DR.

JACOB A LEBIN (Orcid ID : 0000-0003-1553-3363)

Accepted Article
Article type : Original Contribution

Title: Psychiatric Outcomes of Patients with Severe Agitation Following Administration of

Prehospital Ketamine

Short Running Title: Psychiatric Outcomes Following Prehospital Ketamine

Jacob A Lebin MD1, Arvin R Akhavan MD1, Daniel S Hippe MS2, Melissa H Gittinger DO3,
Jagoda Pasic MD4, Andrew M McCoy MD MS1, & Marie C Vrablik MD MCR1

1. Department of Emergency Medicine, University of Washington, Seattle WA

2. Department of Radiology, University of Washington, Seattle WA
3. Department of Emergency Medicine, Emory University, Atlanta GA
4. Department of Psychiatry, University of Washington, Seattle WA

Email Addresses:
Jacob A Lebin MD – lebin@uw.edu
Arvin R Akhavan MD – arvrad@uw.edu
Daniel S Hippe MS – dhippe@uw.edu
Melissa H Gittinger DO – Melissa.l.gittinger@emory.edu
Jagoda Pasic MD – jpasic@uw.edu
Andrew M McCoy MD MS – mccoya2@uw.edu
Marie C Vrablik MD MCR – mavrab@uw.edu

Corresponding Author:
Jacob Lebin, MD
Harborview Medical Center
Department of Emergency Medicine, University of Washington
325 Ninth Avenue
Seattle, Washington 98104-2499
Email: lebin@uw.edu

Author contributions: Study concept and design (JAL, ARA, MHG, JP, MCV), acquisition
of the data (JAL, ARA, AMM), analysis and interpretation of the data (JAL, DSH, MCV),
drafting of the manuscript (JAL, DSH, MCV), critical revision of the manuscript (MHG, JP,
AMM), statistical expertise (DSH). JAL takes responsibility for the paper as a whole.

Keywords: ketamine, agitation, psychiatry

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/acem.13725
This article is protected by copyright. All rights reserved.
 Conflicts of Interest: The authors [JAL, ARA, DSH, MHG, JP, AMM, MCV] have no
conflicts of interest to disclose.
Accepted Article
Abstract

Background: Ketamine is an emerging drug used in the management of undifferentiated,

severe agitation in the prehospital setting. However, prior work has indicated that ketamine

may exacerbate psychotic symptoms in patients with schizophrenia. The objective of this

study was to describe psychiatric outcomes in patients who receive prehospital ketamine for

severe agitation.

Methods: This is a retrospective cohort study, conducted at two tertiary academic medical

centers, utilizing chart review of patients requiring prehospital sedation for severe agitation

from 01/01/2014 - 06/30/2016. Patients received either intramuscular (IM) vs IV ketamine or

IM vs IV benzodiazepine. The primary outcome was psychiatric inpatient admission with

secondary outcomes including ED psychiatric evaluation and non-psychiatric inpatient

admission. Generalized estimating equations and Fisher’s exact tests were used to compare

cohorts.

Results: During the study period, 141 patient encounters met inclusion with 59 (42%)

receiving prehospital ketamine. There were no statistically significant differences between

the ketamine and benzodiazepine cohorts for psychiatric inpatient admission (6.8% vs. 2.4%;

difference: 4.3%; 95% CI: -2% to 12%, p=0.23) or ED psychiatric evaluation (8.6% vs. 15%;

difference: -6.8%; 95% CI: -18% to 5%, p=0.23). Patients with schizophrenia who received

ketamine did not require psychiatric inpatient admission (17% vs 10%; difference: 6.7%; CI

(-46% to 79%, p=0.63) or ED psychiatric evaluation (17% vs 50%; difference: -33%; 95%

CI: -100% to 33%, p=0.55) significantly more than those who received benzodiazepines,

though the subgroup was small (n=16). While there was no significant difference in non-

psychiatric admission rate between the ketamine and benzodiazepine cohorts (35% vs. 51%,

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 p=0.082), non-psychiatric admissions in the benzodiazepine cohort were largely driven by

intubation (63% vs. 3.8%; difference: 59%; 95% CI: 38% to 79%, p<0.001).
Accepted Article
Conclusions: Administration of prehospital ketamine for severe agitation was not associated

with an increase in rate of psychiatric evaluation in the emergency department or psychiatric

inpatient admission when compared with benzodiazepine treatment, regardless of the

patient’s psychiatric history.

Introduction

Acute, undifferentiated agitation is a commonly encountered problem in the

prehospital and emergency department (ED) setting.1-2 When verbal de-escalation is

ineffective, pharmacologic management may be required to ensure safety for both patients

and providers. Traditional pharmacologic treatments for severe agitation, such has

benzodiazepines or haloperidol, have relatively slow onset of action and often require re-

dosing to achieve adequate sedation.3 Ketamine, a dissociative agent with rapid onset and

wide therapeutic index, is an emerging alternative in the management of undifferentiated,

severe agitation in the prehospital and ED setting.3-6

In addition to rapid sedation, ketamine is well known to cause emergence reactions,

often described as vivid dreams or hallucinations, which has tempered its use in certain

populations.7 Currently, practice guidelines recommend against the use of ketamine for

procedural sedation in patients with schizophrenia given concern for exacerbation of

underlying psychotic disorders.8 Several studies suggest that the glutamatergic N-methyl-D-

aspartic acid (NMDA) receptor is involved in the pathophysiology of schizophrenia and

ketamine, through NMDA receptor antagonism, can trigger recrudescence of psychotic

symptoms.9-10 However, there is little data evaluating whether patients who receive ketamine

in the prehospital or ED setting have clinically significant psychiatric exacerbations.

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 This study compares psychiatric outcomes in patients administered prehospital

ketamine to patients administered prehospital benzodiazepines in the setting of severe

Accepted Article
agitation. Specifically, our primary objective was to compare rates of clinically significant

psychiatric exacerbation, in patients with and without schizophrenia, using admission to an

inpatient psychiatry service as a surrogate marker. Our secondary objective was to assess

other markers of psychiatric exacerbation, such as need for psychiatric evaluation in the ED

and ED length of stay (LOS). We hypothesized that ketamine would not result in worsened

psychiatric outcomes when compared to benzodiazepines in patients with acute,

undifferentiated prehospital severe agitation.

Methods

Study Design and Setting

This was a retrospective cohort study performed at two urban, academic centers, in

conjunction with the fire department-based emergency medical services (EMS) system. The

emergency departments have a combined annual census of 100,000 visits and are served by

the same EMS system. Consecutive adult patients who received prehospital sedatives for

acute, undifferentiated severe agitation were evaluated from January 1, 2014 to June 30,

2016. During the first 18 months of the study period, prehospital providers administered

benzodiazepines, specifically midazolam or diazepam, for sedation of severe agitation.

Ketamine was added to the prehospital pharmacy for the management of severe agitation on

June 1, 2015. During the last 13 months of the study, prehospital providers could administer

benzodiazepines, ketamine, or both agents for sedation at their discretion. Institutional

Review Board approval was obtained for all study procedures.

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 Selection of Participants

In this EMS system, all advanced life support charts are reviewed by two EMS
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medical directors. The presence of severe agitation, defined as profound agitation with

imminent risk of injury to patient or provider, was determined by EMS medical director

review of each chart. Patients who were determined to have severe agitation, required

sedation, and presented to the ED were eligible for the study. Exclusion criteria included

patients who were administered sedating medications for indications other than severe

agitation (such a seizure or other medical indication), patients who were taken to other

hospitals so their medical records were unavailable, and patients missing other critical data

such as hospital record number or administered medications.

Variables and Outcomes

We defined two cohorts: patients who received prehospital ketamine, with or without

benzodiazepines to manage severe agitation, and patients who received prehospital

benzodiazepines only. Prehospital medications were administered at the discretion of

prehospital providers with approval of hospital-based physician medical control. Prehospital

guidelines in this system suggest the following doses: ketamine 3-5 mg/kg intramuscular

(IM) or 1-2 mg/kg intravenous (IV), midazolam 5–10 mg IM, 1-10 mg IV, or 2.5-10 mg

intranasal (IN), and diazepam 2.5–10 mg IV. The dose calculation was made by prehospital

providers based on estimated weight in the field. Due to the retrospective nature of the study,

medication dosages were not uniform across cohorts. Patient weights were not available for

all patients and weight-based dosing could not be reported.

The primary outcome of the study was admission to an inpatient psychiatry service as

a surrogate marker for clinically-relevant exacerbation of psychiatric disease. We did not find

a prior consensus definition for psychiatric exacerbation in the literature. Secondary

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 outcomes included need for psychiatric evaluation in the ED, which occurred after medical

clearance from ED providers, and ED length of stay (LOS), defined as time of presentation to
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final disposition (discharge or admission). Patients requiring psychiatric evaluation were

usually seen in a separate psychiatric unit within the ED, but may have been seen in their ED

bed depending on bed availability. Disposition was categorized as discharge, admission to

inpatient psychiatry, or admission for any other non-psychiatric indication. Non-psychiatric

hospital admission diagnoses were based on the primary hospital discharge diagnosis and

broadly categorized as altered mental status, drug-related, medical indication, trauma related,

or due to intubation. Notably, intubated patients were excluded from the outcomes of

psychiatric admission and psychiatric evaluation in the ED as their psychiatric illness could

not be assessed.

Data Collection and Processing

Data was abstracted from EMS reports and our hospital-based electronic medical

record. The date of service and prehospital medications were abstracted from EMS reports by

two reviewers on a structured data abstraction form and reviewed for consensus. EMS reports

were then matched to hospital-based electronic medical records (EMR). The covariates of ED

visits in the prior year and history of substance use, identified by ICD code, were abstracted

from the hospital EMR. Additional covariates, including prior psychiatric diagnoses, ED

LOS, ED disposition, and hospital LOS were manually abstracted from the hospital electronic

medical record by two reviewers on a structured data abstraction form. Prior psychiatric

diagnosis was defined as any of the following: depression, bipolar disorder, personality

disorder, substance induced psychosis, schizophrenia, post-traumatic stress disorder (PTSD),

anxiety, psychosis not otherwise specified, and personality disorder. All data abstracted by

manual review was confirmed by both reviewers. Full consensus between authors was

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 required for inclusion. If consensus was not reached, the case was adjudicated by another

reviewer. A written definition of each variable guided the data abstraction (Appendix).
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Analysis

Continuous variables were summarized as median (range) and categorical variables as

count (percentage). Demographics and outcomes were compared between benzodiazepines

and ketamine cohorts using generalized estimating equations (GEE) based logistic regression

to account for any non-independence of multiple visits by the same patient. Confidence

intervals (CIs) for absolute differences in percentages and medians were calculated using

GEE-based regression with the identity link or the non-parametric bootstrap, with resampling

performed by patient and stratified by prehospital medication group. Fisher’s exact test was

used to compare outcomes between groups in the subgroup with schizophrenia. All statistical

calculations were conducted with the statistical computing language R (version 3.1.1; R

Foundation for Statistical Computing, Vienna, Austria). Throughout, two-sided tests were

used, with statistical significance defined as p<0.05.

Results:

During the study period, 173 patients received sedation for prehospital severe

agitation. There were 141 visits by 134 patients that met inclusion and exclusion criteria and

were included in the analysis (Figure 1). Benzodiazepines were administered in 82 visits

(58%) and ketamine was administered in 59 visits (42%). During the time period when

ketamine was available, patients were exposed to ketamine in all but 9 of the 68 visits (87%).

Demographic data is presented in Table 1. Age (median 32 vs. 33 years, p=0.81), site

(p=0.59), history of substance use (87% vs. 88%, p=0.79), ED visits in the prior year

(p=0.30), and history of mental illness (p=0.32) were not statistically significantly different

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 between the benzodiazepines and ketamine treatment groups, respectively. The

benzodiazepine group was more often male (92% vs. 80%, p=0.033) than the ketamine group
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and there were also differences in the racial distribution between the two groups (p<0.001),

though race was categorized as ‘other or not reported’ in 36% of visits (Table 1). Dosages of

prehospital medications are summarized in Table 2.

The rate of inpatient psychiatric admission was low in both in both cohorts at 2.4%

for the benzodiazepine cohort and 6.8% for the ketamine cohort (Table 3). The difference of

4.3% (95% CI: -2.4% to 12.1%, p=0.23) in these two rates was relatively small, though the

upper bound of the CI included a 12% higher inpatient admission rate in the ketamine cohort.

In contrast, the ketamine cohort was observed to have a somewhat lower rate of psychiatric

evaluation in the ED compared to the benzodiazepine cohort (15% vs. 8.6%, difference: -

6.8%, 95% CI: -18% to 4.7%, p=0.23). In this case, the upper bound of the CI was a 5%

higher rate in the ketamine cohort.

The estimated difference between groups in the rate of psychiatric evaluation in the

ED became somewhat larger (greater in the benzodiazepine group than the ketamine group)

after adjusting for history of any mental illness (difference: -10.3%, 95% CI: -21% to 0.8%,

p=0.069 for the difference between the two groups), but was little changed by separate

adjustments for male sex (difference: -5.9%), history of schizophrenia (difference: -5.4%),

history of substance use (difference: -7.2%), or number of prior ED visits in the last year

(difference: -4.3%). There was no significant difference in median ED LOS between the

ketamine and the benzodiazepine cohort (median: 394 vs. 353 minutes, difference: -40

minutes, 95% CI: -152 to 68 minutes) (Table 3).

Out of the 124 visits analyzed, there were 16 visits by 15 patients with schizophrenia,

with 10 in the benzodiazepine cohort and 6 in the ketamine cohort (Table 4). Only one patient

in each cohort had an inpatient psychiatric admission (10% vs. 17%, difference: 6.7%, 95%

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 CI: -35% to 49%). Three patients in the benzodiazepine cohort underwent psychiatric

evaluation in the ED compared to one in the ketamine cohort (50% vs. 17%, difference: -
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33%; 95% CI: -100% to 33%).

Overall, there was no significant difference in the rate of hospital admission between

the benzodiazepine and ketamine cohorts (35% vs. 51%, difference: 16%, 95% CI: -2% to

33%, p=0.082) (Table 3). The majority of hospital admissions were for non-psychiatric

indications for both the benzodiazepine (93%) and ketamine (87%) cohort. As with the

overall analysis, in the schizophrenia subgroup, there was no significant difference in the rate

of hospital admission between the ketamine and benzodiazepine cohort (50% vs. 67%,

difference: 17%, CI: -46 to 79%, p=0.63), but these were mainly for non-psychiatric

indications (Table 4).

Of the non-psychiatric hospital admission diagnoses, drug-related (15% vs. 62%) and

trauma-related indications (0% vs. 12%) tended to be more common in the ketamine cohort

while intubations (63% vs. 4%) tended to be less common in the ketamine cohort, relative to

the benzodiazepine cohort (Table 3). In patients with schizophrenia, there were 3 non-

psychiatric admissions in the ketamine group, of which 2 (67%) were drug-related and 1

(33%) had a medical indication (Table 4). The benzodiazepine group had 4 non-psychiatric

admissions, all of which were due to intubation. Of those admitted, the median hospital LOS

was two days in both groups (Table 3 & 4). Outcomes comparing patient cohorts with and

without history of any mental illness were completed (see Appendix).

Discussion

In this retrospective evaluation of prehospital ketamine for the management of severe,

undifferentiated agitation, we did not find significantly increased rates of psychiatric

evaluation when compared to treatment with benzodiazepines alone. However, patients in

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 both cohorts were likely to require inpatient admission, though primarily for non-psychiatric

indications. Despite the small cohort size, this is one of the largest studies examining
Accepted Article
psychiatric outcomes of patients with schizophrenia who received high dose ketamine.

Even with the widespread use of ketamine for procedural sedation, rapid and delayed

sequence intubation, and more recently behavioral control of acute agitation, few studies have

examined ketamine associated psychiatric outcomes in the ED or prehospital setting. In a

single-center observational study by Riddell et al., patients who received ketamine for

undifferentiated agitation in the ED did not require psychiatric admission more than patients

who received benzodiazepines, haloperidol, or a combination of benzodiazepines or

haloperidol.6 Our study adds important subgroup analyses for patients with a history of

mental illness, and specifically, schizophrenia. While the small sample size limits our ability

to reach statistically significant conclusions in this population, our study further supports the

hypothesis that in undifferentiated, highly agitated patients, receiving ketamine rather than

benzodiazepines for sedation has a minimal impact on meaningful psychiatric outcomes,

notably psychiatric admission.

While ketamine has seen a resurgence in recent years, clinical practice guidelines

recommend against using ketamine for procedural sedation in patients with schizophrenia due

to the potential for psychiatric exacerbation and decompensation.8 However, the evidence for

this precaution must be applied in the context of the literature. In the oft-cited paper by Lahti

et al., nine patients with schizophrenia were administered subanesthetic doses of ketamine

(0.1-0.5 mg/kg IV) and demonstrated positive symptoms (hallucinations, delusions, thought

disorder), similar to the patient’s psychotic episodes over the course of 30 minutes.11

However, a subsequent study by the same group demonstrated that subanesthetic doses of

ketamine in both healthy volunteers and schizophrenic patients induced a similar pattern of

symptoms.12 We hypothesize that patients with schizophrenia are at no greater risk for

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 developing psychotic symptoms than the general population following ketamine

administration and that the risk for psychiatric symptom exacerbation may lie with
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subanesthetic ketamine dosing. Additional studies assessing healthy volunteers and patients

with schizophrenia have demonstrated similar symptom patterns when using subanesthetic

doses of ketamine.13-14

Consistent with prior work, patients in the present study frequently required inpatient

admission following pharmacologic management of prehospital severe agitation. The

majority of these admissions, as in our study and others, are for non-psychiatric indications.
3,6
While not measured as a primary outcome in this study, patients who received ketamine

were less likely to be intubated when compared to patients who received benzodiazepines

(3.8% vs. 63%, p<0.001). This is notable as other studies have demonstrated high rates of

intubation following ketamine for severe agitation.3,15,16 However, we cannot rule out the

presence of confounding factors, such as presentation severity, which may have biased the

results towards a particular agent for a given presentation. In the current study, the majority

of intubations (76%) in both cohorts occurred prior to the introduction of ketamine to the

prehospital pharmacy, further supporting the presence of temporal confounders that may have

contributed to the differences observed.

There is little discussion in the literature regarding the indications for these non-

psychiatric admissions, but one study refers to the need for “ongoing workup of altered

mental status”.3,6,15 In the current study, drug-related admissions comprised the majority of

admissions, especially in the ketamine cohort. For non-psychiatric admissions, the hospital

length of stay was usually brief, suggesting readily reversible etiologies.

While no study to date has evaluated the long-term psychiatric outcomes in patients

who receive ketamine for acute agitation, long-term outcomes have been documented in

schizophrenic volunteers who receive subanesthetic ketamine.12 In an observational study of

This article is protected by copyright. All rights reserved.

 schizophrenic volunteers who received multiple doses of subanesthetic ketamine over two

weeks, there were no differences in adverse events, PRN medication administration, or

Accepted Article
amount of discharge neuroleptic medication when compared to schizophrenic patients who

did not receive ketamine at multiple times points over a mean follow-up period of eight

months. Further studies are needed to evaluate the long-term psychiatric outcomes in patient

who receive high dose ketamine for acute agitation.

Limitations

The findings of this study must be applied in the context of its limitations. First, this is

a non-randomized, retrospective study conducted at two sites, both affiliates under the same

academic institution. Given the retrospective nature, we were unable to control the selected

sedative for any given patient. Therefore, we cannot establish causal relationships between

our outcomes and the received sedative. Additionally, the data used in this study were

collected through chart review, which can introduce additional biases, though we utilized a

structured data abstraction form and two trained abstractors who achieved consensus to

reduce some of these potential biases.17 Second, the observed differences in racial

distribution are significantly limited by missing data as race was categorized as ‘other or not

reported’ in over one third of visits. Third, the overall sample size was not large, though it

was larger than most prior studies. Nevertheless, some small differences between cohorts

may not have been statistically detectable due to sample size and the subgroup analysis of

schizophrenic patients should be considered exploratory due to the limited number of such

patients available. The confidence intervals reported throughout provide a useful measure of

the margin-of-error of each analysis and ranges of potential differences between groups that

are still consistent with the observed data. However, confidence intervals do not account for

any bias due to retrospective bias or confounders. Finally, we did not account for further

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 interventions taken during the ED course. It is possible that patients received additional

diagnostics or interventions that contributed to their ultimate disposition.

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Notably, intubated patients were excluded from both the primary and ED psychiatric

evaluation outcome, which may bias the results towards more mild presentations of severe

agitation. Intubated patients were excluded from this part of the analysis as psychiatric

outcomes could not be reliably evaluated in the ED in these patients. Potential confounders,

such as ICU delirium and other administered medications, would be difficult to control for in

evaluating psychiatric outcomes during or after intubation. Further, time to initial psychiatric

evaluation may be significantly delayed following intubation. It is unlikely that the observed

psychiatric outcomes following intubation would be related to the ketamine exposure, which

may have occurred days earlier.

Conclusion

In summary, administration of prehospital ketamine for severe agitation was not

associated with an increase in rate of psychiatric evaluation or psychiatric inpatient admission

when compared with benzodiazepine treatment, regardless of the patient’s psychiatric history.

However, patients who received a sedative for prehospital agitation were likely to require

inpatient hospitalization for non-psychiatric indications.

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 References
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1. Pajonk FG, Schmitt P, Biedler A, Richter JC, Meyer W, Luiz T, et al. Psychiatric

emergencies in prehospital emergency medical systems: a prospective comparison of two

urban settings. Gen Hosp Psychiatry. 2008;30:360-6.

2. Miner JR, Klein LR, Cole JB, Driver BE, Moore JC, Ho JD. The Characteristics and

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2018;72:361-370.

3. Cole JB, Moore JC, Nystrom PC, Orozco BS, Stellpflug SJ, Kornas RL, et al. A

prospective study of ketamine versus haloperidol for severe prehospital agitation. Clin Tox.

2016;854:556-62.

4. Hopper AB, Vilke GM, Castillo EM, Campillo A, Davie T, Wilson MP. Ketamine use for

acute agitation in the emergency department. J Emerg Men. 2015;48:712-9.

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to-sedate severe acute behavioral disturbance in the emergency department. Ann Emerg Med.

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6. Riddell J, Tran A, Bengiamin R, Hendey GW, Armenian P. Ketamine as a first-line

treatment for severely agitated emergency department patients. Am J Emerg Med.

2017;35:1000-4.

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 7. Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a

review. Psychopharmacology. 2006;188:408-24.

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8. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for

emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med.

2011;57:449-61.

9. Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, et al.

Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and

psychosis. Neuropsychopharmacology. 1999;20:106-18.

10. Frohlich J, Van Horn JD. Reviewing the ketamine model for schizophrenia. J.

Psychopharmacology. 2014;28:287-302.

11. Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine

stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13:9.

12. Lahti AC, Weiler MA, Michaelidis BT, Parwani A, Tamminga CA. Effects of ketamine

in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25:455-67.

13. Alder CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, et al. Comparison of

ketamine–induced thought disorder in health volunteer and thought disorder in schizophrenia.

Am J Psychiatry. 1999;156:1646-9.

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 14. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, et al. Ketamine-

induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free

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schizophrenics. Neuropsychopharmacology. 1997;17:141.

15. Burnett AM, Peterson BK, Stellpflug SJ, Engebretsen KM, Glasrud KJ, Marks J, et al.

The association between ketamine given for prehospital chemical restraint with intubation

and hospital admission. Am J Emerg Med. 2015;33:76-9.

16. Olives TD, Nystrom PC, Cole JB, Dodd KW, Ho JD. Intubation of profoundly agitated

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Figure Legends:

Figure 1: Patient Enrollment

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 Figure 1:
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 Table 1: Demographics of visits.

Visit Group*
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Benzodiazepine Ketamine
Variable (n=82) (n=59) P-value†
Age, years 32 (17 - 58) 33 (19 - 59) 0.81
Male sex 76 (92.7) 47 (79.7) 0.033
Race <0.001‡
Caucasian 45 (54.9) 29 (49.2)
Black or African American 0 (0.0) 10 (16.9)
Asian 5 (6.1) 1 (1.7)
Other/not reported 32 (39.0) 19 (32.2)
Site 0.59
Academic medical center 5 (6.1) 5 (8.5)
Level 1 trauma center 77 (93.9) 54 (91.5)
History of substance use 71 (86.6) 52 (88.1) 0.79
ED visits in the prior year 1 (0 - 30) 1 (0 - 21) 0.30
0 39 (47.6) 27 (45.8)
1-2 17 (20.7) 10 (16.9)
3-10 22 (26.8) 13 (22.0)
≥10 4 (4.9) 9 (15.3)
History of mental illness 0.32
Schizophrenia 10 (12.2) 6 (10.2)
Other 28 (34.1) 28 (47.5)
None 44 (53.7) 25 (42.4)

*Values are median (range) or no. (%);

†Generalized estimating equations based logistic regression (Wald test);
‡Fisher’s exact test was used due to the cell with 0 observations (Black or African American)

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 Table 2: Prehospital medications administered

Cohort
Benzodiazepine Ketamine
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Route† Route†
Medication IV IM IN N/A IV IM IN N/A
Ketamine (mg) - - - - 200 (50 - 300 (205 - - -
500) 700)
(no. of (n=6) (n=56)
encounters)

Midazolam (mg) 5 (2 - 30) 10 (5 - 5 (5 - 5 (1 - 20) 5 (1 - 15) 5 (5 - 10) - 10 (5 -

15) 25) 10)
(no. of (n=38) (n=16) (n=21) (n=23‡) (n=18) (n=5) (n=4‡)
encounters)

Diazepam (mg) 10 (2 - - - 12 (5 - - - - -
10) 30)
(no. of (n=3) (n=6)
encounters)

IV = intravenous; IM = intramuscular; IN = intranasal; UK = unknown

Values are median (range);
†Dosages by each medication and route were summarized separately; some patients may have received multiple
medications through multiple routes as part of the same encounter; the route of administration was unavailable
in some cases and summarized in the N/A column;
‡The dosage was not available for one patient in the benzodiazepine group and one patient in the ketamine
group.

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 Table 3: Comparison of outcomes between benzodiazepine and ketamine cohorts.

Cohort* Difference
Benzodiazepine Ketamine (Ketamine minus
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Benzodiazepine)
Variable (n=82) (n=59) Value† (95% CI) P-value
ED psychiatric evaluation 10 (15.4) 5 (8.6) -6.8% (-18.0, 4.7%) 0.23
(excludes intubated patients)
ED length of stay, minutes 394 (115 - 353 (133 - -40 (-152, 68) 0.56
2352) 2412)

Hospital admission 29 (35.4) 30 (50.8) 15.5% (-1.9, 32.7%) 0.082

Psychiatric hospital admission 2 (2.4) 4 (6.8) 4.3% (-2.4, 12.1%) 0.23
Non-psychiatric hospital admission 27 (32.9) 26 (44.1) 11.1% (-5.8, 28.4%) 0.21

Non-psychiatric hospital admission

diagnoses‡
Altered mental status 2 (7.4) 1 (3.8) -3.6% (-16.7, 8.7%) 0.56
Drug-related 4 (14.8) 16 (61.5) 46.7% (21.4, 69.3%) <0.001
Medical 4 (14.8) 5 (19.2) 4.4% (-16.9, 27.0%) 0.66
Trauma 0 (0.0) 3 (11.5) 11.5% (-1.0, 24.1%) 0.071
Intubated 17 (63.0) 1 (3.8) -59.1% (-79.3, -37.9%) <0.001

Hospital length of stay, days§ 2 (1 - 89) 2 (1 - 14) 0 (-0.5, 1.0) >0.99

*Values are no. (%) or median (range);

†The estimated difference in percentages (binary variables) or medians (continuous variables);
‡Of visits with an inpatient non-psychiatric admission; there were n=27 visits in the benzodiazepine group and
n=26 in the ketamine group;
§Of visits with an admission; there were n=28 visits in the benzodiazepine group and n=27 in the ketamine
group after excluding patients who were transferred to outside facilities after admission.

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 Table 4: Comparison of outcomes between benzodiazepine and ketamine cohorts in patients with schizophrenia.

Cohort* Difference
Benzodiazepine Ketamine (Ketamine minus
Accepted Article
Benzodiazepine)
Variable (n=10) (n=6) Value† (95% CI) P-
value
ED psychiatric evaluation 3 (50.0) 1 (16.7) -33.3% (-99.9, 0.55
(excludes intubated patients) 33.2%)
ED length of stay, minutes 406 (148 - 301 (167 - -104 (-898, 689) 0.64
2532) 1365)

Hospital admission 5 (50.0) 4 (66.7) 16.7% (-45.5, 0.63

78.8%)
Psychiatric hospital admission 1 (10.0) 1 (16.7) 6.7% (-35.1, >0.99
48.5%)
Non-psychiatric hospital 4 (40.0) 3 (50.0) 10.0% (-50.2, >0.99
admission 70.2%)

Non-psychiatric hospital admission

diagnoses‡
Altered mental status 0 (0.0) 0 (0.0)
Drug-related 0 (0.0) 2 (66.7)
Medical 0 (0.0) 1 (33.3)
Trauma 0 (0.0) 0 (0.0)
Intubated 4 (100.0) 0 (0.0)

Hospital length of stay, days§ 2 (1 - 27) 2 (1 - 2) 0 (-14, 14) >0.99

*Values are no. (%) or median (range);

†The estimated difference in percentages (binary variables) or medians (continuous variables);
‡Of visits with an inpatient non-psychiatric admission; there were n=4 visits in the benzodiazepine group and
n=3 in the ketamine group;
§Of visits with an admission; there were n=5 visits in the benzodiazepine group and n=3 in the ketamine group
after excluding patients who were transferred to outside facilities after admission.

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ccepted Articl
Appendix

Table 1: Demographics of visits.

No Mental Illness History of Mental Illness History of Schizophrenia

(N=69) (N=72) (N=16)

Visit Group Visit Group Visit Group

Standard Care Ketamine Standard Care Ketamine Standard Care Ketamine
Variable (n=44) (n=25) P-value (n=38) (n=34) P-value (n=10) (n=6) P-value
Age, years 27 (17 - 50) 31 (19 - 59) 0.52 36 (20 - 58) 35 (20 - 54) 0.44 33 (21 - 46) 31 (20 - 51) 0.66
Male sex 41 (93.2) 20 (80.0) 0.13 35 (92.1) 27 (79.4) 0.15 10 (100.0) 6 (100.0) >0.99
Race 0.15 0.001 0.42
Caucasian 21 (47.7) 17 (68.0) 24 (63.2) 12 (35.3) 4 (40.0) 3 (50.0)
Black or African American 0 (0.0) 1 (4.0) 0 (0.0) 9 (26.5) 0 (0.0) 1 (16.7)
Asian 4 (9.1) 1 (4.0) 1 (2.6) 0 (0.0) 0 (0.0)
Other/not reported 19 (43.2) 6 (24.0) 13 (34.2) 13 (38.2) 6 (60.0) 2 (33.3)
Site 0.450 0.94 -
Academic medical center 4 (9.1) 4 (16.0) 1 (2.6) 1 (2.9) 0 (0.0) 0 (0.0)
Level 1 trauma center 40 (90.9) 21 (84.0) 37 (97.4) 33 (97.1) 10 (100.0) 6 (100.0)
History of substance use 34 (77.3) 21 (84.0) 0.76 37 (97.4) 31 (91.2) 0.28 10 (100.0) 6 (100.0) >0.99
ED visits in the prior year 0 (0 - 11) 0 (0 - 8) 0.50 2 (0 - 30) 3 (0 - 21) 0.28 2 (0 - 11) 2 (0 - 14) 0.87
0 28 (63.6) 18 (72.0) 11 (28.9) 9 (26.5) 3 (30.0) 3 (50.0)
1-2 9 (20.5) 5 (20.0) 8 (21.1) 5 (14.7) 3 (30.0) 0 (0.0)
3-10 6 (13.6) 2 (8.0) 16 (42.1) 11 (32.4) 3 (30.0) 2 (33.3)
≥10 1 (2.3) 0 (0.0) 3 (7.9) 9 (26.5) 1 (10.0) 1 (16.7)

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ccepted Articl
Table 2A: Comparison of outcomes between standard care and ketamine cohorts (no mental illness, N=69).

Cohort* Difference
Standard Care Ketamine (Ketamine minus Standard)
Variable (n=44) (n=25) Value† (95% CI) P-value
ED psychiatric evaluation 1 (2.7) 0 (0.0) -2.7% (-10.6, 5.2%) >0.99
(excludes intubated patients)
ED length of stay, minutes 352 (124 - 1246) 335 (133 - 815) -18 (-164, 130) 0.50

Hospital admission 12 (27.3) 13 (52.0) 24.7% (-2.0, 51.5%) 0.067

Non-psychiatric hospital admission 12 (27.3) 13 (52.0) 24.7% (-2.0, 51.5%) 0.067
Psychiatric hospital admission 0 (0.0) 0 (0.0) 0.0% - >0.99

Hospital length of stay, days‡ 1 (1 - 89) 2 (1 - 3) 1 - 0.83

*Values are no. (%) or median (range);

†The estimated difference in percentages (binary variables) or medians (continuous variables);
‡Of visits with an admission; there were n=12 visits in the standard group and n=13 in the ketamine group.

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ccepted Articl
Table 2B: Comparison of outcomes between standard care and ketamine cohorts (history of mental illness, N=72).

Cohort* Difference
Standard Care Ketamine (Ketamine minus Standard)
Variable (n=38) (n=34) Value† (95% CI) P-value
ED psychiatric evaluation 9 (32.1) 5 (14.7) -17.4% (-37.9, 3.6%) 0.11
(excludes intubated patients)
ED length of stay, minutes 426 (115 - 2532) 389 (167 - 2412) -37 (-220, 204) 0.87

Hospital admission 17 (44.7) 17 (50.0) 5.3% (-18.9, 28.9%) 0.68

Non-psychiatric hospital admission 15 (39.5) 13 (38.2) -1.2% (-26.5, 23.2%) 0.90
Psychiatric hospital admission 2 (5.3) 4 (11.8) 6.5% (-5.4, 20.1%) 0.28

Hospital length of stay, days‡ 2 (1 - 27) 2 (1 - 14) 0 (-1, 1) >0.99

*Values are no. (%) or median (range);

†The estimated difference in percentages (binary variables) or medians (continuous variables);
‡Of visits with an admission; there were n=6 visits in the standard group and n=14 in the ketamine group after excluding patients who were transferred to
outside facilities after admission.

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ccepted Articl
Definitions

1. Inpatient psychiatry admission: Admission to a primary psychiatry service at our institution or another psychiatric institution.

2. ED psychiatric evaluation: Psychiatric evaluation by a psychiatry provider during the emergency department visit.

3. ED LOS: Time from ED arrival to nursing note documentation of discharge. This time includes ED psychiatric evaluation.

4. Hospital LOS: Time from ED arrival to nursing note documentation of discharge.

5. ED visits in prior year: Number of ED visits in prior calendar year from encounter date of service. Data abstracted from the Emergency
Department Information Exchange (EDIE).

6. History of substance use: Alcohol dependence 303.00-303.99, alcohol abuse 305.00-305.09, opioid dependence 304.00-304.01, opioid
abuse 305.50-305.59, cocaine dependence 304.20-304.29, cocaine abuse 305.60-305.69, amphetamine dependence 304.40-304.49, amphetamine
abuse 305.70-305.79, marijuana dependence 304.30-304.39, marijuana abuse 305.20-305.23, sedative abuse 305.4, poly-drug dependence
304.70-304.99, poly-drug abuse 305.90-305.99, and tobacco 305.1.

7. Prior psychiatric diagnoses: Attending psychiatrist diagnosis of schizophrenia, substance induced psychosis, bipolar disorder, depression,
PTSD, anxiety, or psychosis not otherwise specified in our system.

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