Pharmacotherapy considerations for pediatric acute agitation management in the emergency department

Abstract

Purpose

To review the current literature regarding the pharmacological management of acute agitation in pediatric patients and practical considerations when comparing agents for empiric use in the emergency department (ED).

Summary

ED providers play an integral role in the management of acute agitation in pediatric patients. The development of acute agitation is multifactorial, and patients may quickly escalate upon arrival or while boarding in the ED. Non-pharmacological de-escalation strategies should be prioritized. If a patient poses a safety risk to themself or staff members, the administration of pharmacological treatment may be necessary to target the underlying cause and allow for the patient to safely engage in assessment and treatment. There is limited guidance regarding medication selection and dosing for acute agitation in pediatrics despite being a key facet of multimodal management.

Conclusion

The literature regarding pharmacotherapy for acute agitation management in pediatric patients remains scarce. Medications utilized vary depending on institutional practice as well as provider preference. Evidence suggests that implementing an institutional protocol for pediatric acute agitation in the ED may improve patient outcomes. Additional studies are needed optimize the pharmacological management of acute pediatric agitation and patient outcomes in the ED.

Management of acute agitation in pediatric patients presents a significant challenge to emergency departments (EDs) across the country. Agitation can be associated with underlying medical conditions, acute intoxication, withdrawal from substances, or underlying psychiatric illness. An existing diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), conduct disorder (CD), substance use disorder, or psychosis is a known predictor of agitation resulting in restraint use during ED visits.¹ A variety of neurotransmitter imbalances have been implicated in the mediation of agitation, including dopamine, norepinephrine, acetylcholine, and glutamate hyperfunction as well as serotonin and gamma-aminobutyric acid (GABA) hypofunction.² Alterations in these neurotransmitters has also been associated with several psychiatric illnesses associated with an increased risk of agitation.³ Utilizing medications that target these neurotransmitters is considered a key component of agitation management.

The “Best Practices for Evaluation and Treatment of Agitated Children and Adolescents (BETA) in the Emergency Department: Consensus Statement of the American Association for Emergency Psychiatry," which will be referred to as pBETA, provides treatment goals and pharmacologic recommendations based on expert consensus.⁴ Initial treatment recommendations include behavioral techniques, such as verbal de-escalation. If escalation continues, pro re nata (PRN) medications that address the underlying cause of agitation are suggested. Pharmacotherapy is considered an important component of treatment to calm the patient to allow for participation in behavioral de-escalation techniques without causing oversedation. However, the literature supporting the use of specific medications in this population remains sparse, and medication utilization for agitation in the ED remains highly variable amongst pediatric institutions.^1,5-8 Several comprehensive reviews of pharmacological agents for the management of acute pediatric agitation have been recently published.^9,10 This review focuses on the literature regarding both parenteral and oral pharmacological treatment options, in addition to practical implications specific to the pediatric population, such as weight-based dosing guidance, dosage formulations, and adverse effect considerations. The aim of this article is to review the pediatric literature and provide recommendations when evaluating empiric first- and second-line agents for acute agitation management in the ED.

Haloperidol

Haloperidol is the most commonly used first-generation antipsychotic (FGA) for the management of acute agitation in the ED for adults, according to the “Psychopharmacology of Agitation: Consensus Statement of the American Association for Emergency Psychiatry Project BETA Psychopharmacology Workgroup,” which will be referred to as aBETA.¹¹ Efficacy has also been demonstrated in the pediatric population, and oral and parenteral weight-based and fixed dosing for acute agitation have been reported.¹² However, haloperidol is not as commonly utilized in pediatrics, whereas use of second-generation antipsychotics (SGAs) and alternative FGAs for the acute management of pediatric agitation is growing.^1,5-8,13 Because haloperidol predominantly antagonizes dopamine receptors, it is often administered concomitantly with a benzodiazepine for additional sedative properties.¹⁴ The combination of haloperidol and lorazepam is also reportedly safe in pediatric patients and is recommended per the pBETA consensus statement.⁴ Yet, pediatric patients have a greater risk of developing acute dystonia and extrapyramidal symptoms (EPS) than the adult population.^15-17 In contrast, SGAs are associated with a lower risk of EPS and are preferred for the treatment of acute agitation related to psychiatric disorders in adults.¹¹

Ziprasidone

Ziprasidone was the first parenteral SGA that received US Food and Drug Administration (FDA) approval for the treatment of acute agitation in adults with psychotic disorders.¹⁸ In adult patients with acute psychotic agitation, intramuscular (IM) ziprasidone 10 to 20 mg was associated with a rapid (15- to 30-minute) reduction in agitation score, did not lead to oversedation, and was associated with a low incidence of dystonia and EPS.¹⁹ According to the aBETA guidance, IM ziprasidone is recommended over IM haloperidol for acute agitation in adults related to psychiatric illness.¹¹

The literature regarding the safety and efficacy of ziprasidone in pediatrics is limited to case reports and retrospective reviews, but parenteral fixed and weight-based dosing guidance is available for acute agitation (Table 1). In contrast to the adult literature, Barzman et al²² found that in adolescent patients (mean [SD] age, 15 [2.1] years), a dose of 20 mg of IM ziprasidone commonly led to a sedating effect, as determined by a Behavioral Activity Rating Scale (BARS) score of less than 4.²⁵ In fact, 3 patients (4%) were unarousable after ziprasidone administration, and while far fewer patients received 10 mg IM, it more commonly led to the intended calming effect. Similarly, in a separate study, ziprasidone was concluded to have efficacy comparable to that of haloperidol combined with lorazepam. There was also a statistically significant decrease in the BARS score reported in a subset of 7 adolescent patients who received 20 mg of IM ziprasidone. However, the mean BARS score after 45 minutes until 120 minutes remained below the goal threshold of 4.²³ More recently, weight-based parenteral ziprasidone dosing was derived by comparing initial doses that led to a response, defined as no additional medication administration within 30 minutes, to doses that did not. While a statistically significant distinction in weight-based doses was reported, with initial doses of approximately 0.2 mg/kg being more likely to be associated with a response, an agitation scale was not utilized. Therefore, the incidence of oversedation could not be assessed. Somnolence also was not included in the assessment of adverse effects.²⁴ Despite the majority of the SGA literature in pediatric agitation treatment being focused on ziprasidone, the pBETA consensus statement cautions against its use due to the potential risk of QTc prolongation and need to administer oral ziprasidone with food to maximize absorption.⁴ Additionally, ziprasidone was categorized as a group 3 hazardous agent on the National Institute for Occupational Safety and Health (NIOSH) list in 2016. NIOSH recommended additional personal protective equipment for staff during preparation and administration of ziprasidone, which further limited the drug’s clinical utility for the management of acute agitation.²⁶

Olanzapine

Intramuscular olanzapine is also FDA approved for the treatment of agitation in adults with psychiatric disorders.²⁷ Olanzapine 10 mg IM had efficacy comparable to that of both IM haloperidol monotherapy and IM haloperidol with lorazepam in adults with acute agitation related to schizophrenia. IM olanzapine administration resulted in rapid onset of action and was not associated with acute dystonia or QTc prolongation.^28,29 Similar to ziprasidone, IM olanzapine is also preferred over IM haloperidol for agitation in adults related to psychiatric disorders.¹¹

The pediatric literature regarding olanzapine use for acute agitation is sparse (Table 2). In a comparison of IM ziprasidone and IM olanzapine administration, olanzapine appeared to be equally effective. Efficacy was based on standardized intervention form documentation because agitation scores were not routinely collected. While oversedation was not assessed, somnolence was the most reported adverse effect in both groups.³⁰ Additionally, the mean study dose of olanzapine was approximately 5 mg in children and 10 mg in adolescents, whereas the mean study dose of ziprasidone was 20 mg for both children and adolescents. Given the potential for 20 mg of IM ziprasidone to cause oversedation in pediatric patients, the optimal dose of olanzapine in pediatrics remains difficult to elucidate. Weight-based dosing for olanzapine is not currently reported in the pBETA consensus statement. Instead, a fixed-dose range is provided, and it is recommended that the parenteral dose should be one-fourth to one-half of the oral dose.⁴ Provider unfamiliarity and extremes of body weight may cause uncertainty when trying to select an appropriate dose, particularly in the ED. In a 10-year retrospective review of intravenous, IM, and oral olanzapine use in an ED, the median reported dose for agitation was approximately 0.1 mg/kg. Of note, the majority of patients were teenagers, and ethanol ingestion was the most common etiology of agitation, which limits the generalizability of the results to younger patients and agitation related to psychiatric disorders. Agitation scores and the incidence of oversedation were not reported, and while the efficacy of olanzapine 0.1 mg/kg for the treatment of acute agitation remains uncertain, it appeared that this regimen was safe.³¹ However, there is an ongoing trial aimed at assessing the efficacy of oral olanzapine versus diazepam for the management of acute pediatric agitation in the ED.³²

Chlorpromazine

In direct contrast to the aBETA guidance that cautions against the use of low-potency FGAs in adults due to adverse effect profiles, chlorpromazine is recommended for the treatment of pediatric acute agitation per pBETA.^4,11,33 Despite a paucity of literature describing the safety and efficacy of chlorpromazine in pediatric patients, oral weight-based dosing guidance is available for acute agitation, with the recommendation that the IM dose should be one-half of the oral dose (Table 3).⁴ In pediatric patients admitted to a mental healthcare center, chlorpromazine, lorazepam, and olanzapine were the most common medications administered for acute agitation. A statistically significant association between medication type and time to settle was observed, with olanzapine being the only agent that was found to be more likely to produce a settling effect within "30 minutes or less" versus "more than 30 minutes" after administration. While the authors concluded that chlorpromazine, lorazepam, and olanzapine were all safe and effective, dosing information, administration route, frequency of adverse effects, and definitions of settling effects were not described.³⁴ A more recent comparison of oral, instant-release quetiapine, haloperidol, loxapine, and chlorpromazine concluded that all agents had similar efficacy for managing acute pediatric agitation in the ED. Of note, the mg/kg and mg doses reported were descriptive of the entire cohort, including responders and non-responders, and an agitation scale was not utilized, so oversedation was not evaluated.³⁵ IM chlorpromazine was also compared to IM olanzapine by applying the BARS tool retrospectively based on nursing and physician documentation 30 to 60 minutes after IM administration.²⁵ Olanzapine led to a greater reduction in BARS score, whereas a postinjection target BARS score of 4 was more commonly reported with chlorpromazine. Of note, for both agents the change in BARS score and frequency of achieving a BARS score goal of 4 were comparable to those reported with IM ziprasidone in pediatric patients.²² The study’s authors concluded that both agents appeared to be safe and effective and acknowledged that the greater reduction in the BARS score and incidence of somnolence in the olanzapine arm may have been influenced by frequent coadministration with diphenhydramine. Additionally, as only whole-point scores can be assigned using the BARS assessment, the results for mean (SD) post–IM injection BARS scores (2.71 [0.98] after olanzapine versus 3.21 [1.09] after chlorpromazine) may be less clinically significant in practice, despite the statistically significant difference.³⁶ Furthermore, a study aimed at assessing the institution's utilization of oral and IM chlorpromazine in adolescents for agitation identified potential safety concerns, such as drug interactions, inappropriate weight-based dosing, and adverse effects, despite promising efficacy outcomes. Sedation was the most common adverse effect possibly caused by chlorpromazine even after excludingany administration after 10 pm and coadministration with potentially sedating medications, such as diphenhydramine or melatonin, from the sedation assessment. The study’s authors identified opportunities to improve safety, such as incorporating weight-based guidance to avoid supratherapeutic dosing and electrocardiogram (EKG) monitoring for potential QTc-prolonging interactions, but also highlighted the importance of avoiding oversedation to optimize patient care.³⁷

Droperidol

Droperidol for acute, undifferentiated agitation in adults is cautioned against per aBETA and is an off-label indication despite its increasing use in this population.^11,38 Similarly, there is growing interest in this FGA for acute agitation management in pediatric patients, although droperidol is not currently included in the pBETA guidance.^4,6,39,40 Droperidol for the treatment of acute pediatric agitation was first reported over 20 years ago, with more recent safety and efficacy data emerging in the prehospital and ED settings (Table 4).⁴¹ Although shortages and the debated boxed warning for QTc prolongation may have contributed to more limited reported use of droperidol in pediatrics, no study has compared droperidol to another medication regarding the treatment of acute agitation.³⁹ Additionally, comparing droperidol to other, previously reviewed agents in terms of efficacy and incidence of oversedation remains challenging because alternative agitation scales, such as the Agitation Unit Scale and Sedation Assessment Tool, were utilized instead of the BARS score that was more commonly reported in other pediatric studies.^25,43,46 Furthermore, the incidence of somnolence and drowsiness were not consistently reported. Fortunately, there is an ongoing trial comparing IM droperidol to IM olanzapine that should address certain gaps in the pediatric literature.⁴⁷ Currently, EKG monitoring prior to droperidol administration is still recommended. A statistically significant QTc prolongation has been historically reported with droperidol use in pediatric patients; however, more recent literature has not demonstrated the same risk.^39,48 Per the pBETA guidance, oral medications should be offered first as an attempt to avoid the trauma associated with IM administration, but droperidol is only available as a parenteral formulation.^4,38

Risperidone and quetiapine

Oral administration of the agents reviewed previously is predominantly considered an off-label indication in the adult and pediatric population, despite most patients reporting a preference for oral formulations over IM administration during behavioral emergencies.^49,50 According to the aBETA guidance, oral risperidone is considered a first-line agent for patients willing to take an oral medication on the basis of efficacy and safety data from comparisons to IM haloperidol for acute agitation management. Despite less extensive literature surrounding its use, oral olanzapine is also a recommended first-line therapy given that IM olanzapine, olanzapine orally disintegrating tablet (ODT), and oral risperidone were shown to be equally effective as IM haloperidol in the management of agitation.⁵¹ Quetiapine is not recommended as a first-line agent for adult agitation in the ED due to limited efficacy data and the potential risk of orthostatic hypotension, particularly in volume-depleted patients.^11,52

There are even fewer trials assessing the safety and efficacy of oral antipsychotics in the management of acute pediatric agitation.³⁵ In contrast to the aBETA consensus statement, risperidone, quetiapine, and olanzapine are all recommended for the management of acute pediatric agitation, although most of this guidance is extrapolated from efficacy and safety data regarding pediatric delirium treatment.^4,53,54 Quetiapine and risperidone are also both FDA approved for pediatric patients with schizophrenia and bipolar disorder, and risperidone is approved for the treatment of irritability, aggression, and self-injurious behaviors associated with ASD in pediatric patients.^55,56 Additionally, risperidone may be beneficial in targeting disruptive and aggressive behavior in pediatric patients with CD or oppositional defiant disorder (ODD).^57-59

Clonidine

The role of immediate-release clonidine for acute agitation related to psychiatric illness is the least described in both the adult and pediatric literature. Clonidine is typically reserved for treatment of agitation secondary to withdrawal in adult populations, albeit as an off-label indication, whereas it is recommended for agitation related to several specific psychiatric illnesses in pediatrics.^4,11,60 Clonidine appears to be effective in managing noradrenergic hyperactivity related to posttraumatic stress disorder in adults; however, the data are more limited in pediatrics.^61,62 It has also been theorized that clonidine may reduce norepinephrine-mediated aggressivity in ADHD.^63,64 There is also very low-quality evidence that clonidine may be beneficial in managing oppositional behavior and conduct problems in pediatric patients with ADHD both with and without ODD or CD.⁶⁵ Similarly, while the evidence is very limited, clonidine may be effective for the treatment of behavioral problems in patients with autism.⁶⁶ A pilot trial in pediatric patients with CD also suggested that clonidine may increase plasma GABA concentrations and decrease aggressiveness.⁶⁷ Based on expert opinion, PRN clonidine may be a reasonable option to control more severe aggression episodes in pediatric patients with CD who pose a safety risk to themselves or their caregivers.⁵⁸

Diphenhydramine

Diphenhydramine monotherapy for acute agitation is not recommended per the aBETA guidance but is often administered concomitantly with haloperidol to mitigate the risk of EPS.^11,68 Diphenhydramine was the first parenteral agent studied in pediatric patients for acute agitation. IM and oral diphenhydramine were compared to IM and oral placebo in a double-blind randomized controlled trial in 21 children 5 to 13 years of age who were admitted to an inpatient psychiatric unit. The study’s authors concluded that the IM route was more effective than the oral route but that IM diphenhydramine was not superior to placebo.⁶⁹ Despite the strong placebo effect, diphenhydramine is still recommended per the pBETA consensus statement, although it is cautioned against in patients at risk for paradoxical inhibition.⁴ However, reported use for agitation at pediatric institutions is extremely variable.^1,5-8,13

Benzodiazepines

Benzodiazepines are not recommended for first-line treatment of acute agitation in adults related to psychiatric conditions because while they are calming, they do not target the underlying disease contributing to agitation.¹¹ Benzodiazepine monotherapy for the acute management of pediatric agitation has been both historically utilized and remains a frequently reported treatment approach, with lorazepam being the most commonly used agent.^1,5-8,13,70 While midazolam and diazepam have been used in the management of acute agitation in pediatrics, lorazepam has the most favorable pharmacokinetic and pharmacodynamic profile and is the only benzodiazepine recommended for pediatric acute agitation.^4,71,72 There is a paucity of quality literature regarding the efficacy of lorazepam in the management of acute agitation related to psychiatric conditions in both adults and pediatrics, although the sedative and anxiolytic properties as well as provider familiarity make it a reasonable agent to consider during an acute episode of agitation, especially in the ED.^73,74 However, in addition to the risks of hypotension and respiratory depression, paradoxical reactions have been more frequently reported with benzodiazepine use in pediatric patients.^5,34,75

Recommendations and future directions

ED providers often have limited resources and guidance on selecting medications for acute pediatric agitation. While the clinical decision flow chart in pBETA recommends certain agents based on the etiology of agitation, there is limited guidance on how to select from the various options provided.⁴ Additionally, provider comfortability has been shown to influence treatment decisions more so than evidence-based recommendations, especially when reacting to acute episodes in the ED.⁷⁶ The implementation of institutional protocols for acute pediatric agitation management in the ED have been associated with improved patient outcomes, such as increased verbal de-escalation attempts, increased oral medication administration, and reduced physical restraint duration.^40,77 Protocolizing pharmacological options as a proactive strategy rather than a reaction to an acute agitation event, may, therefore, improve patient care. A summary of the literature reviewed regarding pediatric dosing, formulations, and cost considerations, as well as advantages and disadvantages considered when standardizing empiric recommendations, are presented in Table 5.

Based on available literature, SGAs can be considered first-line therapy for acute agitation in pediatric patients with a known psychiatric illness.⁴ Olanzapine is a preferred empiric first-line agent for the management of acute agitation; it is available as an ODT for patients willing and safely able to take an oral medication and as an IM injection for patients who cannot or will not . Unlike the pBETA guidance, the same 0.1 mg/kg dose can be considered for both oral and IM dosing.^4,31 While olanzapine reaches a greater peak concentration following IM administration, the area under the curve remains the same.²⁷ Therefore, limiting both oral and IM doses to no more than 30 mg daily in adolescents based on available safety data is reasonable, which aligns with the American Academy of Pediatrics olanzapine dosing guidance for psychiatric emergencies.^12,79

While there are data to support the efficacy of ziprasidone for acute agitation, it is not a first-line agent because of the risk of QTc prolongation, need to administer oral ziprasidone with food, and the NIOSH group 3 hazardous drug classification. Risperidone and quetiapine may be efficacious first-line options in managing acute agitation in pediatric patients willing to take oral medications. Based on the established literature on risperidone in a wider variety of pediatric populations, as well as the more favorable dosage forms available, it is reasonable to consider risperidone over quetiapine, particularly given the concern for hypotension in volume-depleted adults in the ED, although this safety concern has not been demonstrated in pediatrics.⁵²

Haloperidol and chlorpromazine are both recommended in pBETA, yet these agents have less favorable adverse effect profiles, particularly in pediatric patients.^15-17 Despite data supporting the efficacy of both haloperidol and chlorpromazine in pediatric agitation, these agents should be reserved as alternative first-line agents in patients for whom SGAs were not effective. While there is growing interest in use of droperidol for pediatric agitation, there are persistent concerns related to adverse effects, not only the potential risk of QTc prolongation but also the incidence of EPS reported in pediatric patients and the unclear frequency of oversedation.

While antipsychotic medications are preferred first-line agents to target the underlying causes of agitation in patients with known psychiatric illness, adjunctive agents can also be effective second-line agents to help calm patients. The pBETA recommends repeat use of the same agent due to pediatric vulnerability to medication interactions and adverse effects, with the exception being haloperidol and lorazepam coadministration.⁴ In contrast, diphenhydramine can be trialed after antipsychotic therapy for added sedative effects, to reduce the overall exposure to antipsychotics, and to mitigate the risk of EPS. Diphenhydramine is a reasonable empiric second-line agent in pediatrics because of the various oral dosage formulations and IM availability, favorable adverse effect profile, and reported safety during concomitant administration with antipsychotics documented in the pediatric literature.³⁶

Due to the potential increased risk of paradoxical reactions in pediatrics and antipsychotic agents providing more targeted management of neurotransmitter alterations in agitation related to psychiatric conditions, lorazepam should be reserved for second-line therapy. Concomitant parenteral benzodiazepine and olanzapine administration is cautioned against in both adult and pediatric populations due to potential cardiovascular complications.^4,11,27 Therefore, oral or IM lorazepam can be considered for use in combination with or following haloperidol, chlorpromazine, or risperidone.

Despite limited data for clonidine in acute agitation, pBETA recommends oral clonidine in patients with underlying ASD or developmental disabilities.⁴ Clonidine has a favorable adverse effect profile, and its safety has been demonstrated in pediatric patients for alternative indications. Clonidine could be considered as an alternative second-line therapy for patients willing to take an oral medication to avoid the risk of paradoxical disinhibition with diphenhydramine or benzodiazepines. There is, however, concern for additive hypotensive properties with concomitant antipsychotic administration, which should be closely monitored.^{4,18,27,33,55,56}

Institutional protocolization of the management of acute pediatric agitation in the ED, including pharmacotherapy, appears to be associated with improved patient outcomes.^40,77 However, standardizing empiric pharmacotherapy should be one aspect of a comprehensive plan to improve the management of agitated patients in the ED. Staff training should also include nonviolent crisis interventions and therapeutic/trauma-informed approaches that focus on using verbal de-escalation followed by disengagement skills and therapeutic holds to engage with a person in crisis. Pharmacological management should supplement non-pharmacologic interventions and promote ED staff and provider familiarity with standardized medications as an early intervention for agitated patients in the ED. Additional studies are needed to better elucidate optimal pharmacological agents as well as IM and oral pediatric dosing for acute agitation management that allow for patients to safely engage in behavioral de-escalation while minimizing the incidence of oversedation and adverse effects, such as EPS.

Conclusion

The literature regarding pharmacotherapy for acute agitation management in pediatric patients remains scarce. Medications utilized vary depending on institutional practice, as well as provider preference. Evidence suggests that implementing an institutional protocol for pediatric acute agitation in the ED may improve patient outcomes. Additional studies are needed optimize the pharmacological management of acute pediatric agitation and patient outcomes in the ED.

Acknowledgments

The authors thank Patrick Feldman, BS Pharm, for collaborating with the protocolization build in the electronic medical record, and Jody Sims, CPNP-PC/AC, for assistance with education and implementation.

Disclosures

The authors have declared no potential conflicts of interest.

References