Management of Acute Agitation and Aggression in Children and Adolescents with Pro Re Nata Oral Immediate Release Antipsychotics in the Pediatric Emergency Department

Abstract

Background:

Acute agitation in the pediatric emergency department (ED) has the potential to escalate into aggression and result in harm. Rapid and effective management may be warranted. Use of pro re nata (prn) oral immediate-release (IR) quetiapine, haloperidol, loxapine, and chlorpromazine has been observed in the pediatric ED at Surrey Memorial Hospital to manage this condition; however, evidence for oral prn antipsychotic use is limited in the pediatric population.

Objectives:

The primary objective is to characterize the dose of prn oral IR quetiapine used to manage acute agitation or aggression in a pediatric ED. Secondary objectives include characterizing the dose of prn oral IR haloperidol, loxapine, and chlorpromazine; and describing the 1-hour response rate, admission rate, length of stay (LOS), and adverse drug effects.

Method:

The medical records of pediatric patients who received at least one prn oral dose of IR quetiapine, haloperidol, loxapine, or chlorpromazine for acute agitation and aggression, without regard to the etiology of symptom presentation, between January 1, 2012 and December 31, 2016, were analyzed retrospectively.

Results:

Sixty-nine patients met the inclusion criteria. The mean dose of quetiapine was 32 mg/dose (0.54 mg/kg per dose); and the response rate was 53%. The mean haloperidol, loxapine, and chlorpromazine doses were 4 mg (0.07 mg/kg per dose), 13 mg (0.19 mg/kg per dose), and 29 mg/dose (0.53 mg/kg per dose) respectively; and the response rates were 36%, 30%, and 50%, respectively. Between 19% and 60% of patients were admitted, majority to the psychiatry ward. The median LOS in the ED was between 5 and 18 hours for nonadmitted patients. Extrapyramidal side effects (EPS) were reported with first-generation antipsychotics (FGA), but not with quetiapine.

Conclusion:

Quetiapine appears to be a viable agent for managing acute agitation and aggression in the pediatric ED with low rates of EPS. Further studies are encouraged to compare the effectiveness of quetiapine with FGA. A Clinical Trial Registration number is not applicable for this study.

Introduction

Acute agitation in the emergency department (ED) is a state of behavioral dyscontrol characterized by excessive motor or verbal activity (Citrome 2004; Zimbroff 2008). It has the potential to escalate into aggression, which can cause harm to the patient or others (Zimbroff 2008; Sonnier and Barzman 2011; Marzullo 2014; Gerson et al. 2019). Therefore, an acutely agitated and aggressive patient may constitute a medical emergency and often necessitates rapid effective treatment in the ED to avoid negative outcomes (Zimbroff 2008; Marzullo 2014).

The primary goals of managing an acutely agitated or aggressive pediatric patient in the ED are to preserve the safety of the child and those in the immediate vicinity, and to avoid adverse effects (AE) such as sedation and extrapyramidal side effects (EPS), so that clinicians can accurately assess the underlying etiology for the presentation (Zimbroff 2008; Adimando et al. 2010; Wilson et al. 2012; Gerson et al. 2019).

If the patient is not at risk of harming self or others, initial strategies for management in the ED include verbal de-escalation, addressing underlying medical etiology, and environmental modifications such as removal of external triggers and offers of basic needs (Adimando et al. 2010; Garriga et al. 2016; Gerson et al. 2019). However, if safety is an immediate concern or the aforementioned strategies are ineffective, the additional use of pharmacological interventions and/or physical restraints may be required (Adimando et al. 2010; Sonnier and Barzman 2011; Gerson et al. 2019).

Where pharmacological interventions are necessary, antipsychotics are one of the three main classes of pro re nata (as needed) (hereafter referred to as prn) medications typically prescribed in the ED (Sonnier and Barzman 2011). However, there are no studies comparing the efficacy and safety of these agents in the pediatric ED setting (Gerson et al. 2019).

Evidence for prn antipsychotic use in the pediatric ED setting is lacking (Gerson et al. 2019). Recent systematic reviews and guidelines that provide recommendations for antipsychotic use are limited to pediatric outpatients with chronic aggression or psychiatrically hospitalized youth (Findling et al. 2005; Swart et al. 2011; Carubia et al. 2016; Gerson et al. 2019). Prn chlorpromazine, loxapine, and quetiapine were reported to be the most commonly used prn antipsychotics administered to manage acute agitation and aggression in pediatric patients admitted to a single-center psychiatric ward in one retrospective study (Nugent et al. 2019). In another retrospective study conducted by Swart et al., prn chlorpromazine was found to be effective at producing a settling effect for pediatric inpatients admitted in the psychiatric ward; however, no dosing information was provided (Swart et al. 2011). One retrospective study of prn haloperidol, given intramuscularly, reported no difference in restraint duration and prn medications in adolescents with severe agitation when given together with intramuscular (IM) lorazepam in comparison with single-dose IM ziprasidone (Jangro et al. 2009; Gerson et al. 2019).

For second-generation antipsychotics (SGA), olanzapine when given as a prn medication was found to be more effective at producing a settling effect than lorazepam and chlorpromazine among pediatric inpatients admitted in the psychiatric ward (Swart et al. 2011). In the same study by Swart et al., prn quetiapine was administered 2.2% of the time, but it was given concomitantly with other antipsychotics (Swart et al. 2011). It was reported that 63.9% of patients in the combined group of quetiapine and other agents responded at 30 minutes or less and the remaining 36.1% responded at >30 minutes (Swart et al. 2011). No dosing information was provided for quetiapine in this study (Swart et al. 2011). In another retrospective study characterizing the use of antipsychotics in a pediatric ED, the most commonly administered antipsychotics were olanzapine (51.1%), aripiprazole (26.6%), haloperidol (24%), risperidone (11.8%), and quetiapine (10%) (Rudolf et al. 2019). This study concluded that administration of multiple medications and parenteral administration of antipsychotics were associated with a significantly longer length of stay (LOS) in the ED (Rudolf et al. 2019). However, no dosing was reported for the oral agents and the study did not explore other outcomes such as time to effect and response rate.

EPS generally present as dystonia, akathisia, and parkinsonism with acute antipsychotic use, and as tardive akathisia and tardive dyskinesia with chronic antipsychotic use (Divac et al. 2014; Marzullo 2014). EPS were reported to be more frequent with first-generation antipsychotics (FGA) than with SGA in one double-blind study of 50 pediatric patients, diagnosed with schizophrenia spectrum or affective disorders, with psychotic symptoms (Sikich et al. 2004). FGA primarily block dopamine receptors, whereas SGA block both serotonin and dopamine receptors (Marzullo 2014). This has been the proposed mechanism for a lower EPS risk with SGA (Marzullo 2014). An estimated 50% of patients treated with high-potency FGA such as haloperidol may develop acute EPS for the first few days of treatment (Divac et al. 2014). The risk of EPS is among the lowest for FGA chlorpromazine and for SGA clozapine and quetiapine (Divac et al. 2014). This is an important AE to monitor, as children are at an increased risk of developing EPS compared with adults (Mathews et al. 2005; Marzullo 2014).

However, given the lack of evidence for prn antipsychotic use in the pediatric ED setting, it has been reported that emergency physicians have a tendency to prescribe FGA as first-line agents for acute agitation and aggression over SGA due to a sense of familiarity, even though FGA may or may not be the most effective or safest choice (Sonnier and Barzman 2011; Baeza et al. 2013; Gerson et al. 2019). Recent use of oral immediate-release (IR) prn quetiapine, haloperidol, loxapine, and chlorpromazine have been observed in our pediatric ED for the management of acute agitation and aggression in the pediatric population; however, the dose, as well as the effectiveness and safety of these agents have not been well characterized in the setting of the pediatric ED. Given the limited evidence examining oral prn antipsychotic use in the pediatric ED, the purpose is to characterize the dosing of oral IR prn quetiapine, haloperidol, loxapine, and chlorpromazine, and the effectiveness and safety of these agents for management of acute agitation and aggression in the pediatric ED. Considering SGA have a lower risk of EPS compared with FGA, we were particularly interested in exploring the outcomes of patients who received quetiapine.

Methods

Study design and setting

This was a retrospective chart review study conducted at Surrey Memorial Hospital (SMH), a pediatric and adult academic medical centre in Surrey, British Columbia. Ethics approval was obtained from the site's local research ethics board and the need for informed consent was waived. Ethics approval was obtained from the site's local research ethics board (equivalent to IRB) and the need for informed consent was waived, as stated here.

Selection of participants

The study included patients aged ≥5 years to <17 years with acute agitation or aggression (as defined in Supplement 1) who received at least one oral prn dose of IR quetiapine, haloperidol, loxapine, or chlorpromazine between January 1, 2012 and December 31, 2016 at the pediatric ED, without regard to the etiology of their symptom presentation. If a child or adolescent had more than one ED visit during the study period, only data from the first ED visit were included. Each patient was allocated to the group of the first antipsychotic they received during the visit. Patients were identified through reports from the automated dispensing cabinets located near or within the pediatric emergency ward, as well as from pharmacy dispensing records.

Outcomes

The primary objective of this study is to characterize the dose of prn oral IR quetiapine for managing pediatric patients with acute agitation or aggression in the pediatric ED. The secondary objectives are to characterize the dose of prn oral IR haloperidol, loxapine, and chlorpromazine, and describe the following for all antipsychotics:

Proportion of patients who respond to treatment within or at 1-hour postfirst dose of antipsychotic (as defined in Supplement 1)

Earliest recorded onset of action postfirst-dose antipsychotic, defined as time from ED triage to response

Proportion of admitted patients, including proportion admitted to the inpatient psychiatry unit

Median LOS in the ED

Proportion of patients with repeat visit to the ED within 30 days postdischarge for mental health reasons

AE related to antipsychotic therapy.

We chose to assess response (or time to effect) at 1 hour after the first dose because this is the time point when clinicians typically decide if additional pharmacological or nonpharmacological interventions are required based on practice. Moreover, 1 hour is consistent with the time point used in previous literature to assess response of agitation to pharmacotherapy, as it allows for adequate absorption and takes into consideration the expected onset of action of the oral agent (Currier and Simpson 2001). The reported onset of action for oral IR quetiapine is 30 minutes, and between 30 and 60 minutes for haloperidol, loxapine, and chlorpromazine (Lexi-Comp, Inc. 2020). We evaluated ED revisits at 30 days after discharge because previous studies have used this time frame to evaluate rate of ED returns for psychiatric emergencies (Mapelli et al. 2015). Thirty-day ED revisits is a typical time frame for assessment of ED revisits (MHASEF Research Team 2018). It is a common hospital performance metric to assess health care system gaps (MHASEF Research Team 2018). High rates of 30-day ED revisits may suggest limitations in outpatient care (MHASEF Research Team 2018).

Data collection

Data were collected by one investigator using a standardized data collection form. A second reviewer checked a subset of the medical records for congruence of data collection. Any differences were reconciled by discussion. The chart reviewer was not blinded to the study objectives and hypothesis. Our standardized data collection form included the following information from the patients' medical records: (1) demographic characteristics; (2) level of acuity using the Canadian Triage and Acuity Scale (CTAS); (3) mode of ED visit; (4) psychiatric and substance use history; (5) psychiatric medications before visit; (6) ED physician diagnoses; (7) other pharmacological interventions or use of restraints specific to the management of acute agitation or aggression prior, with, or postfirst-dose antipsychotic (the period prior is defined as the 24-hour period after presentation to the ED but before the administration of the first dose of antipsychotic, and the period postdose is defined as the period up to and including 1 hour after the administration of the first dose); (8) dose of first antipsychotic given; (9) number of doses of antipsychotic administered 24 hours after first dose of antipsychotic or up until ED discharge, whichever is earlier; (10) time from initiation of treatment to response; (11) LOS in the ED, defined as time from ED triage to time of disposition (discharged home, admitted to hospital, or transferred out); (12) admission to inpatient ward; (13) patients with repeat visit to the ED within 30 days postdischarge for mental health reasons; and (14) any AE related to the antipsychotic therapy, including the associated Naranjo score for each AE (Naranjo et al. 1981).

Every patient who arrives at our institution's pediatric emergency is assigned a CTAS score. We were interested in collecting a patient's CTAS score as it can provide a picture of a patient's level of acuity upon arrival in the ED. CTAS is a scale used in the ED to facilitate triaging of patients (Warren et al. 2008). It assesses patient's priority to be seen in the ED and how long they can safely wait to be seen (Warren et al. 2008). It consists of five acuity levels with level 1 being of highest urgency, requiring immediate medical attention, and level 5 being nonurgent (Warren et al. 2008). The Naranjo scale was incorporated into our study as a means to estimate the probability that a drug caused an adverse reaction (Naranjo et al. 1981). It consists of 10 questions and a score is assigned to how each of the questions are answered (Naranjo et al. 1981). Total scores range from −4 to +13; the reaction is considered definite if the score is ≥9, probable if 5–8, possible if 1–4, and doubtful if ≤0 (Bethesda 2019).

Analyses

Results were reported using descriptive statistics. Quantitative variables were reported as means, medians, and interquartile ranges. Categorical variables were reported as frequencies and percentages.

Results

Characteristics of study subjects

Sixty-nine patients, between the ages of 6 and 16 years, were identified as having met the inclusion criteria (Fig. 1 and Table 1). Our study included subjects between the ages of 5 and 16 years a priori, but after reviewing the charts, there were no 5-year-old subjects who met the inclusion criteria. The majority of patients were female in the quetiapine and loxapine groups, and male in the haloperidol and chlorpromazine groups. The median weight was between 54 and 64 kg in all groups. The median level of acuity on the CTAS was between 2 and 3. The majority of patients arrived in ED under police custody, and had a documented psychiatric and substance use history. Most patients were not on an antipsychotic at home. In terms of presenting complaint, the majority of patients presented with suicidal ideation in the quetiapine group, psychosis in the haloperidol group, psychosis or suicidal ideation in the loxapine group, and a behavioral issue in the chlorpromazine group.

FIG. 1.

Flowchart of the study population. ^aAs subsequent ED visits were excluded, each patient had no more than one visit; hence, the number of visits is equivalent to the number of patients that were included in the study. ED, emergency department.

Table 1.

Demographic Characteristics of Patients Who Received At Least One Dose of Pro Re Nata Oral Immediate-Release Quetiapine, Haloperidol, Loxapine, or Chlorpromazine

	Quetiapine	Haloperidol	Loxapine	Chlorpromazine
	n = 32	n = 11	n = 10	n = 16
Age, years, median (age range)	15 (9–16)	14 (10–16)	15 (14–16)	14 (6–16)
≤12 years, n (%)	5 (16)	2 (18)	0 (0)	7 (54)
>12 years, n (%)	27 (84)	9 (82)	10 (100)	9 (56)
Gender, male, n (%)	10 (31)	6 (55)	3 (30)	11 (69)
Weight, kg, median (IQR)	56 (53–67)	59 (47–69)	64 (51–71)	54 (42–59)
Weight, kg, median (IQR)	(n = 31)^a	59 (47–69)	64 (51–71)	(n = 14)^a
CTAS, level, median (IQR)	3 (2–3)	3 (2–3)	3 (2–3)	2 (2–3)
Mode of ED visit, n (%)
Ambulance	3 (9)	4 (36)	2 (20)	3 (19)
Family member/caregiver	12 (38)	2 (18)	2 (20)	4 (25)
Police	11 (34)	4 (36)	6 (60)	7 (44)
Other	6 (19)	1 (9)	0 (0)	2 (13)
Documented psychiatric history, n (%)	25 (78)	8 (73)	6 (60)	11 (69)
Documented substance use history, n (%)	16 (50)	4 (36)	6 (60)	5 (31)
Psychiatric medications before visit, n (%)^b
FGA	1 (3)	0 (0)	0 (0)	0 (0)
SGA	9 (28)	1 (9)	4 (40)	5 (31)
Benzodiazepine	4 (13)	2 (18)	0 (0)	2 (13)
Clonidine	2 (6)	0 (0)	1 (10)	1 (6)
SSRI	12 (38)	3 (27)	3 (30)	2 (13)
Stimulant	5 (16)	3 (27)	1 (10)	3 (19)
Other^c	2 (6)	2 (18)	1 (10)	1 (6)
None or unknown	11 (34)	5 (45)	4 (40)	7 (44)
ED physician diagnosis, n (%)^b
Psychosis	3 (9)	6 (55)	3 (30)	1 (6)
Suicidal	17 (53)	1 (9)	3 (30)	3 (19)
Behavioral issue	4 (13)	0 (0)	0 (0)	7 (44)
Situational crisis/acute stress	6 (19)	0 (0)	0 (0)	1 (6)
Intoxication	3 (9)	1 (9)	2 (20)	1 (6)
Other^d	11 (34)	4 (36)	4 (40)	3 (19)
Time to administration of antipsychotic postpresentation to ED, hours, median (IQR)	4 (2–6)	2 (1–3)	4 (2–8)	2 (1–5)
	(n = 30)^a	(n = 10)^a	4 (2–8)	2 (1–5)

Number of patients different from the total number of patients in each group due to missing data.

Percentages do not sum to 100 because in some cases patients may be on more than one medication and have more than one diagnosis.

Other psychiatric medications before visit: buspirone, atomoxetine, lithium, methotrimeprazine, topiramate, and trazodone.

Other ED physician diagnosis: anxiety, adjustment disorder, ADHD, depression, mood disorder, and posttraumatic stress disorder.

ADHD, attention-deficit/hyperactivity disorder; CTAS, Canadian Triage and Acuity Scale; ED, emergency department; FGA, first-generation antipsychotics; IQR, interquartile range; SGA, second-generation antipsychotics; SSRI, selective serotonin reuptake inhibitor.

Main results

The mean first dose of oral prn IR antipsychotic given was 32 mg (0.54 mg/kg per dose), 4 mg (0.07 mg/kg per dose), 13 mg (0.19 mg/kg per dose), and 29 mg (0.53 mg/kg per dose) of quetiapine, haloperidol, loxapine, and chlorpromazine, respectively (Table 2). Fifty-three percent of patients in the quetiapine group, 36% in the haloperidol group, 30% in the loxapine group, and 50% in the chlorpromazine group responded within or at 1 hour after the first dose (Fig. 2). Patients in all groups received a mean of one dose in 24 hours or up until discharge from the ED, whichever was earlier (Table 2). The median earliest recorded onset of action was between 70 and 90 minutes in all groups (Table 2). Oral prn lorazepam was commonly prescribed in all groups (Supplementary Table S1). Concomitant prn lorazepam was administered to 6 patients in the quetiapine group, 10 patients in the haloperidol group, 8 patients in the loxapine group, and 4 patients in the chlorpromazine group (Supplementary Table S1). It was the only oral prn benzodiazepine administered. Concomitant benztropine was administered to two patients in the haloperidol group, four patients in the loxapine group, and one patient in the chlorpromazine group (Supplementary Table S1).

FIG. 2.

Percentage of patients who responded within or at 1-hour postfirst-dose antipsychotic.

Table 2.

Dose of Antipsychotic and Outcomes

	Quetiapine	Haloperidol	Loxapine	Chlorpromazine
	n = 32	n = 11	n = 10	n = 16
First dose, mg/kg, mean (SD)	0.54 (0.27)	0.07 (0.03)	0.19 (0.08)	0.53 (0.24)
First dose, mg/kg, mean (SD)	(n = 31)^a	0.07 (0.03)	0.19 (0.08)	(n = 14)^a
First dose, mg, mean (SD)	32 (18)	4 (2)	13 (7)	29 (16)
Total 24 hours dose, mg/kg, mean (SD)	0.71 (0.53)	0.08 (0.04)	0.24 (0.09)	0.78 (0.58)
Total 24 hours dose, mg/kg, mean (SD)	(n = 31)^a	0.08 (0.04)	0.24 (0.09)	(n = 14)^a
Total 24 hours dose, mg, mean (SD)	42 (32)	5 (3)	15 (7)	44 (37)
Number of doses in 24 hours, mean (SD)	1 (1)	1 (1)	1 (0)	1 (1)
Earliest recorded onset of action, minutes, median (IQR)	90 (40–150)	82 (48–154)	88 (64–104)	70 (35–120)
Earliest recorded onset of action, minutes, median (IQR)	(n = 27)^a	(n = 10)^a	88 (64–104)	(n = 15)^a
LOS in the ED for nonadmitted patients, hours, median (IQR)	15 (9–22)	14 (4–15)	18 (13–21)	5 (2–15)
Patient admission, n (%)	14 (44)	6 (55)	6 (60)	3 (19)
Admission to inpatient psychiatry, n (% of patient admission)	10 (71)	6 (100)	6 (100)	2 (67)
Patients with repeat visit to the ED within 30 days postdischarge for mental health reasons, n (%)	11 (34)	5 (45)	4 (40)	9 (56)

Number of patients different from the total number of patients in each group due to missing data.

ED, emergency department; IQR, interquartile range; LOS, length of stay; SD, standard deviation.

The three most common types of agitation or aggression patients presented with in decreasing frequency were as follows: verbal threats, excessive verbal activity (not abusive), and physical aggression against other person(s) (Supplementary Table S2).

Between 19% and 60% of patients were admitted to the hospital in all groups, all for mental health reasons (Table 2). At least 67% of the patients admitted were admitted to the inpatient psychiatry unit across all groups (Table 2). For patients who were not admitted, the median LOS in the ED was between 5 and 18 hours. Between 34% and 56% of patients returned to the ED within 30 days postdischarge for mental health reasons.

In terms of documented AE, two (18%) patients in the haloperidol group, one (10%) patient in the loxapine group, and one (6%) patient in the chlorpromazine group reported EPS, either as dystonia or parkinsonism (Table 3). No EPS were reported in the quetiapine group. Two (6%) patients reported headache in the quetiapine group. Each documented AE was associated with a Naranjo score of 2–4.

Table 3.

Documented Adverse Effects

	Quetiapine	Haloperidol	Loxapine	Chlorpromazine
	n = 32	n = 11	n = 10	n = 16
Headache, n (%)	2 (6)	0 (0)	0 (0)	0 (0)
Nausea, n (%)	0 (0)	1 (9)	0 (0)	0 (0)
EPSE^a, n (%)	0 (0)	2 (18)	1 (10)	1 (6)

Parkinsonism, characterized as muscle rigidity, was documented in one patient in the haloperidol, loxapine, and chlorpromazine groups; and akathisia, characterized as restlessness, was documented in the second patient in the haloperidol group.

EPSE, extrapyramidal side effects.

Discussion

Acute agitation and aggression can lead to serious outcomes if not managed appropriately. Despite these implications, there is a lack of literature in the pediatric population on the management of acute agitation and aggression, specifically, with the use of prn oral IR antipsychotics in the pediatric ED setting. To our knowledge, this is the first study in the literature characterizing the dose and outcomes of effectiveness, such as response rate, of oral prn IR quetiapine, haloperidol, loxapine, and chlorpromazine for the management of acute agitation and aggression in the pediatric ED.

The mean doses of oral prn IR quetiapine (32 mg/dose and 0.54 mg/kg per dose), haloperidol (4 mg/dose and 0.07 mg/kg per dose), and chlorpromazine (29 mg/dose and 0.53 mg/kg per dose) reported in this study were consistent with what is reported in published literature for pediatric outpatients with chronic aggression and pediatric inpatients (Table 2) (Adimando et al. 2010; Marzullo 2014; Carubia et al. 2016). To the investigators' knowledge there were no previously reported doses of prn oral loxapine for management of acute agitation and aggression in the pediatric population in the literature.

Previous adult trials comparing oral haloperidol with oral risperidone, olanzapine, and quetiapine for the management of acutely agitated patients have not shown significant differences between treatment groups for their time to calming effect (Villari et al. 2008; Garriga et al. 2016). The reported time of onset for oral IR quetiapine is 30 minutes, and between 30 and 60 minutes for haloperidol, loxapine, and chlorpromazine (Lexi-Comp, Inc. 2020). In our study, the median earliest recorded onset of action was between 70 and 90 minutes for the quetiapine, haloperidol, loxapine, and chlorpromazine groups (Table 2). The difference in the observed and reported time of onset may be explained by inconsistent nursing documentation. At SMH, nurses tend to monitor pediatric patients with psychiatric emergencies every 15–30 minutes in the pediatric ED, and not more frequently. The patients may have responded before the nurses had an opportunity to document their response. As a result, the earliest observed onset of action is only an estimate of the actual onset of action.

The study conducted by Swart and colleagues is the only existing study evaluating the management of acute agitation and aggression in pediatrics with quetiapine, but as an adjunctive therapy. Our study adds to the literature by examining quetiapine monotherapy in a different specific patient population, while also characterizing effective doses. Fifty-three percent of patients in the quetiapine group responded within 1 hour after the first dose (Fig. 2). This response rate is lower than reported in the literature (Swart et al. 2011). Swart and colleagues studied the use of prn antipsychotics in pediatric inpatients and reported the settling effect at two time points (≤30 minutes and at >30 minutes postdose) for prn quetiapine grouped with other agents such as risperidone, loxapine, and haloperidol as one group (Swart et al. 2011). They concluded that 63.9% of patients in the combined group of quetiapine and other agents responded at ≤30 minutes and the remaining 36.1% responded at >30 minutes (Swart et al. 2011). This study did not define what time to effect meant. The difference in response rate could be due to differences in how response was defined. It could also be a result of other agents being given, since the response rate reported for quetiapine is grouped with the response rate for other agents. Baseline characteristics were different as well. Unlike our patient population, patients in this study were reported to have severe to profound level of intellectual disability, with the majority requiring feeding tubes (Swart et al. 2011).

Swart and colleagues also concluded that 55.3% of patients in the chlorpromazine group responded at ≤30 minutes and the remaining 44.7% responded at >30 minutes postdose (Swart et al. 2011). This is slightly higher than the response rate of 50% reported in our study (Fig. 2). Again, this discrepancy could be due to use of different definitions of response. The study also did not specify if the chlorpromazine was given orally, intramuscularly, or both, making it difficult for us to compare the results of this study with our own, as we only reported the results of oral chlorpromazine (Swart et al. 2011). IM administration may have led to a quicker therapeutic response than oral administration (Garriga et al. 2016).

Between 19% and 60% of patients in all groups (44% in the quetiapine group) were admitted for mental health reasons after presentation to the pediatric ED, the majority of whom were admitted to the inpatient psychiatry unit (Table 2). This is higher than what is suggested in the literature (Mapelli et al. 2015). The literature suggests 35.5% of patients are admitted after presentation to the pediatric ED with a psychiatric emergency (Mapelli et al. 2015). The most common mental health-related diagnoses reported by Mapelli and colleagues were other diagnoses, substance-related disorder, mood and anxiety, followed by behavioral disorder (Mapelli et al. 2015). The most common presenting complaints reported in our study were behavioral issue, suicidal ideation, and psychosis. It is interesting to note that chlorpromazine was prescribed more commonly for behavioral issue, quetiapine for suicidal ideation, and haloperidol for psychosis in our study, which have not been previously described by other studies evaluating the management of acute agitation and aggression with antipsychotics in the pediatric ED (Table 2). Further studies are encouraged to evaluate if there is a correlation between antipsychotic prescribed and presenting complaints in the pediatric ED.

The median LOS in the ED for nonadmitted patients was between 5 and 18 hours (15 hours in the quetiapine group) (Table 2). This is longer than the average LOS in the pediatric ED of 4.7–9 hours for psychiatric emergencies reported in the literature (Mapelli et al. 2015; Carubia et al. 2016; Rudolf et al. 2019). This difference could be explained by differences in the availability of inpatient psychiatric services and variation in strategies used to manage patients with psychiatric emergencies (Brown and Schubert 2010). Mapelli and colleagues also included multiple visits by the same patient in their study (Swart et al. 2011). Our study excluded all revisits. A health care team may be more familiar with managing a patient who returned to the ED on a subsequent visit as compared with a patient who is presenting to the ED for the first time because the team may have a better idea of what has worked previously for that patient. Patient familiarity may result in a shorter LOS for a patient during an ED revisit. Further studies are encouraged to evaluate how and if there is an impact on LOS in the ED by the choice prn oral IR antipsychotic. This information may have the potential to reduce overall health care costs and utilization.

Between 34% and 56% of patients re-presented to the ED within 30 days postdischarge (Table 2). We identified only one article that reported a return to ED rate, and this article reported a lower return to ED rate than our study. This difference may be explained by differences in the methods used to calculate ED revisits. Mapelli and colleagues calculated the proportion of mental health-related visits returning to the ED within 30 days of the original visit as a proportion of all ED revisits, whereas we calculated the proportion of mental health-related ED revisit as a proportion of the number of patients who were included in each antipsychotic group (Mapelli et al. 2015). This could have resulted in a smaller denominator and thus a larger proportion of ED revisits than reported elsewhere in the literature. Our study did not explore the reasons for using the pediatric ED, but a high rate of ED revisit may indicate limitations in outpatient care and a shortage in community resources (Mapelli et al. 2015; MHASEF Research Team 2018).

The risk of acute EPS development related to one-time use of antipsychotics in the pediatric ED has not been previously reported. Acute EPS were observed in four patients who received FGA in our study (Table 3). Parkinsonism and akathisia were the two types of EPS reported. Each documented AE was associated with a Naranjo score of 2–4, as each reaction followed a temporal sequence after antipsychotic administration; and for the two patients in the haloperidol and loxapine groups who developed EPS, the reaction improved after benztropine administration (Supplementary Table S1). This score suggests that there is a possible association between the reported EPS and the administered FGA (Naranjo et al. 1981). Low rates of acute EPS were observed in this study, compared with an estimated reported EPS risk of 50% associated with high-potency FGA, captured over the first few days of therapy (Divac et al. 2014). However, it is important to note that benztropine was administered concurrently with FGA in some patients to prevent EPS (Supplementary Table S1). This could have led to fewer reports of EPS in this study (Supplementary Table S1). No patients in the quetiapine group received benztropine and none experienced EPS (Supplementary Table S1 and Table 3). SGA are associated with a lower risk of EPS compared with FGA in the literature (Divac et al. 2014). The results of this study appear to support this observation.

A number of limitations have been identified in this study. This is a single-center study with a small sample size, which may give rise to selection bias. This study was carried out in the ED setting, so extrapolation of findings outside the ED setting may be difficult. We were also unable to account for ED visits to sites outside our health authority. In addition, given the study's retrospective nature, validated scoring tools to monitor response were not used; and underreporting and inconsistent reporting of effectiveness and safety outcomes on the medical records may have led to bias in our results. Moreover, there were a number of patients who received concomitant lorazepam and/or benztropine either before, during, or after antipsychotic administration, which could have confounded the effectiveness and safety results of this study. The chart reviewer was not blinded to the study objectives and hypothesis, which could lead to detection bias. Finally, we also assumed that patient trends such as ED diagnosis were consistent throughout the 5-year study period. These variables may not have been consistent each year and there could have been trends that we were unable to capture in this study.

Conclusions

In summary, we reported a prn oral IR quetiapine, haloperidol, loxapine, and chlorpromazine dose for the management of acute agitation and aggression in the pediatric ED. EPS were observed with FGA, but not with quetiapine. Given the low risk of acute EPS and the benefit of quetiapine in the pediatric ED for managing acute agitation and aggression observed in this study, further studies are encouraged to compare the effectiveness of quetiapine and FGA for the management of acute agitation and aggression in the pediatric ED.

Clinical Significance

To our knowledge, this is the first study in the literature to characterize the dose, as well as the effectiveness and safely of prn oral IR quetiapine, haloperidol, loxapine, and chlorpromazine for the management of acute agitation and aggression in the pediatric ED.

Footnotes

Author Contributions

The study was conducted at the Pharmacy Department at Surrey Memorial Hospital. L.Y., E.A., and D.E. designed the trial. E.A. and D.E. supervised the conduct of the trial and data collection. L.Y. abstracted data from charts, managed the data, including quality control, and analyzed the data. L.Y., E.A., and D.E. contributed substantially to article drafting, revision, preparation, and final approval of the article to be published.

Disclosures

All authors received no financial support for the research, authorship, and/or publication of this article. L.Y. and E.A. report no conflicts of interest. Dean Elbe was a paid reviewer for preparation of a Canadian ADHD training module for pharmacists and the public, by Teva Pharmaceutical Industries, Ltd. in 2017.

Supplementary Material

Supplement 1

Supplementary Table S1

Supplementary Table S2

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Supplementary Material

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