a b s t r a c t

Purpose: acute agitation and violent behavior in the emergency department (ED) can lead to significant patient morbidity and contribute to the growing problem of workplace violence against health care providers. To our knowledge, there is no available literature directly comparing intramuscular ketamine to intramuscular droperidol in ED patients presenting with undifferentiated agitation. The purpose of this investigation was to compare the effectiveness and safety of these agents for acute agitation in the ED.

Methods: This was a retrospective observational study conducted at an urban, academic ED. The primary endpoint was time from the first dose of study medication to restraint removal. Safety endpoints included inci- dence of bradycardia (heart rate < 60 bpm), hypotension (systolic blood pressure < 90 mmHg), hypoxia (oxygen saturation < 90% or need for respiratory support), and incidence of intubation for ongoing agitation or respiratory failure.

Results: An initial 189 patients were screened, of which, 92 met inclusion criteria. The median time from initial drug administration to restraint removal was 49 min (IQR 30, 168) in the ketamine group and 43 min (IQR 30, 80) in the droperidol group (Median difference 6 min; 95% CI [-7, 26]). There was no significant difference in rates of bradycardia (3% vs 3%, 95% CI [-7%, 8%]), hypotension (0% vs 2%, 95% CI [-5%, 2%]), or hypoxia (7% vs 10%, 95% CI [-15%, 9%]) in the ketamine versus droperidol groups respectively. One patient in the ketamine group was intubated for ongoing agitation, and one patient in the droperidol group was intubated for respiratory failure.

Conclusions: Intramuscular droperidol and intramuscular ketamine were associated with similar times from drug administration to restraint removal in patients presenting to the ED with undifferentiated agitation. Prospective studies are warranted to evaluate IM droperidol and IM ketamine head-to-head as first line agents for acute agitation in the ED.

(C) 2023

1. Introduction

Acute agitation in the emergency department (ED) can lead to significant patient morbidity and contribute to workplace violence against health care providers [1]. Possible etiologies include psychiatric conditions, intoxication, acute medical illness, or trauma [2]. While verbal de-escalation and treatment of underlying cause should be attempted first, physical restraints or medications for agitation may be required in patients who are a danger to themselves or others [3,4].

There are many pharmacologic agents used for acute agitation including benzodiazepines, antipsychotics, and dissociative agents. The ideal agent would have a rapid onset when administered

* Corresponding author at: 800 Washington Street, Department of Pharmacy, Boston, MA 02111, United States of America.

E-mail address: [email protected] (J.R. Krenz).

intramuscularly (IM), moderate Duration of action to allow providers to assess and treat the patient without over-sedation, and a favorable safety profile.

Benzodiazepines are commonly utilized for acute agitation, but

there is concern benzodiazepine use may contribute to over-sedation and respiratory depression [5,6]. Available literature suggests benzodi- azepines often fail to control agitation when used as monotherapy, necessitating additional doses or Alternative agents [5 -8].

Both first- and second-generation antipsychotics are commonly utilized for acute agitation in the ED and are recommended first-line when the etiology of agitation is due to underlying psychiatric disorders [4]. Haloperidol, as monotherapy or in combination with benzodiaze- pines, and olanzapine are frequently utilized in the ED setting [9]. Haloperidol has a delayed onset of 20 min when administered IM, while olanzapine effects can be seen within 15 min after IM administra- tion. Alternatively, IM droperidol’s onset of action is 3 to 10 min [10].

https://doi.org/10.1016/j.ajem.2023.03.058

0735-6757/(C) 2023

Droperidol has been shown to more rapidly control agitated patients compared to haloperidol and requires less medications for rescue sedation compared to olanzapine IM [11-13]. The routine use of droperidol in the US declined significantly after the FDA issued a boxed warning for potential QT prolongation and Torsade de pointes and recommended obtaining an EKG prior to drug administration [14]. However, this warning has been extensively debated, and significant evidence supports the safety of IM droperidol at doses up to 20 mg [15-17]. drug shortages and manufacturing delays have also impacted the availability of droperidol in the US market [13].

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has become an increasingly popular agent for undifferentiated agitation, given its onset of 3 to 5 min after IM administration [18]. While keta- mine achieves more rapid control of agitation compared to haloperidol monotherapy or with benzodiazepines, ketamine has been associated with higher rates of intubation [19-21].

To our knowledge, there is no available literature directly comparing IM ketamine to IM droperidol in ED patients presenting with undiffer- entiated agitation. The purpose of this investigation was to evaluate the effectiveness and safety of IM ketamine versus IM droperidol for acute agitation in ED patients requiring physical restraints and medica- tions for agitation.

1. Methods
   1. Study design and setting

This was a retrospective study conducted at an urban, academic ED that sees approximately 60,000 patient visits per year. This study was granted exempt status after IRB review.

At our institution extensive efforts are made to avoid restraints in acutely agitated or violent ED patients. If verbal de-escalation and treatment of potential underlying causes fail, medications for agitation and physical restraints may be utilized. Use of restraints requires frequent monitoring and compliance with federal laws and strict insti- tutional policies to ensure patient rights and safety are maintained. Physical restraints are only utilized when a patient is deemed an immediate danger to themselves or others. Patients placed in restraints must have a face-to-face evaluation by an attending physician within one hour. Patients must be evaluated again at 4 h after restraint place- ment to determine patient response and whether restraints should be continued. Per institutional policy, patients also receive one-to-one observation and continuous monitoring via pulse oximetry during the entire time they are in restraints, regardless of shift, time of day, or cur- rent staff-to-patient ratios. Institutional policy also requires a registered nurse to evaluate the patient every fifteen minutes and record the following on a standardized physical restraint form: (1) assessment of response to treatment, (2) measures taken to ensure patient safety,

(3) comfort measures provided (e.g. repositioning, toileting), and

(4) evaluation of readiness for restraint discontinuation, including doc- umentation of an agitation score (Fig. 1). Nurses are also encouraged to document patient vitals if appropriate based on patient condition and ability to maintain safety.

To limit duration of physical restraints, medications for agitation are commonly administered just prior to or immediately after physical restraint placement. Choice of agent is based on individual practitioner preference, as our ED does not have a standardized guideline or order

1 = Calm and Resting

2 = Pulls at medical devices

3 = Confused and disoriented

4 = Agitated and restless, pacing, yelling

5 = Physically aggressive/self-injurious

Fig. 1. Institutional patient agitation scale.

set for medications for agitation. Before droperidol was available at our institution, ketamine was often utilized when rapid control of acute agitation was warranted in patients requiring physical restraint without intravenous access. After droperidol was reintroduced to the US market, ED physicians requested it be added to formulary. Following droperidol’s formulary addition to our institution in August of 2020 and ED-pharmacist-led education efforts, droperidol became the preferred agent in these patients.

• 1. Patient population and selection

All patients presenting to the ED between January 2017 and Decem- ber 2020 who received a dose of IM ketamine or droperidol were iden- tified via a computer- generated medication administration report and screened for eligibility. Patients were included if they required physical restraints for violent or self-destructive behavior and received either IM ketamine or IM droperidol within 1 h of restraint placement. We chose to evaluate only patients requiring physical restraints, given they were less likely to have missing data due to strict documentation require- ments per institutional policy. Our institutional policies do not require agitation scores to be documented for patients receiving medications for agitation if physical restraints are not used. Patients were excluded if they were <18 years old, did not require restraints, or received both ketamine and droperidol.

• 1. Outcomes and measurements

Data was collected via manual chart review and recorded using a standardized data collection form. The primary endpoint was time from the first dose of study medication to restraint removal. This endpoint was chosen for several reasons. First, our ED utilizes an institution-specific agitation scale, limiting its external validity. Second, investigators anticipated lack of consistent documentation in agitation scores, particularly in patients who did not require physical restraints. Date and time physical restraints are placed and date/time removed are required by institutional policy to be documented in the patient’s medical chart. Documentation of date and time of medications adminis- tered is also required, providing objective data to determine time to restraint removal. Finally, time to restraint removal is a patient- centered outcome, as the goal of providing medications for agitation is to limit the amount of time patients are in restraints.

Secondary endpoints included incidence of agitation score of 1 and time to first agitation score of 1. Our ED utilizes an institution-specific agitation score which rates acute agitation on a 5-point Likert scale (Fig. 1). Secondary endpoints also included length of restraints, ED length of stay, and re-initiation of restraints at 2, 4, and 6 h after initial removal. Parenteral medications administered prior to and after the initial dose of ketamine or droperidol were recorded via documented administrations in the medical record. Safety endpoints included inci- dence of bradycardia (heart rate < 60 bpm), hypotension (systolic blood pressure < 90 mmHg), hypoxia (oxygen saturation < 90% or need for respiratory support), and incidence of intubation for ongoing agitation or respiratory failure.

• 1. Data analysis

Descriptive statistics with medians and interquartile ranges were calculated. Continuous variables were compared utilizing difference in medians and 95% confidence intervals (CIs) calculated using a Hodges-Lehmann estimation. Categorical variables were compared using difference in proportions test and associated 95% CIs. 95% CIs not containing zero were considered statistically significant. All statisti- cal analysis was conducted in SPSS (IBM Corporation, version 28.0.1).

1. Results

An initial 189 patients were screened, and 92 met inclusion criteria. Thirty patients received IM ketamine, and sixty-two received IM droperidol (Fig. 2). Six patients received ketamine after the introduction of droperidol in our ED. Baseline characteristics are displayed in Table 1. Patients in the ketamine group had a lower rate of ED discharge than those in the droperidol group (53% vs 76%; 95% CI [-43%, -2%]).

The most common dose of IM ketamine was 4 mg/kg with median initial dose 290 mg (IQR 169, 300). The median initial dose of IM droperidol administered was 5 mg (IQR 5, 5). Parenteral medications administered prior to and after the first dose of study medication are displayed in Table 2. Oral medications were offered but declined, or patients were unable to take oral medications due to the severity of their agitation. Fifty (81%) patients in the droperidol group received no medications prior to the initial study medication, compared to four (13%) patients in the ketamine group (95% CI [-83%, -52%]). Patients in the ketamine group were more likely to receive IM haloperidol (Proportion difference 43%; 95% CI [26%, 61%]), lorazepam (Proportion

difference 34%, 95% CI [15%, 52%]), and olanzapine (Proportion differ- ence 37%; 95% CI [19%, 55%]). After the initial medication dose, however, there was no significant difference between the proportion of patients who did not require additional medications (Difference - 9%; 95% CI [-30%, 12%]).

Effectiveness endpoints are displayed in Table 3. Median time from initial drug administration to restraint removal was 49 min (IQR 30, 168) in the ketamine group and 43 min (IQR 30, 80) in the droperidol group (Median difference 6 min; 95% CI [-7, 26]). Median time to first agitation score of 1 was 33 min in the ketamine group and 32 min in the droperidol group (95% CI [-4, 46]). Patients who received ketamine had a longer median time in restraints than those who received droperidol (Median difference 85 min; 95% CI [50, 105]). Pa- tients receiving ketamine had a longer ED length of stay than those who received droperidol (Median difference 3.8 h; 95% CI [0.78, 7.8]).

There was no significant difference in rates of bradycardia (3% vs 3%, 95% CI [-7%, 8%]), hypotension (0% vs 2%, 95% CI [-5%, 2%]), or hypoxia (7% vs 10%, 95% CI [-15%, 9%]) in the ketamine versus droperidol groups respectively. One patient in the ketamine group required respiratory support with a non-rebreather mask. Two patients in the droperidol group required nasal cannula and one required non- rebreather mask. One patient in the ketamine group was intubated for ongoing agitation, and one patient in the droperidol group was intubated for respiratory failure.

1. Discussion

To our knowledge, the Clinical effectiveness of IM ketamine and droperidol has not been directly compared in an ED population for acute undifferentiated agitation. Currently published studies are difficult to compare due to heterogenous patient populations, different routes of administration, and different scoring tools utilized. Pharmaco- kinetic data suggests both droperidol and ketamine should have a quick onset of action when administered IM, with the onset of droperidol being 3 to 10 min and the onset of ketamine being 3 to 5 min [10,18]. Ketamine attains peak concentrations within 15 min while peak con- centrations of droperidol are achieved at 30 min [10,18]. This difference in time to peak concentration may explain why the typical time to ade- quate sedation is shorter with ketamine in currently published studies. Studies evaluating time to adequate sedation have shown ketamine achieves adequate sedation in 4.2 to 7.7 min [19,21,22]. Similar studies conducted with droperidol have shown time to adequate sedation ranges from 15 to 25 min [6,13,15,23,24]. In our study, IM ketamine and IM droperidol were equally effective at achieving sedation in acutely agitated, restrained patients in the ED as evidenced by no difference in the time from drug administration to restraint removal, no difference in time from drug administration to agitation score of 1 (calm/resting), and no difference in additional sedative medication re- quirements after administration. Further studies may look to evaluate patient populations in which the faster onset of ketamine may be preferrable to that of droperidol for patient outcomes or safety.

While ketamine and droperidol have similar onset of action, their

duration of action differs significantly. IM ketamine lasts only 25 to 30 min while IM droperidol effects can last 2 to 4 h [25,26]. Based on the shorter duration of ketamine, it is reasonable to predict that patients who receive ketamine would be more likely to require additional seda- tion or have reemergence of agitation. However, in this study, the rates at which patients required additional sedative medications after the first dose of study medication were the same in both groups. Addition- ally, we did not find patients in the ketamine group had higher rates of re-initiation of restraints at 2, 4, or 6 h after the initial dose of study medication indicating there was not an increased rate of reemergence of agitation in the ketamine group.

Patients in the ketamine group received more parenteral medica- tions for agitation prior to the first dose of the study drug, suggesting ketamine was more likely to be utilized for refractory agitation while droperidol was more commonly utilized as a first-line agent. The cumu- lative effects of parenteral sedative medications may have contributed

Fig. 2. Patients assessed for eligibility.

Table 1 Baseline characteristics.
	Ketamine (n = 30)	Droperidol (n = 62)	Difference (95% CI)
Age, years?	39 (31, 48)	42 (33, 53)	-3 (-10,1)
Male Sex^	26 (87)	47 (76)	9% (11%, 23%)
Race or Ethnicity^
White	17 (57)	39 (63)	-6% (-28%, 15%)
Black	9 (30)	15 (24)	6% (-14%, 25%)
Hispanic	0 (0)	6 (10)	-10% (-17%, -2%)
Asian	1 (3)	0 (0)	3% (-3%, 10%)
Other	3 (10)	2 (3)	7% (-5%, 18%)
Initial Agitation Score?	5 (4, 5)	5 (5, 5)	0 (0,0)
Heart Rate, bpm?	102 (81, 113)	100 (85, 114)	2 (-12, 8)
Systolic Blood Pressure, mmHg?	136 (126, 153)	127 (111, 145)	9 (1,20)
Oxygen Saturation, %?	98 (96, 99)	98 (96, 100)	0 (-1,1)
Respiratory Support^ None	29 (97)	59 (95)	2% (-7%, 10%)
Nasal Cannula	0 (0)	2 (3)	-3% (-8%, 10%)
Non-rebreather	1 (3)	1 (2)	1% (-5%, 9%)
ED Discharge Diagnosis^? Alcohol Use	7 (23)	19 (31)	-8% (-26%, 12%)
Other Substance Use	6 (20)	18 (29)	-9% (-27%, 9%)
Psychiatric Condition	10 (33)	15 (24)	9% (-11%, 29%)
Medical Condition	10 (33)	7 (11)	22% (34%, 41%)
Trauma	1 (3)	6 (10)	-7% (-16%, 3%)
Other	4 (13)	6 (10)	3% (-11%, 18%)
Disposition^
Discharge	16 (53)	47 (76)	-23% (-43%, -2%)
Transfer	1 (3)	4 (7)	-4% (-12%, 6%)
Admit, Medical Floor	4 (13)	6 (10)	3% (-11%, 18%)
Admit, Psychiatric Floor	5 (17)	4 (7)	10% (-5%, 25%)
Admit, ICU	4 (13)	1 (2)	11% (-1%, 24%)

* Reported as Median (IQR); Difference reported as median difference with associated 95% Confidence Interval.

^{^} Reported as n (%); Difference reported as difference of proportions with associated 95% Confidence Interval.

^? Some patients had more than one discharge diagnosis.

to prolonged sedation in the ketamine group and explain why reemer- gence of agitation was not observed. These additive effects may also ex- plain why the ketamine group had longer cumulative time in restraints and a longer ED length of stay. Another explanation may be patients in the ketamine group were more agitated or medically complex, given

Table 2

Parenteral medications administered before and after first dose of study medication.

ketamine patients had a higher frequency of medical diagnoses and were more likely to be admitted to an inpatient service.

Previous studies have reported prehospital ketamine for undifferen- tiated agitation was associated with increased rates of intubation [13,27]. One study found ketamine 5 mg/kg IM achieved adequate sedation more rapidly but was associated with higher rates of intuba- tion than haloperidol 10 mg IM, (39% vs 4%) [28]. In our study, however,

Table 3

Medication Ketamine (n = 30)

Droperidol (n = 62)

Difference in Proportions (95% CI)

Outcomes.

Ketamine

Droperidol

Difference with

1, minutes?JPY

Before					(n = 30)	(n = 62)	associated 95% CI
None	4 (13)	50 (81)	-68% (-83%, -52%)	Time from Drug	49 (30, 168)	43 (30, 80)	6 (-7, 26)
Chlorpromazine	1 (3)	0 (0)	3% (-3%, 10%)	Administration to
IM				Restraint Removal,
Haloperidol IM	13 (43)	0 (0)	43% (26%, 61%)	minutes?
Lorazepam IM	12 (40)	4 (7)	33% (15%, 52%)	Time in Restraints,	135 (98, 193)	50 (33, 90)	85 (50, 105)
Lorazepam IV	0 (0)	1 (2)	-2% (-5%, 2%)	minutes?
Midazolam IM	7 (23)	6 (10)	13% (-3%, 31%)	Agitation Score at	1 (1,1)	1 (1, 1)	0 (0, 0)
Midazolam IV	1 (3)	0 (0)	3% (-3%, 10%)	Restraint Removal?
Olanzapine IM	12 (40)	2 (3)	37% (19%, 55%)	Achieved Agitation	20 (67)	43 (69)	-2% (-23%, 18%)
				Score 1^
After None	18 (60)	43 (69)	-9% (-3%, 12%)	Time to Agitation Score	33 (23,100)	32 (23.5, 62.5)	1 (-4, 46)
Chlorpromazine	1 (3)	0 (0)	3% (-3%, 10%)	Reinitation of Restraints	3 (10)	1 (2)	8% (-3%, 20%)
IM Droperidol IM	0 (0)	12 (19)	-19% (-29%, -10%)	at 2 h^ Reinitation of Restraints	1 (3)	1 (2)	1% (-5%, 9%)
Droperidol IV	0 (0)	1 (2)	-2% (-5%, 2%)	at 4 h^
Haloperidol IM	1 (3)	1 (2)	1% (-5%, 9%)	Reinitation of Restraints	3 (10)	1 (2)	8% (-3%, 20%)
Ketamine IM	5 (17)	0 (0)	17% (3%, 30%)	at 6 h^
Lorazepam IM	2 (7)	3 (5)	2% (-9%, 12%)	ED LOS, hours?	13 (7.6, 25.4)	9.2 (6.1, 13.7)	3.8 (0.78, 7.8)

Lorazepam IV 5 (17) 4 (7) 10% (-5%, 25%)

Midazolam IM 0 (0) 3 (5) -5% (-10%, 1%)

Midazolam IV 2 (7) 0 (0) 7% (-2%, 16%)

Olanzapine IM 2 (7) 0 (0) 7% (-2%, 16%)

Reported as n (%).

* Reported as Median (IQR); Difference reported as median difference with associated 95% Confidence Interval.

^{^} Reported as n (%); Difference reported as difference of proportions with associated

95% Confidence Interval.

^JPY n = 70 (Ketamine 21, Droperidol 49) due to missing data.

we did not observe higher rates of intubations in the ketamine group despite a median dose of 4 mg/kg IM and high utilization of parenteral sedatives prior to ketamine administration. There was also no difference in other adverse events including bradycardia, hypotension, or hypoxia between the groups.

1. Limitations

This study’s generalizability is limited by its retrospective, single- center design. We were unable to determine the underlying cause of agitation in all cases due to limitations in documentation. Additionally, we were unable to evaluate whether patients had a history of violent behavior or had previously required restraints. This may influence the initial choice of pharmacologic agent or time to restraint removal. In clinical practice, however, clinicians often need to intervene before the cause is identified or may not have time to review previous presenta- tions. This may be especially true if patients are an immediate danger to themselves or others. Thus, this study may still provide insight on choice of pharmacologic agent when acute agitation is undifferentiated. In 2001 the FDA issued a boxed warning for droperidol over con- cerns of QT prolongation and extensive monitoring recommendations including an EKG prior to administration and cardiac monitoring for 2 to 3 h after droperidol administration [29]. Studies since have found the incidence of cardiac adverse events is low and routine EKG monitor- ing for one-time doses may not be necessary [15-17,30]. In 2014, the American Academy of Emergency Medicine (AAEM) released a position statement that droperidol is a safe and effective and literature did not support mandating an EKG or cardiac monitoring for doses <2.5 mg given IV or IM. They further stated IM doses up to 10 mg of droperidol appear to be as safe and effective as other sedative medications [29]. Based on these recommendations, EKG monitoring is not required at our institution; thus, we were unable to evaluate the incidence of QTc

prolongation with droperidol due to missing EKG data.

Finally, we were unable to evaluate certain adverse events related to ketamine such as vomiting, hypersalivation, laryngospasm, or emer- gence reactions due to the retrospective nature of this study, which may over-estimate the safety of ketamine.

1. Conclusion

Intramuscular droperidol and intramuscular ketamine were associated with similar times from drug administration to restraint removal in patients presenting to the ED with undifferentiated agitation. Prospective studies are warranted to evaluate IM droperidol and IM ke- tamine head-to-head as first line agents for acute agitation in the ED.

CRediT authorship contribution statement James R. Krenz: Writing - review & editing, Writing - original draft,

Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Kristin Medeiros: Writing - review & editing, Writing - original draft, Supervision, Project administration, Methodology, Investigation, Conceptualization. Kathryn Lupez: Writing - review & editing, Writing - original draft, Project administra- tion, Methodology, Investigation, Conceptualization.

Declaration of Competing Interest

None.

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