl-71563 or loxitane or cloxazepin* or oxilapin*).mp.
      • (lurasidone or latuda or mk3756 or mk-3756 or sm13496 or sm-13496 or smp13496 or smp-13496).mp.
      • (bunil or buronil or eunerpan or fg5111 or fg-5111 or flubu- perone or melperon* or methylperon* or metylperon*).mp.
      • (mesoridazin* or serentil).mp.
      • (methiothepin* or metitepin*).mp.
      • (levopromazin* or tisercin* or tizercin* or methotrimepra- zin* or levomepromazin* or levomeprazin or tizertsin).mp.
      • (moban or molindone).mp.
      • (moperon* or luvatren* or methylperidol* or methyl- peridol* or r1658 or r-1658).mp.
      • (hydroxyrisperidone or hydroxy-risperidone or invega or xeplion or r76477 or r-76477 or ro76477 or ro-76477 or ro92670 or ro-92670).mp.
      • (periciazin* or pericyazin* or properciazin* or propericiazin* or aolept or neulactil or neuleptil* or rp8909 or rp-8909 or skf20716 or skf-20716).mp.
      • (ondansetron or gr38032f or gr-38032f or sn307 or sn-307 or Zofran).mp.
      • (paliperidon* or invega or r76477 or r-76477 or ro76477 or ro-76477 or ro92670 or ro-92670 or xeplion).mp.
      • (r16341 or r-16341 or semap or penfluridol).mp.
      • (perazin* or taxilan).mp.
      • (pipotiazin* or pipothiazin* or piportil or rp19366 or (rp adj2 ”19366″)).mp.
      • (perfenazin* or trilafon or perphenazin* or chlorpiprazin*). mp.
      • (orap or antalon or pimozid* or r6238 or r-6238).mp.
      • (oxipertin* or oxypertin* or cl77328 or cl-77328 or forit or opertil or win18501* or win-18501*).mp.
      • (prochlorperazin* or Compazin*).mp.
      • (promazin* or sinophenin or sparin* or protactyl).mp.
      • (prothipendyl or prothipendil or protipendil or protipendyl or ay5603 or ay-5603 or azacon or d206 or d-206 or dominal or dominalforte or largophren or lg206 or lg-206 or phreno- tropin or timovan or tolnate or tumovan).mp.
      • (racloprid* or flb-472 or flb472 or fla-870 or fla870 or flb472 or flb-472).mp.
      • (remoxiprid* or fla731 or fla-731).mp.
      • (serpivit* or vserp or v-serp or raunervil or rausedil or rause- dyl or serpasil or raupasil or reserpin*).mp.
      • (Risperdal or Risperidal or r64766 or r-64766 or risperi- done).mp.
      • (ritanserin* or r-55667 or r55667).mp.
      • (spiperone or spiroperone or spiroperidol).mp.
      • (sulpiride or sulperide or tepavil or lebopride or vertigo- meresa or pontiride or ekilid or sulp or sulpor or dolmatil or digton or aiglonyl or guastil or sulpitil or meresa or syne- dil or deponerton or arminol or neogama or eglonyl or sulpi- vert or desisulpid or psicocen or dogmatil).mp.
      • (thiopropazat* or thipropazat* or artalan or dartal or darta- lan or dartan or sc7105 or sc-7105).mp.
      • (melleretten or thioridazine or sonapax or thiozine or rideril or meleril or melleril or melleryl or mellaril or thiori- dazineneurazpharm or apothioridazine or melzine or alda- zine).mp.
      • (thioproperazin* or thioperazin* or rp7843 or rp-7843).mp.
      • (thiothixene or tiotixene or navan or navane).mp.
      • (tiaprid* or flo-1347 or flo1347 or tiaprizal or equilium).mp.
      • (trifluperidol or trisedil).mp.
      • (siquil or triflupromazin* or trifluopromazin* or fluopro- mazin*).mp.
      • (trifluperazin* or trifluoperazin* or triftazin* or trifluoroper- azin* or eskazin* or stelazin* or flupazin* or apotrifluoper- azin* or terfluzin*).mp.
      • (zuclopenthixol or zuclopentixol or clopenthixol or cisordi- nol or sedanxol or dihydrochloride or di-hydrochloride or clopixol).mp.
      • ((amitriptyline adj2 perphenazine) or amperozide or arip- iprazole or Asenapine or bromperidol or clothiapine or dapiprazole or dicarbine or dixyrazine or DN1417 or DN1417 or DuP-734 or Dup734 or ecopipam or fananserin or fencamfamine or fluanisone or fluperlapine or isoflox- ythepin or metylperon or nemonapride or olanzapine or perospirone or piflutixol or pipamperone or quetiapine or rimcazole or 22-1319 or Ro221319 or ro-221319 or sertin- dole or SR142801 or sr-142801 or stepholidine or sulfori- dazine or sultopride or tetrahydropalmatine or timiperone or veralipride or zetidoline or ziprasidone or zotepine).mp.
      • or/1-73
      • exp cocaine/
      • exp Amphetamines/
      • Sympathomimetics/
      • or/75-77
      • exp ”Drug-Related side effects and Adverse Reactions”/
      • Drug Overdose/
      • Poisoning/
      • (to or po).fs.
      • (overdos* or over-dos* or OD or toxicit* or toxicosis or toxi- coses or cardiotoxic* or intoxicat* or poison* or megados* or mega-dos*).tw,kf.
      • or/79-83
      • 78 and 84
      • ((cocain* or crack) adj5 (overdos* or over-dos* or OD or tox- icit* or toxicosis or toxicoses or cardiotoxic* or intoxicat* or poison* or megados* or mega-dos*)).tw,kf.
      • (sympathomimetic* adj5 (overdos* or over-dos* or OD or toxicit* or toxicosis or toxicoses or cardiotoxic* or intoxicat* or poison* or megados* or mega-dos*)).tw,kf.
      • ((Adipex-P or AdipexP or Amfetamin* or amphetamin* or Avipron or Benzfetamin* or Benzphetamin* or Centramina or Chloramphetamin* or chloroamphetamin* or Chlorphen- termin* or Curban or Deoxyephedrin* or desoxyphedrin* or Desopimon or Desoxyn or Desoxynorephedrin or Dexamfe- tamin* or Dexamphetamin* or Dexedrin* or dextroamfe- tamin* or dextroamphetamin* or DextroStat or Didrex or Duromine or Ecstacy or Ecstasy or Fenamin* or Hydroxyam- fetamin* or Hydroxyamphetamin* or Hydroxyphenyliso- propylamin* or Ly123362 or Ly-123362 or Ly-121860 or Ly121860 or iodine-123 or iodoamfetamin* or iodoam- phetamin* or Iofetamin* or Iophetamin* or Ionamin* or Levoamfetamin* or Levoamphetamin* or Madrine or MDMA or Metamfetamin* or methamfetamin* or Metamphetamin* or methamphetamin* or Mephentermin* or methylamfe- tamin* or methylamphetamin* or Methylenedioxyamfe- tamin* or Methylenedioxyamphetamin* or Methyltyramin* or Mydrial or Norpholedrin or Oxyamfetamin* or Oxyam- phetamin* or Oxydess or Paredrin* or Phenamin* or Pheno- promin* or Phentermin* or Pre-Sate or Thyramin* or crystal meth*) adj5 (overdos* or over-dos* or OD or toxicit* or tox- icosis or toxicoses or cardiotoxic* or intoxicat* or poison* or megados* or mega-dos*)).tw,kf.
      • or/85-88
      • 74 and 89
      • limit 90 to (comment or editorial or letter)
      • 90 not 91
      • remove duplicates from 92

        Appendix 2. Supplementary data

        Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajem.2019.01.001.

        References

        1. Center for Behavioral Health Statistics and Quality. Behavioral health trends in the United States: results from the 2014 National Survey on Drug Use and Health. In: HHS Publication No. SMA 15-4927, NSDUH Series H-50. , http:// www.samhsa.gov/data.
        2. Substance Abuse and Mental Health Services Administration. Drug abuse warning network, 2011: national estimates of drug-related emergency department visits. In: HHS Publication No. (SMA) 13-4760, DAWN Series D-

           39. , https://www.samhsa.gov/data/sites/default/files/DAWN127/DAWN127/ sr127-DAWN-highlights.htm.

           Lathers CM, Tyau LSY, Spino MM, Agarwal I. Cocaine-induced seizures, arrhythmias and sudden death. J Clin Pharmacol 1988;28(7):584-93.

        3. Gray SD, Fatovich DM, McCoubrie DL, Daly FF. Amphetamine-related presentations to an inner-city tertiary emergency department: a prospective evaluation. Med J Aust 2007;186(7):336-9.
        4. Marzuk PM, Tardiff K, Leon AC, Hirsch CS, Portera L, Iqbal I, et al. ambient temperature and mortality from unintentional cocaine overdose. JAMA-J Am Med Assoc 1998;279(22):1795-800. https://doi.org/ 10.1001/jama.279.22.1795.
        5. Schifano F, Corkery J, Deluca P, Oyefeso A, Ghodse AH. Ecstasy (MDMA, MDA, MDEA, MBDB) consumption, seizures, related offences, prices, dosage levels and deaths in the UK (1994-2003). J Psychopharmacol 2006;20(3):456-63. https://doi.org/10.1177/0269881106060147.
        6. Laskowski LK, Landry A, Vassallo SU, Hoffman RS. Ice water submersion for rapid cooling in severe drug-induced hyperthermia. Clin Toxicol (Phila) 2015;53(3):181-4. https://doi.org/10.3109/15563650.2015.1009994.
        7. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: consensus statement of the American association for Emergency psychiatry project Beta psychopharmacology workgroup. West J Emerg Med 2012;13(1):26-34. https://doi.org/10.5811/ westjem.2011.9.6866.
        8. Whelan KR, Dargan PI, Jones AL, O’Connor N. Atypical antipsychotics not recommended for control of agitation in the emergency department. Emerg Med J 2004;21(5):649.
        9. Lee KC, Finley PR, Alldredge BK. Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings. Expert Opin Drug Saf 2003;2(3):233-47.
        10. Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R. Effects of psychotropic drugs on seizure threshold. Drug Saf 2002;25(2):91-110.
        11. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med 1998;16(4):567-73.
        12. Chase PB, Biros MH. A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population. Acad Emerg Med 2002;9(12):1402-10.
        13. Fishbain DA, Wetli CV. cocaine intoxication, delirium, and death in a body packer. Ann Emerg Med 1981;10(10):531-2. https://doi.org/10.1016/S0196- 0644%2881%2980010-8.
        14. Molina DK, Hargrove VM. Fatal cocaine interactions: a review of cocaine- related deaths in Bexar County, Texas. Am J Forensic Med Pathol 2011;32 (1):71-7.
        15. Merigian KS. Adrenergic crisis from crack cocaine ingestion: report of five cases. J Emerg Med 1994;12(4):485-90. https://doi.org/10.1016/0736-4679% 2894%2990345-X.
        16. Klein C, Balash Y, Pollak L, Hiss J, Rabey MJ. Body packer: cocaine intoxication, causing death, masked by concomitant administration of major tranquilizers. Eur J Neurol 2000;7(5):555-8.
        17. Cox RD, Koelliker DE, Bradley KG. Association between droperidol use and sudden death in two patients intoxicated with illicit Stimulant drugs. Vet Hum Toxicol 2004;46(1):21-3.
        18. Espelin DE, Done AK. Amphetamine poisoning. Effectiveness of chlorpromazine. N Engl J Med 1968;278(25):1361-5.
        19. Derlet RW, Rice P, Zane Horowitz B, Lord RV. Amphetamine toxicity: experience with 127 cases. J Emerg Med 1989;7(2):157-61. https://doi.org/ 10.1016/0736-4679(89)90263-1.
        20. Calver L, Isbister GK. High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings. Br J Clin Pharmacol 2013. https://doi.org/ 10.1111/bcp.12272.
        21. Ginsberg MD, Hertzman M, Schmidt-Nowara WW. Amphetamine intoxication with coagulopathy, hyperthermia, and reversible renal failure - a syndrome resembling heatstroke. Ann Intern Med 1970;73(1):81-5.
        22. Soong WJ, Hwang B, Tsai WJ, Deng JF. Amphetamine poisoning in infant: report of two cases. Chin Med J (Taipei) 1991;48(3):228-31.
        23. Richards JR, Derlet RW, Duncan DR. Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone. Eur J Emerg Med 1997;4 (3):130-5.
        24. Guharoy R, Medicis J, Choi S, Stalder B, Kusiowski K, Allen A. Methamphetamine overdose: experience with six cases. Vet Hum Toxicol 1999;41(1):28-30.
        25. Ruha AM, Yarema MC. pharmacologic treatment of acute pediatric methamphetamine toxicity. Pediatr Emerg Care 2006;22(12):782-5.
        26. Gullatt R. Acute methamphetamine poisoning in a child. South Med J 1957;50 (8):1068.
        27. Hall CD, Blanton DE, Scatliff JH, Morris CE. Speed kills: fatality from the self- administration of methamphetamine intravenously. South Med J 1973;66 (6):650-2.
        28. Gary NE, Saidi P. Methamphetamine intoxication. A speedy new treatment. Am J Med 1978;64(3):537-40.
        29. Brown C, Osterloh J. Multiple severe complications from recreational ingestion of MDMA (‘Ecstasy’). JAMA 1987;258(6):780-1. https://doi.org/ 10.1001/jama.1987.03400060056021.
        30. Lehmann ED, Thom CH, Croft DN. Delayed Severe rhabdomyolysis after taking ‘ecstasy’. Postgrad Med J 1995;71(833):186-7. https://doi.org/10.1136/ pgmj.71.833.186-a.
        31. Russell T, Riazi S, Kraeva N, Steel AC, Hawryluck LA. Ecstacy-induced delayed rhabdomyolysis and neuroleptic malignant syndrome in a patient with a novel variant in the Ryanodine receptor type 1 gene. Anaesthesia 2012;67 (9):1021-4. https://doi.org/10.1111/j.1365-2044.2012.07226.x.
        32. United Nations Office on Drugs and Crime. World drug report 2016, https:// www.unodc.org/wdr2016/, ; 2016.
        33. Battaglia J. Pharmacological management of acute agitation. Drugs 2005;65 (9):1207-22.
        34. Juurlink D. Antipsychotics. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, editors. Goldfrank’s toxicologic emergencies. New York, NY: McGraw-Hill Education; 2015.