Geriatrics

Safety and effectiveness of benzodiazepines and antipsychotics for agitation in older adults in the emergency department

a b s t r a c t

Purpose: To examine the safety and effectiveness of benzodiazepines (BZD) as compared to antipsychotics for the management of Acute agitation in older adults in the emergency department (ED).

Basic procedures: retrospective observational cohort study of 21 EDs across four states in the US, including adults

>=60 years old who received either BZD or antipsychotics for acute agitation in the ED and subsequently were ad- mitted to the hospital. Safety was measured as presence of adverse events: respiratory depression, cardiovascular

effects, extrapyramidal side effects, or a fall during hospitalization. Effectiveness was measured as indicators of treatment failure: need for additional medication, one-to-one observation, or physical restraints following initial medication administration. Proportions and odds ratios with 95% confidence intervals (CI) were calculated. Univariable and multivariable logistic regression were used to assess the association between potential risk factors and for efficacy and Safety endpoints.

Main findings: A total of 684 patients were included (63.9% received a BZD and 36.1% an antipsychotic). There was no difference in the incidence of adverse events between groups (20.6% vs 14.6%, difference 6.0%, 95% CI -0.2% to 11.8%), but there was a higher Intubation rate in the BZD group (2.7% vs 0.4%, difference 2.3%). There were more treatment failures in the antipsychotic group for the composite primary efficacy endpoint (94.3% vs 87.6%, differ- ence 6.7%, 95% CI 2.5% to 10.9%). This appears to have been driven by the need for 1:1 observation; sensitivity analysis excluding 1:1 observation in the Composite outcome demonstrated no significant difference with a failure rate of 38.5% in the antipsychotic group and 35.2% in the benzodiazepine group.

Principal conclusions: Overall there are high rates of treatment failure among agitated older adults receiving phar- macological treatment for agitation in the emergency department. The optimal selection of pharmacological treatment for agitation in older adults should be made considering patient-specific factors that could increase the risk of adverse effects or treatment failure.

(C) 2023

  1. Introduction
    1. Background

Altered mental status accounts for 5-10% of all emergency depart- ment (ED) visits, and a subset of these patients present with acute agitation [1]. Management of agitation often relates to the likely cause of agitation including primary psychiatric disorders, substance use,

* Corresponding author at: Mayo Clinic, Department of Pharmacy, 200 First St SW, Rochester, MN 55901, USA.

E-mail address: [email protected] (K. Engstrom).

hyperactive delirium, and symptoms of dementia, among others [2]. Acute agitation is often multifactorial, and in older adults a sizeable share of agitation presentations actually represent hyperactive delirium [3]. Delirium is common in older patients, affecting approximately 10% of Geriatric patients in the ED. [4] Delirium among older adults discharged from the ED is associated with a nearly 5-fold increase in 30-day mortality; and up to 33% of older adults admitted from the ED with delirium will die during hospitalization [5,6].

Current treatment guidelines for acute agitation focus on treating the suspected underlying cause and caution against use of pharmaco- logic interventions [7]. When utilized, medications should be targeted to the underlying cause of agitation. Agitation related to medication

https://doi.org/10.1016/j.ajem.2023.02.032

0735-6757/(C) 2023

intoxication should be treated with benzodiazepines (BZD) [8], except in cases of intoxication with central nervous system depressants such as alcohol, where antipsychotics play a more prominent role [9]. Anti- psychotics are preferred first-line for patients with psychosis and known psychiatric disorders, with BZD added if agitation persists. BZD are recommended for patients with undifferentiated agitation [10].

    1. Importance

Guidelines specifically for agitated delirium emphasize that inter- ventions should be targeted to delirium phenotypes based on biologic plausibility of effect and pathophysiologic etiology of the current epi- sode of delirium [11]. Pharmacologic approaches for management of de- lirium symptoms are considered the last resort, only for severe agitation when the patient is a threat to themselves or others. Such management should include utilizing evidence-based protocols and the lowest phar- macological dose for the shortest duration possible [3]. Severe agitation can complicate the delivery of appropriate care; and the use of pharma- cologic agents may sometimes be necessary to safely complete physical examination, imaging, laboratory testing, and patient discussions. How- ever, both BZD and antipsychotics have been associated with serious adverse effects in older adult populations [12]. Both Medication classes remain on the Beers criteria list of inappropriate medications to use in older adults [13]. The use of antipsychotic and BZD have been associated with Oxygen desaturation, apnea, and QT prolongation, as well as longer ED lengths of stay and increased rates of hospital admission [14,15]. BZD have been associated with falls with both short and long term use [7]. Most studies do not provide enough evidence to support the use of pharmacological treatment of agitation in ED older adults. As a result, the safety and effectiveness of short-term use of BZD or antipsychotics in agitated older adult patients is unknown.

    1. Goals of this investigation

The Geriatric EMergency Care Applied Research (GEAR) Network consensus statement highlighted the lack of evidence for effective ED- based treatment strategies for delirium and recommended further in- vestigation in this area as a priority [11]. In this study we examine the safety and effectiveness of BZD and antipsychotics when administered for the management of agitation in older adults in the ED.

  1. Methods

We followed the Strengthening the Reporting of Observational Stud- ies in Epidemiology (STROBE) guidelines for reporting observational studies [16]. Medical record review was conducted utilizing specific methodology to reduce the risk of bias [17].

    1. Study design and setting

This was a retrospective cohort study including patients 60 years of age and older presenting to one of 21 EDs located across four different states (MN, AZ, FL, WI). The settings included academic and community EDs with annual volumes of 35,000 to 77,000 per year with older adults contributing 27 to 40% of visits. Patients who presented to the ED and were admitted between July 2018 and July 2020 were identified through the electronic health record. This study was approved and deemed exempt by the Mayo Clinic Institutional Review Board.

    1. Selection of subjects

Patients aged 60 and older were included if they presented with an ED chief complaint of altered mental status, behavioral dyscontrol, or agitation, and received a BZD or antipsychotic during the ED stay. Only patients who ultimately required hospital admission were included to ensure an adequate time frame for assessment of all Safety outcomes.

ED discharge diagnoses were extracted through an electronic data pull. Patients were excluded if they received a BZD or antipsychotic for alcohol withdrawal, seizure, intubation, headache, anxiety, or nausea. Any patient with insufficient data to determine medication indication were excluded from the study. If patients received concurrent benzodi- azepines and antipsychotics (this represented zero cases in this cohort) or ketamine as a first-line agent for agitation they were excluded. Pa- tients with no authorization for medical record review were excluded.

    1. Variables and interventions

The BZD group included patients who received lorazepam, midazo- lam, diazepam, alprazolam, or clonazepam. The antipsychotic group included patients who received olanzapine, quetiapine, ziprasidone, haloperidol, droperidol, or risperidone. Included medications were chosen based on previous literature on Pharmacological management of acute agitation [18]. Patients could have received medications intra- venously, intramuscularly, or orally. Patients were grouped based on the first medication they received in the ED for the treatment of their agitation but remained eligible for inclusion if they received medication from the other class subsequently in their ED stay as this was accounted for in the definition of treatment failure.

    1. Measurements

Demographic information including age, weight, gender, and hospi- tal length of stay were collected through a biostatistical informatics data pull from the electronic health record. Patient history of schizophrenia, bipolar disorder, Alzheimer’s disease and other dementias were identi- fied utilizing ICD-10 codes. To confirm data query accuracy the medical chart was manually reviewed for a random 10% of the final patient cohort, which confirmed the accuracy of endpoint ascertainment. The accuracy of demographic characteristics, safety and efficacy endpoints pulled electronically was 98.6%. We did not impute any data for subjects with incomplete data in the calculation of respective adverse effect Incidence rates.

    1. Outcomes

The safety outcome included the following adverse events: respira- tory depression, Cardiovascular effects, extrapyramidal side effects, and falls (within 24 h from medication administration). Death at 30 days as documented in the electronic medical record was recorded as a separate outcome. Respiratory depression was defined as desaturation (any recorded oxygen saturation < 90%), new oxygen requirement (need for supplemental oxygen via nasal cannula or high-flow or the initiation of non-invasive mechanical ventilation [BiPAP or CPAP]), need for intubation, and hypoventilation (any recorded respiratory rate < 10 breaths per minute) within one hour of medication adminis- tration. Cardiovascular effects included hypotension (systolic blood pressure < 100 mmHg and at least 20% reduction from the previously documented blood pressure) within one hour of medication adminis- tration and QTc prolongation. Patients were considered to have QTc pro- longation if they were found to have a new QTc >500 msec within three hours of medication administration and had an EKG in the prior 60 days with a QTc <500 msec. The definition allowed for a longer time frame for this outcome given potential delays in obtaining an EKG following medication administration. Extrapyramidal side effects were defined as a need for diphenhydramine or benztropine within 90 min of medi- cation administration. A longer time frame from initial medication ad- ministration was allowed for this outcome based on potential delays in obtaining and administering medications for symptom control.

The effectiveness outcome assessed treatment failure and included

need for re-dosing of medication or switch of medication class within 90 min of the initial medication dose, the need for one to one (1:1) care and use of physical restraints as documented in the electronic

health record at any time during the ED stay. Based on general pharma- cokinetic and pharmacodynamic principles of the included agents, the 90-min time frame was an appropriate period to assess for inadequate treatment with the initial pharmacological agent.

    1. Analysis

Power calculations were not performed as this was a consecutive co- hort and every patient that presented within the time frame was in- cluded. Data were summarized using frequencies and percentages for categorical data, and either means and standard deviations or medians and interquartile ranges for continuous data. The proportions of the safety endpoint (oxygenation, extrapyramidal symptoms, falls, and car- diovascular events), mortality within 30 days of ED visit, and treatment failure were compared between those that received a BZD and those that received an antipsychotic using a two proportion Z-test, and the corresponding difference in proportions and 95% confidence intervals (CI) are reported. Univariate and multivariable logistic regression were used to assess the association between potential risk factors and the outcomes of treatment failure and adverse events. Multivariable lo- gistic regression models adjusted for age, sex, weight, hospital length of stay, history of dementia, schizophrenia, and bipolar disorder as deter- mined a priori. Due to a low number without a failure event, we re- moved one variable from the model using backward elimination (history of dementia). Associations were summarized using odds ratios (OR) and 95% CI. All analyses were performed using SAS version 9.4 soft- ware (SAS Institute Inc., Cary, NC) by a biostatistician.

  1. Results
    1. Characteristics of study subjects

A total of 7621 patients 60 years and older presented to institutional EDs and were admitted to an institutional hospital during the study pe- riod, 684 of these patients met criteria for inclusion. Refer to Table 1 for patient demographic information. The most common reason for exclu- sion was medication administration for a non-agitation related indica- tion (Fig. 1). BZD were used more frequently as a First-line treatment for agitation, with 437 (63.9%) patients in the BZD group and 247 (36.1%) in the antipsychotic group. The most frequent BZD utilized was lorazepam, which accounted for over 80% of benzodiazepine use. The most common antipsychotic utilized was haloperidol, followed by quetiapine (Table 2). The most common route utilized was intravenous, followed by oral, with intramuscular administration accounting for only 14.5% of this cohort (Table 1). Female patients were more likely to re- ceive benzodiazepines for agitation (53.1% vs 44.9%, difference 8.2%, 95% CI 0.1% to 16.2%), and patients in the antipsychotic group were older than the BZD group (79.3 vs 74.9 years of age, p < 0.001). Patients who received antipsychotics were more likely to have a diagnosis of

Table 1

Baseline patient characteristics.

Characteristic

Antipsychotic

Benzodiazepine

(n = 247)

(n = 437)

Age (mean years (SD))

79.3 (10.5)

74.9 (9.9)

Female, n (%)

111 (44.9)

232 (53.1)

History of Alzheimer’s or other dementias,

169 (68.4)

176 (40.3)

n (%)

History of schizophrenia, n (%) 11 (4.5) 15 (3.4)

History of bipolar disorder, n (%) 48 (19.4) 80 (18.3) Medication Route

Intramuscular 71 (28.8) 28 (6.4)

Intravenous 67 (27.1) 351 (80.3)

Nasal 0 (0) 1 (0.2)

Oral 103 (41.7) 51 (11.7)

Rectal

3 (1.2)

0 (0)

Sublingual

3 (1.2)

6 (1.4)

Alzheimer’s disease and other dementias compared to those who re- ceived BZD as first medication for agitation (68.4% vs 40.3%, estimated difference 28.1%, 95% CI 20.7% to 35.5%).

    1. Safety/adverse events results

The BZD group had an incidence of adverse effects of 20.6% com- pared to an incidence of 14.6% in the antipsychotic group, however the difference was not statistically significant (difference 6%, 95% CI

-0.2% to 11.8%). There was no difference in the need for additional oxy-

gen or non-invasive mechanical ventilation between the antipsychotic and BZD groups (Table 3). However, the BZD group had a higher rate of intubation within one hour of medication administration than the an- tipsychotic group (2.7% vs 0.4%, difference 2.3%, 95% CI 0.3% to 4.4%). Hy- poventilation and oxygen desaturation data were incomplete, with 314 in BZD group and 273 in the antipsychotic group lacking recorded data to allow assessment of these outcomes.

There were no statistically significant differences between groups in the incidence of hypotension (6.9% vs 8.2%, difference – 1.3%, 95% CI

-5.7% to 3.0%) or QTC prolongation (16.7% vs 18.4%, difference – 1.7%,

95% CI -18.4% to 15.0%). However, only 112 patients (16.3%) had an EKG completed within 3 h of analysis that could be analyzed for com- parison. There were similar rates of extrapyramidal side effects with 4.5% in the antipsychotic group and 2.5% in BZD (difference 2.0%, 95% CI -1.3% to 5.2%). There were no documented in-hospital falls within

24 h of medication administration in either group. Mortality at 30 days did not differ significantly between the two groups, with a mor- tality rate of 16.2% in the antipsychotic group and 19.7% in the BZD group (difference – 3.5%, 95% CI -9.4% to 2.4%).

    1. Effectiveness/treatment failure results

Treatment failure was common for both groups (Table 4), with 94.3% of those receiving antipsychotics and 87.6% of those in the BZD group needing additional medication, 1:1 observation or restraints (dif- ference 6.7%, 95% CI 2.5% to 10.9%). The outcome of treatment failure was driven by a higher use of one-to-one observation in the antipsy- chotic group compared to the BZD group (93.1% vs 86.3%, difference 6.8%, 95% CI 2.3% to 11.4%). There was no difference in the need for ad- ditional medication within 90 min of initial medication administration

(19.8% in the antipsychotic group vs 20.6% in BZD, difference – 0.8%, 95% CI -7.3% to 5.8%), or need for physical restraints between the two

groups (27.5% vs 23.1%, difference 4.4%, 95% CI -2.4% to 11.2%).

    1. Multivariable analysis results

The risk of adverse events (safety) and treatment failure (effective- ness) were assessed using multivariable logistic regression. After adjusting for age, sex, weight, hospital length of stay, history of demen- tia, history of schizophrenia and history of bipolar disorder, patients re- ceiving antipsychotics were as likely to have safety events than those receiving BZD (adjusted OR 0.81, 95% CI 0.52 to 1.27). However, in a similar adjusted model looking at treatment failure, patients receiving antipsychotics were more likely to have treatment failure outcomes than those receiving BZD (adjusted OR 2.54, 95% CI 1.29 to 5.00). The multivariable analysis demonstrated no significant association between adverse events and patient age, weight, hospital length of stay, a history of schizophrenia or a history of bipolar disorder (Table 5). There was a higher incidence of adverse events in patients who were female (ad- justed OR 1.59, 95% CI 1.02-2.44). Individuals with a history of Alzheimer’s or other dementias were less likely to experience adverse events (adjusted OR 0.61, 95% CI 0.39-0.96). Note that a longer length of stay was associated with treatment failure (per 1 day, adjusted OR 2.08, 95% CI 1.63-2.64). There was no association between patient age, weight, gender, or past medical history and treatment failure (Table 5).

Fig. 1. Consort diagram.

    1. Sensitivity analysis of treatment failure

Due to the inherent need for one-to-one observation for patient safety in many agitated older patients, a sensitivity analysis of the com- posite treatment failure outcome was performed that excluded the need for one-to-one Treatment outcome as an endpoint (Table 4). The results are discordant with the composite efficacy endpoint, with treat- ment Failure rates of 38.5% in the antipsychotic group and 35.2% in the benzodiazepine group (difference 3.3%, 95% CI -4.6% to 11.1%).

    1. Limitations

There are several noted limitations to this study. First, this patient cohort is from a single health care system, limiting the generalizability of the results. However, we included 21 different EDs located in four dif- ferent states and Geographical areas (AZ, FL, MN and WI). Second, we try to utilize non-pharmacological interventions first in all our agitated older adults and reserve pharmacological interventions for only those with more severe symptoms. However, there is no way to account for these patients that were delirious or agitated and did not receive BZD or antipsychotics through the electronic health record retrospectively. For several patients some data points like oxygen saturation and respi- ratory rate were not available, limiting the ability to assess differences in event rates between antipsychotics and BZD. However, our sample size of 684 patients is much larger than previous studies comparing pharma- cological agents for acute agitation, ensuring many patients were still included in analysis of each safety outcome. Additionally, the most im- portant outcomes to patients, including intubation and mortality, were available for all patients in the cohort [19]. A limitation of our data is that no falls were detected, inconsistent with what one would expect to find in this population [20]. The lack of detected falls does

Table 2

medication selection.

Benzodiazepines, n (%)

Antipsychotics, n (%)

n = 437

n = 247

Alprazolam

12 (2.7)

Droperidol

36 (14.6)

Clonazepam

0 (0)

Haloperidol

105 (42.5)

Diazepam

11 (2.5)

Olanzapine

36 (14.6)

Lorazepam

350 (80.1)

Quetiapine

56 (22.7)

Midazolam

64 (14.7)

Risperidone

6 (2.4)

Ziprasidone

8 (3.2)

not negate the established association between sedative use and falls [21]. Finally, we had a rigorous inclusion process, excluding 91% of the initial cohort of 7621 patients because they did not have a clear agitation-related indication for the administration of BZD or antipsy- chotics based on their chief complaint and documented ED discharge di- agnosis; selection bias likely occurred through the exclusion of patients that may have actually received a BZD or antipsychotics for agitation.

  1. Discussion

This study found no difference in the rates of adverse events be- tween BZD and antipsychotic use, this is consistent with previous trials examining different pharmacologic agents for acute agitation in the general population where no significant differences in safety events were found [22]. This study noted a higher rate of intubation in ED geri- atric patients receiving BZD compared to antipsychotics in the unad- justed analysis, though this difference disappeared with multivariable adjustment. That being said, several studies indicate a significantly higher risk of over-sedation and respiratory depression with BZD use for acute agitation [23,24]. Intubation is a patient important outcome, because it requires need for critical care unit admission and has higher morbidity and mortality than, for example, documented hypoventila- tion or Low Oxygen Saturation. The difference on the incidence of hypo- tension between antipsychotics and BZD has not been demonstrated to differ in previous studies, with incidence ranging from 3% to 20%. This study found similar results with an incidence of 6.9% in the antipsy- chotic group and 8.2% in the BZD group [25,26]. The incidence of QTc

prolongation in this cohort (~17% in both groups) is higher than previ- ously published studies which estimated the incidence from 0 to 7%,

but is consistent with prior findings that QTc prolongation incidence does not differ between agents [24,27,28]. Because only 16% had an ECG completed within the predetermined time frame, it is likely that a selection bias was produced and only those with longer QTc on the car- diac monitor had a formal ECG ordered, thus increasing the incidence of prolonged QTc in our cohort. There are no specific studies examining safety of these agents solely among older agitated patients but a higher incidence of adverse effects in this population has been documented in previous studies [7,14], as older adults are more likely to take more medications and to be on more medications that prolong the QTc [29]. A significant difference in treatment failure between BZD and anti- psychotics when treating acute agitation was found in this patient co- hort. This difference was driven by the high number of patients with

Table 3

Safety/Adverse event outcomes.

Safety outcome

Antipsychotic (n = 247)

Benzodiazepines (n = 437)

Difference 95% CI

BiPAP/CPAP, n (%)

0 (0)

3 (0.7)

-0.7% (-1.5% to 0.0%)

Nasal Cannula, n (%)

20 (8.1)

43 (9.8)

-1.7% (-6.1% to 2.7%)

Intubation, n (%)

1 (0.4)

12 (2.7)

-2.3% (-4.1% to -0.6%)

Oxygen Desaturation, n (%)?

8 (6.1)

28 (8.9)

-2.8% (-7.9% to 2.4%)

Hypoventilation, n (%)?

2 (2.2)

0 (0)

2.2% (-0.8% to 5.3%)

Hypotension, n (%)

17 (6.9)

36 (8.2)

-1.3% (-5.4% to 2.7%)

Prolonged QTc, n (%)?

6 (16.7)

14 (18.4)

-1.7% (-16.7% to 13.2%)

Extrapyramidal Side Effects, n (%)

11 (4.5)

11 (2.5)

2.0% (-1.0% to 4.9%)

Fall within 24 h, n (%)

0 (0)

0 (0)

N/A

Composite Adverse Events, n (%)

36 (14.6)

90 (20.6)

-6.0% (-11.8% to -0.2%)

Hospital Length of Stay, days Median (IQR)

5 (3, 9)

5 (3, 8)

5 (3, 9)

Mortality at 30 days, n (%)

40 (16.2%)

86 (19.7%)

-3.5% (-9.4% to 2.4%)

* Data was unable to be assessed for 238 patients with respect to oxygen desaturation, 349 patients with respect to hypoventilation, and 572 with respect to QTc prolongation.

Table 4

Efficacy outcomes.

Efficacy outcome

Antipsychotic (n = 247)

Benzodiazepines (n = 684)

Difference 95% CI

Medication redosing within 90 min, n (%)?

49 (19.8)

90 (20.6)

-0.8%, (-7.0% to 5.5%)

Need for 1:1 observation, n (%)

230 (93.1)

377 (86.3)

6.8%, (2.3% to 11.4%)

Need for physical restraints, n (%)

68 (27.5)

101 (23.1)

4.4%, (-2.4% to 11.2%)

Composite treatment failure, n (%)

233 (94.3%)

383 (87.6%)

6.7%, (2.5% to 10.9%)

Composite treatment failure, n(%) without 1:1 observation

95 (38.5%)

154 (35.2%)

3.3% (-1.2% to 8.95)

* Medication re-dosing can be with the same or different initial medication.

1:1 observation, rather than by medication redosing or physical re- straints. Close observation of these patients is very important for safety; the fact that nearly 90% of the cohort had 1:1 observation may not ex- plicitly represent treatment failure. To the authors knowledge there are no institutional protocols regarding the use of sedatives and need for 1:1 observation that may have influenced this finding. When 1:1 observation is removed from the composite efficacy endpoint, there is no significant difference in the rate of treatment failure with the use of antipsychotics when compared to BZD.

There have been several studies comparing the efficacy of these two agents with mixed results. Several studies demonstrate no difference in efficacy [19,23,30,31], but others show BZD have increased efficacy and faster onset to sedate agitated patients [22,32]. Droperidol and midazo- lam are considered first line treatments for acute agitation due to their quick onset. Droperidol has also been found to be more effective than other antipsychotics or lorazepam for the treatment of acute agita- tion [28], although a recent study suggests similar efficacy with IM olanzapine [33]. Studies comparing midazolam and droperidol had con- flicting findings with one indicating lower need for additional medica- tion dosing with the use of midazolam instead of droperidol [27] and

one indicating lower need for additional medication dosing with the use of droperidol instead of midazolam [24]. When used in combination, the literature suggests that droperidol and midazolam have a quicker onset of action than a combination of lorazepam and haloperidol, and that the use of midazolam instead of lorazepam can decrease ED length of stay [34,35]. A 2017 systematic review including twenty studies and a total of 695 patients determined that there was no significant difference in efficacy between use of BZD and antipsychotics for managing agitation in the first sixteen hours after presentation [36]. Several studies also indicate that use of antipsychotics like droperidol or haloperidol in combination with midazolam decrease the need for res- cue sedation [37,38]. The median age in many acute agitation studies is 30-40 years of age, and no randomized controlled trials have exclu- sively examined comparative efficacy outcomes or the need for medica- tion redosing in the older adult ED population [18]. In a recent study using the National Hospital Ambulatory Medical Care Survey data, 3.5% of patients received an antipsychotic or sedative medication during their ED visit, with most patients (92%) receiving a sedative and only 13% receiving antipsychotics. Those who received antipsychotics were more likely to be from a skilled nursing facility and to have dementia

Table 5

Association of patient characteristics with adverse events and treatment failure.

Characteristic Adverse event Odds Ratio (95% CI) Treatment failure Odds Ratio (95% CI)

Univariable

Multivariable

Univariable

Multivariable

Medication (Antipsychotic vs Benzo)

0.66 (0.43-1.0)

0.81 (0.52-1.27)

2.35 (1.28-4.32)

2.54 (1.29-5.0)

Age (per decade)

0.80 (0.66-0.98)

0.89 (0.71-1.12)

0.94 (0.74-1.19)

0.87 (0.65-1.17)

Female

1.47 (0.99-2.17)

1.59 (1.03-2.44)

0.83 (0.50-1.37)

1.07 (0.57-1.99)

Weight (per 10 kg)

1.04 (0.96-1.13)

1.06 (0.97-1.16)

1.04 (0.92-1.17)

0.94 (0.87-1.17)

History of Alzheimer’s or dementia

0.5 (0.33-0.74)

0.61 (0.39-0.96)

1.24 (0.75-2.05)

N/A*

History of schizophrenia

0.36 (0.08-1.54)

0.36 (0.08-1.62)

2.83 (0.38-21.21)

3.29 (0.39-27.58)

History of bipolar disorder

0.84 (0.5-1.41)

0.79 (0.45-1.38)

0.97 (0.51-1.84)

0.65 (0.31-1.37)

Hospital length of stay (per day)

1.00 (0.98-1.03)

1.01 (0.98-1.03)

2.07 (1.63-2.62)

2.08 (1.63-2.64)

Results are derived from univariable and Multivariable logistic regression models containing medication, age, gender, weight, history of Alzheimer’s/dementia, history of schizophrenia, history of bipolar disorder, and hospital length of stay as covariates. Due to a low number without treatment failure events, history of Alzheimer’s or dementia was removed from the mul- tivariable model using backward elimination.

or delirium. Those that received sedatives were more likely to undergo imaging, present to an urban ED or be of Female gender [15]. Our results indicate that both BZD and antipsychotics have high and similar rates of need for medication re-dosing and need for physical restraint; however, antipsychotics have a higher rate of need for 1:1 observation. It is possi- ble that the group that received antipsychotics was more agitated, or more delirious, and those that received antipsychotics were older and were more likely to have a diagnosis of dementia.

We did not find previous studies demonstrating an increased risk of adverse effects from pharmacological treatment of female agitated pa- tients. Further study is needed to determine how robust this finding is, and to determine etiologies for the differences noted in this study. Fe- males were more likely to receive benzodiazepines, consistent with pre- vious studies, which could explain some differences [15]. The regression findings also indicate a lower risk of adverse events in individuals with a history of Alzheimer’s disease and other dementias, which might be ex- plained by the higher utilization of antipsychotics, which in this study was associated with a lower incidence of safety effects in the older adult population. The regression findings are interesting, but due to the retrospective nature of this study and potential bias in medication selection larger studies are needed to confirm this association.

  1. Conclusion

In summary, there is a high failure rate associated with acute use of BZD or antipsychotics to treat agitation in older adults, with 20% requir- ing re-dosing of medication and 25% requiring physical restraints. A higher percentage of patients receiving antipsychotics needed 1:1 ob- servation, although this may be necessary to maintain patient safety. There was no significant difference in the composite incidence of ad- verse events in the antipsychotic group compared to those that receive BZD. The optimal strategy for pharmacological management of agitated geriatric patients requires consideration to patient-specific factors that could increase the risk of adverse events and treatment failure.

Funding

Funding was received for this work.

All of the sources of funding for the work described in this publica- tion are acknowledged below:

Mayo Midwest Pharmacy Research Committee, Rochester, MN.

Reviewed research study design for feasibility and approved funding for data retrieval.

Meetings

This abstract was presented as research in progress at the American College of Clinical Pharmacy (ACCP) Annual Meeting on October 19th, 2021.

Intellectual property

We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.

Research ethics

We further confirm that any aspect of the work covered in this man- uscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. The Mayo Clinic IRB reviewed the study and deemed it exempt.

Authorship

The International Committee of Medical Journal Editors (ICMJE) rec- ommends that authorship be based on the following four criteria:

  1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND
  2. Drafting the work or revising it critically for important intellectual content; AND
  3. Final approval of the version to be published; AND
  4. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

All listed authors meet the ICMJE criteria. We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.

We confirm that the manuscript has been read and approved by all named authors.

We confirm that the order of authors listed in the manuscript has been approved by all named authors.

Contact with the editorial office

The Corresponding Author declared on the title page of the manu- script is:

Kellyn Engstrom

This author submitted this manuscript her account in Editorial Man- ager. We understand that this Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.

We confirm that the email address shown below is accessible by the Corresponding Author, is the address to which Corresponding Author’s account is linked, and has been configured to accept email from the editorial office of American Journal of Emergency Medicine: engstrom. [email protected]

CRediT authorship contribution statement

Kellyn Engstrom: Writing – review & editing, Writing – original draft, Validation, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. Alicia E. Mattson: Writing – review & editing, Supervision, Project administra- tion, Methodology, Funding acquisition, Conceptualization. Kristin Mara: Writing – review & editing, Methodology, Formal analysis, Data curation. Lucas Oliveira J.E. Silva: Writing – review & editing, Methodology, Investigation, Conceptualization. Fernanda Bellolio: Writing – review & editing, Supervision, Resources, Methodology, Conceptualization. Molly Moore Jeffery: Writing – review & editing, Resources, Methodology. Jessica Stanich: Writing – review & editing, Supervision, Investigation, Conceptualization. Caitlin S. Brown: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization.

Declaration of Competing Interest

No conflict of interest exists. We wish to confirm that there are no known conflicts of interest as-

sociated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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