Parenteral Antipsychotic Choice and Its Association With Emergency Department Length of Stay for Acute Agitation Secondary to Alcohol Intoxication

Design

Retrospective, observational cohort study

N= 11,787

Objective

To determine the median emergency department (ED) length of stay for patients receiving a single parenteral dose of an antipsychotic for acute agitation secondary to alcohol intoxication in an urban Level I trauma center

Study Groups

Droperidol (n= 3,790)

Haloperidol (n= 1,449)

Olanzapine (n= 6,548)

Inclusion Criteria

ED patients, age ≥ 18 years, seen in the dedicated intoxication unit with a chief complaint of alcohol intoxication or altered mental status, ethanol blood concentration ≥ 80 mg/dL, received a single antipsychotic

Exclusion Criteria

Not explicitly stated

Methods

Patients were treated with a single dose of a parenteral antipsychotic (droperidol, haloperidol, or olanzapine) for acute agitation. An anticholinergic agent (e.g., diphenhydramine) could be coadministered with the antipsychotic. 

Duration

October 2011 to September 2016

Outcome Measures

Primary outcome: ED length of stay (LOS)

Baseline Characteristics

Droperidol (n= 3,790)

Haloperidol (n= 1,449)

Olanzapine (n = 6,548)

Median age (interquartile range), years

Male

Median dose, mg

Median breath alcohol level (range),

Admitted

Results

Endpoint

Droperidol (n= 3,790)

Haloperidol (n= 1,449)

Olanzapine (n= 6,548)

Median ED LOS, minutes (95% CI)

Cohort not receiving concomitant diphenhydramine, minutes (95% CI)

499 (493-506)

468 (454-478)

524 (515-537)

506 (488-551)

533 (528-539)

530 (524-536)

The length of stay for patients receiving droperidol was reported to be significantly short than both haloperidol and olanzapine. Additionally, the length of stay for patients not receiving concomitant anticholinergics was reported to be significantly shorter for droperidol compared to haloperidol or olanzapine.

Adverse Events

Common adverse events: Not disclosed

Serious adverse events: Not disclosed

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Droperidol, when given as monotherapy for sedation of acute agitation secondary to alcohol intoxication, was associated with significantly shorter ED LOS than either parenteral haloperidol or parenteral olanzapine. No difference in ED LOS was observed between haloperidol and olanzapine. 

InpharmD Researcher Critique

The inclusion criterion of an ethanol concentration ≥ 80 mg/dL via blood concentration or breath measurement was required for enrollment regardless of chief complaint to accurately ensure patients had acute alcohol intoxication. Only encounters where a single antipsychotic was administered were analyzed, which potentially limited confounders resulting from the sedating effects of multiple medications.

It was reported that droperidol resulted in a significantly shorter ED LOS compared to haloperidol or olanzapine, but only descriptive statistics were used in the data analysis; statistical comparisons were not made.

Rapid-Acting IM Ziprasidone in A Psychiatric Emergency Service: A Naturalistic Study

Design

Retrospective review

N= 119

Objective

To evaluate the effects of intramuscular (IM) ziprasidone on agitation and duration of restraints compared to IM conventional antipsychotics in a psychiatric emergency services (PES) setting

Study Groups

Ziprasidone (n= 110)

Conventional (n= 9)

Inclusion Criteria

Adult with psychiatric, alcohol-induced, or substance-induced agitation; received IM ziprasidone or conventional antipsychotic IM therapy

Exclusion Criteria

Known contraindications to ziprasidone

Methods

Patients were treated with a single dose of either IM ziprasidone 20 mg or IM conventional antipsychotic based on the clinician's choice. All patients were serially rated for agitation immediately before and every 15 minutes for 2 hours after medication was administered. For 2 hours after IM administration, no drug other than the study drugs was given; after 2 hours, patients were allowed to receive additional medications. Agitation was assessed using the Behavioral Activity Rating Scale (BARS; seven-point scale range from 1 [difficult or unable to rouse] to 7 [violent, requires restraints]). Data on restraint duration were restricted to cases in which an IM agent was administered within 5 min of initiation of restraints.

Duration

October 2002 to July 2003

Outcome Measures

BARS scores, time in restraints, time spent in the PES, tolerability

Baseline Characteristics

Ziprasidone (n= 110)

Conventional (n= 9)

Median age (range), years

Male

Agitation etiology

Psychosis

Alcohol-induced

Substance-induced

72 (65.5%)

10 (9.1%)

28 (25.5%)

-

-

-

Medication

Haloperidol with or without lorazepam

Chlorpromazine

Lorazepam

-

-

-

7 (77.8%)

1 (11.1%)

1 (11.1%)

BARS score for alcohol induced-agitation

6.9

-

The mean dose of haloperidol given was 6.5 mg.

The baseline mean BARS score for all patients treated with IM ziprasidone or conventional IM antipsychotics was 6.6.

Results

Endpoint

Ziprasidone (n= 110)

Conventional (n= 9)

p-value (vs. baseline)

Mean improvement in BARS score for alcohol-induced agitation

15 minutes

30 minutes

2 hours

5.3

4.1

2.1

-

-

-

< 0.05

< 0.01

< 0.01

Restraint time, min

Time spent in PES, hours

Improvements in BARS scores were seen in both groups at 15 minutes (p< 0.01, significant for ziprasidone at 15 minutes and thereafter). At 30 min, BARS scores in the ziprasidone- and conventional-treated patients had decreased to 4.2 in both groups (p< 0.01 for both at 30 min and thereafter); at 120 min, scores were 2.4 and 2.9, respectively.

Adverse Events

One patient receiving ziprasidone experienced dystonia. Of the electrocardiograms obtained in 19 patients in the IM ziprasidone group, none showed a prolonged QTc interval (> 460 ms).

Study Author Conclusions

IM ziprasidone appears effective for severe agitation, including agitation associated with alcohol, and may reduce time in restraints.

InpharmD Researcher Critique

A Prospective Study of Intramuscular Droperidol or Olanzapine for Acute Agitation in the Emergency Department: A Natural Experiment Owing to Drug Shortages

Design

Single-center, prospective, open-label, observational study

N= 1,257

Objective

To compare intramuscular droperidol and olanzapine for treating agitation due to acute alcohol or drug intoxication

Study Groups

Droperidol (n= 538)

Olanzapine (n= 719)

Inclusion Criteria

Received either intramuscular droperidol or olanzapine to treat acute agitation due to acute alcohol or drug intoxication

Exclusion Criteria

Received other intramuscular medications (e.g., lorazepam, midazolam, haloperidol, ziprasidone) or intravenous droperidol or olanzapine

Methods

On arrival to the emergency department (ED), the treating physician determined the medication and dose. Data collection was performed beginning when patients received medication for agitation, continuing for 120 minutes after medication administration. The Altered Mental Status Scale (AMSS; ordinal scale from -4 [unresponsive] to 4 [most agitated]) score was used to evaluate sedation after medication administration.

Duration

July 2019 to March 2020

Data collection: 120 minutes after medication administration

Outcome Measures

Primary outcome: time to adequate sedation (elapsed time between administration of medication and reaching an AMSS score of zero or lower)

Secondary outcomes: need for additional (rescue) medications, total time in the ED, adverse events

Baseline Characteristics

Droperidol (n= 538)

Olanzapine (n= 719)

Median age (IQR), years

Male

Race/ethnicity

White

Black

Native American or Alaska Native

Hispanic

Asian

209 (39%)

202 (38%)

77 (14%)

32 (6%)

7 (1%)

287 (40%)

283 (33%)

114 (16%)

23 (3%)

10 (1%)

Alcohol concentration > 0

Median dose (IQR), mg

Presumed cause of agitation^†

Alcohol intoxication

Illicit substance

Psychiatric illness

Medical

461 (86%)

79 (15%)

67 (12%)

9 (2%)

625 (87%)

96 (13%)

93 (13%)

6 (1%)

IQR, interquartile range

*There were 29 patients with no measured alcohol level (11 in the droperidol group and 18 in the olanzapine group) who were assumed to have a value of zero. Apart from 13 blood measurements, all alcohol concentrations were obtained with a breath alcohol device.

†Patients could have more than one cause for agitation.

Results

Endpoint

Droperidol (n= 538)

Olanzapine (n= 719)

Median time to adequate sedation (IQR), min*

16 (10 to 30)

17.5 (10 to 31)

Rescue medications

Entire encounter

Before adequate sedation achieved

After adequate sedation achieved

Median time until first rescue medication given (IQR), min

89 (17%)

44 (8%)

45 (8%)

36 (20 to 60)

173 (24%)

98 (14%)

75 (10%)

37 (22 to 64)

Median total time in ED (IQR), min

444 (349 to 543)

500 (391 to 631)

Adverse events

Extrapyramidal events

Hypotension

Hypoxemia

Oxygen supplementation

Intubation

6 (1%)

13 (2%)

20 (4%)

6 (1%)

4 (1%)

1 (< 1%)

19 (3%)

42 (6%)

30 (4%)

7 (1%)

*There were 35 patients who did not achieve adequate sedation within 120 minutes (12 with droperidol and 23 with olanzapine). There were 4 patients with an unknown time to sedation (2 in the droperidol group and 2 in the olanzapine group).

In a sensitivity analysis for the primary outcome which excluded 125 patients (115 droperidol; 10 olanzapine) who had diphenhydramine coadministered with the initial sedative, the estimated between-group difference for time to adequate sedation was -0.6 minutes (95% confidence interval [CI] -2.1 to 0.7 minutes). The hazard ratio for adequate sedation for droperidol compared with olanzapine was 1.11 (95% CI 0.98 to 1.26).

Adverse Events

See Results section

Study Author Conclusions

We found no difference in time to adequate sedation between intramuscular droperidol and olanzapine.

InpharmD Researcher Critique

This was an open-label, observational study, which may have allowed for certain biases due to physician and patient knowledge of treatment. Additionally, this trial was not randomized, and it was reported that drug shortages made either olanzapine (July to September 2019) or droperidol (November 2019 to March 2020) unavailable, making it uncertain whether the patients who were cared for when only droperidol was available were similar to patients cared for when only olanzapine was available; selection bias may have occurred when both drugs were available.

A Retrospective Analysis of Intramuscular Haloperidol and Intramuscular Olanzapine in the Treatment of Agitation in Drug- and Alcohol-Using Patients

Design

Retrospective chart review 

N= 105

Objective

To evaluate drug- and alcohol-positive (D/A [+]) and drug- and alcohol-negative (D/A[−]) emergency room patients who were treated with intramuscular (IM) haloperidol or IM olanzapine

Study Groups

Drug and/or alcohol positive (n= 76)

Drug and/or alcohol negative (n= 29)

Inclusion Criteria

Agitated emergency department patients; received either IM haloperidol or IM olanzapine

Exclusion Criteria

Lack of urine drug screens (UDS)

Methods

Data were extracted retrospectively from electronic healthcare records at a single medical center. Patients were D/A(+) if they had a UDS that contained amphetamines, cocaine, alcohol, or marijuana, or had notes indicating the presence of alcohol. Patients without documented alcohol or a recorded zero level for alcohol and a negative UDS result were coded D/A(−). Efficacy of the initial intervention was defined as the amount of additional medication used for agitation within 3 h of initial intervention. 

Duration

From 2003 to 2006

Outcome Measures

Baseline Characteristics

Not fully disclosed: Among the 147 initially screened patients, 52% were D/A(+); 26% alcohol(+), 20% amphetamine(+), 19% marijuana(+), 7% cocaine(+) and 15% were positive for more than one of these substances.

Results

Endpoint

D/A(−) (n= 28)

D/A(+) (n= 76)

Alcohol(+) (n= 38)

Haloperidol alone

Haloperidol+any benzodiazepine

Olanzapine+any benzodiazepine

The most common doses in our sample were haloperidol 5 mg and olanzapine 10 mg; lorazepam 2 mg was the most frequently prescribed benzodiazepine.

AMI, additional medication intervention

Adverse Events

Study Author Conclusions

In the D/A(+) group, consistent with earlier studies, the IM haloperidol−benzodiazepine combination and IM olanzapine were more effective than IM haloperidol alone. In reporting on the use of the IM olanzapine+benzodiazepine combination, the authors note published safety concerns with this combination, especially, perhaps, in certain alcohol(+) individuals. 

InpharmD Researcher Critique

Given the retrospective nature of the study, there's a lack of standardized efficacy or safety assessments, such as vital signs, and a lack of documentation of the etiology of agitation or level of intoxication. The findings are descriptive and need to be further confirmed in prospective randomized trials. 

A comparison of the safety of olanzapine and haloperidol in combination with benzodiazepines in emergency department patients with acute agitation

Design

Retrospective chart review

N= 96

Objective

Study Groups

Haloperidol (n= 71)

Haloperidol + benzodiazepines (n= 39)

Haloperidol alone (n= 32)

Olanzapine (n= 25)

Olanzapine + benzodiazepines (n= 10)

Olanzapine alone (n= 15)

Inclusion Criteria

Received parenteral haloperidol, documentation in chart of vital signs and oxygen saturation monitoring before medication administration and within 4 h afterward

Exclusion Criteria

Methods

Duration

Patients received haloperidol between January 1, 2004, and December 31, 2006

Outcome Measures

Lowest oxygen saturation, incidence of hypotension, additional medications

Baseline Characteristics

Haloperidol + benzodiazepines (n= 39)

Haloperidol alone (n= 32)

Age, years

Male, n

Antipsychotics received, mg

Benzodiazepines received, mg

Ethanol level, mg/dL

Oxygen saturation before meds

Blood pressure before meds, mm Hg

Results

Endpoint

Haloperidol + benzodiazepines (n= 39)

Haloperidol alone (n= 32)

Olanzapine + benzodiazepines (n= 10)

Olanzapine alone (n= 15)

Lowest oxygen saturation after meds

Blood pressure after meds

Required additional medications

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

This retrospective review included a small population of intoxicated patients. The accuracy of the data provided in this study is limited by accuracy of the initial documentation on patient charts. Agitated patients were not prospectively rated on a standardized scale, and reduction of agitation was simply assessed based on additional medication intervention.