Emergency Medicine

Prospective study of haloperidol plus lorazepam versus droperidol plus midazolam for the treatment of acute agitation in the emergency department

a b s t r a c t

Study objectives: The objective of this study was to compare the combination of intramuscular droperidol/ midazolam to haloperidol/lorazepam regarding time to sedation in patients with acute undifferentiated agitation in the emergency department (ED).

Methods: This was a prospective, unblinded observational study in the ED of a university teaching hospital. Subjects with acute undifferentiated agitation refractory to verbal de-escalation were assigned to receive a combination of either haloperidol 5 mg/lorazepam 2 mg or droperidol 5 mg/midazolam 5 mg IM. The primary outcome was the proportion of patients adequately sedated at 10 min defined as ED Sedation Assessment Tool (SAT) score of 0 or less. Secondary outcomes included change in ED SAT score at 5, 15, 30, and 60 min, the need for oxygen supplementation, and the need for airway intervention.

Results: A total of 86 patients were enrolled in the study, with 43 patients receiving droperidol/midazolam and 43 patients receiving haloperidol/lorazepam. Ten minutes after receiving medication, 51.2% of patients in the droperidol/midazolam group were adequately sedated compared to 7% of patients in the haloperidol/lorazepam group (OR: 14; 95% CI: 3.7, 52.1). Median time to adequate sedation was 10 min for the droperidol/midazolam group and 30 min for the haloperidol/lorazepam group. Eleven patients (25.6%) in the droperidol/midazolam group received oxygen supplementation compared to four patients (9.3%) in the haloperidol/lorazepam group. No study patients experienced extrapyramidal symptoms or required endotracheal intubation.

Conclusion: Intramuscular droperidol/midazolam was superior to intramuscular haloperidol/lorazepam in achieving adequate sedation at 10 min. Patients in the droperidol/midazolam arm may be more likely to receive oxygen supplementation than those in the haloperidol/lorazepam arm.

(C) 2022

  1. Introduction

In the emergency department (ED), patients with acute agitation present significant Safety concerns not only for themselves but also hos- pital staff. Acute agitation is prevalent in 2.6% of ED patients, and can be associated with a variety of diagnoses including substance use, alcohol intoxication, Mental illness, or a combination [1]. In situations of failed verbal de-escalation, timely sedation with medications represents the safest measure to decrease the risk of harm for patients and providers. Optimal outcomes include timely and adequate sedation to facilitate

* Corresponding author at: UofL Health-University of Louisville Hospital, Department of Emergency Medicine, 530 S Jackson Street, Louisville, KY 40202, USA.

E-mail address: [email protected] (P. Thiemann).

medical evaluation and prevent risk of acidosis, rhabdomyolysis, and restraint injuries while avoiding adverse medication events such as ox- ygen desaturation, hypotension, and extrapyramidal events [2].

The standard of care for acutely agitated patients usually involves a benzodiazepine, an antipsychotic, or both [2]. With a clear cause of the agitation, it is reasonable to select the agent that will best target the underlying diagnosis [2]. However, in cases of unknown etiology, a combination of an antipsychotic and a benzodiazepine usually provides effective sedation. Medication combinations in a single intramuscular (IM) injection limits risk of harm to patient and staff. Common IM ben- zodiazepines include lorazepam and midazolam, with onsets of action of 30 min and 15 min, respectively [3,4]. Of IM antipsychotics, haloper- idol has an onset of 20 min and droperidol 5 min [5,6]. The faster onsets of action for midazolam and droperidol could provide significant bene- fits in cases requiring security personnel and physical restraint.

https://doi.org/10.1016/j.ajem.2022.02.042

0735-6757/(C) 2022

Combinations of these medications are compatible in the same syringe for up to 4 h [7]. Historically, the combination of haloperidol plus loraz- epam was widely utilized as a standard of care in the ED [8]. However, due to more recent safety data, commercial availability, and favorable pharmacokinetic profile, IM midazolam and droperidol have gained popularity [9-11].

Due to the lack of consensus on Optimal treatment in these patients, the study institution implemented a quality improvement protocol to standardize treatment for patients with undifferentiated acute agitation by alternating medication combinations of either droperidol/midazo- lam or haloperidol/lorazepam each month. The purpose of this study was to prospectively evaluate a departmental protocol and compare time to adequate sedation in patients who received either droperidol plus midazolam IM or haloperidol plus lorazepam IM.

  1. Methods
    1. Study design

This study enrolled patients from November 2020 through June 2021 at UofL Health – University of Louisville Hospital, a Tertiary medical center in the United States averaging 60,000 emergency department pa- tient visits annually. Data collection was performed by the investigators who received no funding and had no conflicts of interest regarding this subject. Initially, this study was presented to the institutional review board (IRB) as a prospective, unblinded, randomized controlled trial. It was determined by the IRB that this design would not meet FDA criteria of exemption of informed consent (21 CFR 50.24). Since both medica- tion combinations were considered standard of care at the study institu- tion, a departmental quality improvement protocol was implemented to standardize combination medications in emergent situations. After collaboration with the IRB, this study was approved as an observational study, designed to promptly benefit a process, program or system and may or may not benefit patients. By comparing different established sets of standards, this prospective design was deemed Non-Human Sub- jects Research (NHSR) and posed minimal risk to patients (45 CFR 46.116).

    1. Selection of participants

Patients eligible for inclusion were at least 18 years old with acute undifferentiated agitation, refractory to verbal de-escalation, and who required security personnel activation. Patients were uncooperative with all offered care and the emergency physician deemed patients eligible for IM medication management. Patients were excluded if pregnant, incarcerated, had known acute alcohol withdrawal, had intra- venous (IV) or intraosseous (IO) access at enrollment, received diphen- hydramine concomitantly with study medications, had known allergies to any study medication, or were hemodynamically unstable (defined as a SBP <90 mmHg, HR <50 bpm, or at the discretion of the EM physician).

    1. Interventions and measurements

Similar to previous acute agitation studies, a departmental protocol was created in effort to standardize practice in the ED [12]. Patients re- ceived either a combination of haloperidol 5 mg plus lorazepam 2 mg or droperidol 5 mg plus midazolam 5 mg administered intramuscularly in a single syringe. Doses were selected based on previous comparison studies and data supporting dose equivalence between the two antipsy- chotics and the two benzodiazepines [13-15]. The combination of med- ications alternated monthly based on the departmental protocol. Study personnel educated physicians on the departmental protocol and posted monthly assignments on computer workstations. After the EM physician and/or EM pharmacist determined a patient was eligible for the protocol, a pharmacist or nurse would prepare the month’s assigned

medication combination for IM administration. Patients, physicians, and investigators were not blinded to the study drugs administered. Once study medications were administered, nurses assessed the sedation level utilizing the Sedation Assessment Tool (SAT), monitored oxygen saturation, and recorded occurrence of extrapyramidal symptoms (agitation, restlessness, involuntary muscle contractions, or repetitive movements). The SAT score was previously utilized at the study institu- tion to grade agitation severity and is a validated scoring tool for acutely agitated patients [16,17]. Demographic information and requirement of additional sedation medications were collected via retrospective chart review.

    1. Outcomes

The primary outcome was defined as the proportion of patients with adequate sedation at 10 min. Adequate sedation was defined as a SAT score of 0 or less (Table 1). Secondary outcomes included adequate se- dation within 5, 15, 30 and 60 min, change in ED SAT scores from baseline at all time periods, administration of additional rescue seda- tion, requirement of oxygen supplementation or airway intervention, and occurrence of extrapyramidal symptoms.

    1. Statistical analysis

Statistical power was calculated based on a review of literature uti- lizing combination medication sedation. For the primary outcome of proportion of patients sedated at 10 min, we anticipated a difference rate of 30%. To achieve 80% power with this anticipated difference, the study required enrollment of 42 patients in each group. Time to sedation was analyzed with survival analysis using Cox’s proportional hazards model to calculate Hazard ratios between the two treatments, and Kaplan-Meier plots were presented to visualize difference between groups. For all other outcomes, chi-square or Fisher’s exact tests were utilized. Statistical findings were reported with 95% confidence intervals and set statistical significance at p < 0.05.

  1. Results

A total of 86 patients were enrolled in the study with 43 individuals assigned to droperidol 5 mg plus midazolam 5 mg and 43 assigned to haloperidol 5 mg plus lorazepam 2 mg (Fig. 1). Patient baseline charac- teristics are shown in Table 2.

Ten minutes after medication administration, significantly more patients in the droperidol/midazolam group (51.2%) were adequately sedated (scoring <=0 on SAT) compared to the haloperidol/lorazepam group (7%), OR: 14 (95% CI: 3.7, 52.1). There were statistically significant differences in each of the first four time periods (5, 10, 15, 30 min) when comparing proportions of patients adequately sedated (Table 3).

At each time point after medication, significantly more patients in the droperidol/midazolam group were adequately sedated compared to the haloperidol/lorazepam group (HR: 2.92 (95% CI: 1.82, 4.68).

Median time to adequate sedation was 10 min (95% CI: 7.6, 12.4) for

the droperidol/midazolam group and 30 min (95% CI: 24.9, 35.1) for the haloperidol/lorazepam group. Fig. 2 provides the Kaplan-Meier

Table 1

Sedation assessment tool (SAT) score.

Score Responsiveness Speech

+3

Combative, violent, out of control

Continual loud outbursts

+2

Very anxious and agitated

Loud outbursts

+1

Anxious/restless

Normal/talkative

0

Awake and calm/cooperative

Speaks normally

-1

Asleep, rouses if name is called

Slurring/prominent slowing

-2

Responds to physical stimulation

Few recognized words

-3

No response to stimulation

Nil

Image of Fig. 1

Fig. 1. Patient enrollment and analysis.

curve comparing the proportion of patients sedated at each time point. Supplemental Figure 1 shows changes in SAT scores over time.

Eleven individuals (25.6%) in the droperidol/midazolam group required oxygen supplementation compared to four (9.3%) in the halo- peridol/lorazepam group (p = 0.047). Seven individuals in the haloper- idol/lorazepam group required Rescue medication (benzodiazepine, antipsychotic, or ketamine) for sedation within 60 min compared to no patients in the droperidol/midazolam group (p = 0.006). One pa- tient in the haloperidol/lorazepam group required nasopharyngeal air- way placement, no patients in either group required endotracheal intubation. Table 4 details occurences of secondary Safety outcomes.

time to disposition was similar among groups; the droperidol/mid- azolam median time was 6.7 h [IQR = 5.6, 8.2] compared to the median

Table 2

Baseline patient characteristics.

time of 7 h [IQR = 5.3, 9] for haloperidol/lorazepam group. Disposition rates are provided in Table 5.

  1. Discussion

This prospective, observational study is the first to directly compare combination medication administration in acute undifferentiated agitation. Significantly more acutely agitated patients achieved ade- quate sedation at 5, 10, 15, and 30 min with droperidol/midazolam compared to haloperidol/lorazepam. The median time to adequate se- dation in those receiving droperidol/midazolam was 10 min, 20 min faster than patients receiving haloperidol/lorazepam.

There are many studies evaluating monotherapy medications for acute agitation. One study compared IM midazolam, olanzapine, ziprasidone, and haloperidol and found midazolam resulted in a greater proportion of patients sedated compared to all other study arms [18]. A retrospective review of almost 16,000 patients compared IM droperidol,

Droperidol 5 mg + Midazolam 5 mg

(n = 43)

Haloperidol 5 mg +

Lorazepam 2 mg

(n = 43)

olanzapine, and haloperidol and found that haloperidol was inferior to droperidol regarding the need for additional rescue sedation [19]. Addi- tionally, a prospective, randomized controlled trial comparing

Age, Mean [SD] 34.1 [12.9] 38.3 [9.4]

Male, N (%) 28 (65.1) 24 (55.8)

Race

Black 17 (39.5) 18 (41.9)

White 22 (51.2) 23 (53.5)

Other or Unknown 4 (9.3) 2 (4.7)

Height (cm), Mean [SD] 172.6 [8.2] 172.2 [10.5]

Body Mass Index, Mean [SD] 26.6 [6.8] 25.8 [5.3] Baseline ED SAT

Mean [SD] 2.93 [0.26] 2.83 [0.37]

Median [IQR] 3 [3-3] 3 [3-3]

droperidol, ziprasidone 10 mg, ziprasidone 20 mg, and lorazepam con- cluded that droperidol resulted in significantly more patients ade- quately sedated at 15 min and fewer adverse safety events [20]. Ketamine administered intramuscularly has also been investigated, al- though optimal dosing and safety profile compared to other agents re- main controversial [21-25]. A consensus statement from the American Association for Emergency Psychiatry could not make a recommenda- tion on the optimal combination of benzodiazepines and antipsychotics, citing insufficient evidence for undifferentiated agitation [2]. The state- ment recommends the utilizing a benzodiazepine in patients who do not display psychosis or an antipsychotic in patients with psychotic fea- tures [2]. At patient presentation, the underlying cause of agitation is

Table 3

Proportion of patients sedated at each time point based on medication.

Outcome Droperidol 5 mg + Midazolam 5 mg

Medical History

Known Kidney Disease

1 (2.3)

3 (7)

Known Liver Disease

1 (2.3)

0 (0)

bipolar disorder

5 (11.6)

8 (18.6)

Schizophrenia

4 (9.3)

6 (14)

Anxiety/Depression

8 (18.6)

7 (16.3)

Psych (Other)

6 (14)

3 (7)

Substance Abuse

27 (62.8)

22 (51.2)

Alcohol Abuse

11 (25.6)

7 (16.3)

Hepatitis C

8 (18.6)

6 (14)

HIV

Suspected Etiology of Agitation

2 (4.7)

1 (2.3)

(n = 43)

Haloperidol 5 mg +

Lorazepam 2 mg

(n = 43)

Alcohol Intoxication

13 (30.2)

11 (25.6)

Proportion sedated, N (%)

drug intoxication

23 (53.5)

20 (46.5)

5 min

8 (18.6)

1 (2.3)

Drug Withdrawal

0 (0)

1 (2.3)

10 min

22 (51.2)

3 (7)

Medical

0 (0)

2 (4.7)

15 min?

34 (81)

10 (24.4)

Multifactorial

5 (11.6)

6 (13.9)

30 min

41 (95.3)

28 (65.1)

Psychiatric Emergency

2 (4.7)

3 (7.0)

60 min

41 (95.3)

38 (88.4)

ED SAT = Emergency Department Sedation Assessment Tool.

* Missing data on three individuals at the 15 min interval.

Image of Fig. 2

Fig. 2. Kaplan-Meier curve comparing patient sedation rates over time. The primary outcome of the study was adequate sedation at 10 min.

often unknown, which is why a combination of an antipsychotic and benzodiazepine have been increasingly utilized in the ED.

To date, very few studies have evaluated combination therapies for acute agitation. A prospective study found equal effectiveness for halo- peridol and lorazepam monotherapy, but the combination had lower behavior scores at 1 h compared to either monotherapy [8]. Nobay et al. compared midazolam, haloperidol, and lorazepam monotherapies and found no difference between the haloperidol and lorazepam arms [13]. There are a lack of studies supporting the traditional combination of haloperidol plus lorazepam. Chan et al. found IV droperidol to be ef- fective in combination with midazolam to decrease time to adequate se- dation and reduce the number of patients who require additional sedation from 25% (midazolam monotherapy) to 12.5% (droperidol plus midazolam) [26]. Additionally, the dual action of droperidol plus midazolam given intravenously resulted in more patients sedated at 10 min compared to either agent alone [27]. Investigators found the IV

combination to provide significantly more rapid sedation than either monotherapy [27]. However, obtaining IV access can be difficult and dangerous in the acutely agitated patient. Compared to IM midazolam given as a single agent, the DORM I study found IM midazolam plus droperidol required fewer additional doses of sedation within 60 min. This study did not find a statistically significant difference in the time of security activation between monotherapy and combinations arms, but also did not assess time to adequate sedation at clinically meaning- ful time intervals [28]. One study compared IV midazolam to combina- tions of either IV droperidol or olanzapine as an adjunct to midazolam. Both arms showed improved times to sedation compared to midazolam monotherapy, but overall Combination therapy had similar times to se- dation [26]. The studies evaluating adequate sedation at early time in- tervals (5-15 min after medication administration) continue to show benefit of combination therapy over monotherapy. While the studies discussed have compared combination therapy to monotherapy agents,

Table 4

Description of patients who experienced adverse events and/or requirement of rescue sedation.

Study Drug

Adverse Event

Rescue Sedation

Blood Alcohol Level

Disposition

Oxygen Requirement

Drug + Dose

Time? (min)

DRO + MDZ

Nasal cannula

N/A

Discharge home

DRO + MDZ

Nasal cannula

N/A

Discharge home

DRO + MDZ

Nasal cannula

Negative

Inpatient admission (rhabdomyolysis)

DRO + MDZ

Nasal cannula

Negative

Discharge home

DRO + MDZ

Nasal cannula

0.234

Discharge home

DRO + MDZ

Nasal cannula

N/A

Discharge home

DRO + MDZ

Nasal cannula

N/A

Discharge home

DRO + MDZ

Nasal cannula

N/A

Discharge home

DRO + MDZ

Nasal cannula

N/A

Admit to psychiatry

DRO + MDZ

Nasal cannula

0.244

Discharge home

DRO + MDZ

Nasal cannula

N/A

Discharge home

HAL + LZP

Nasal cannula

Negative

Discharge home

HAL + LZP

Nasal cannula

N/A

Discharge home

HAL + LZP

Nasal cannula

N/A

Discharge home

HAL + LZP

nasopharyngeal airway with bag-valve mask

Ketamine 300 mg IM

53

0.232

Discharge home

HAL + LZP

DRO 5 mg IM

18

N/A

Discharge home

HAL + LZP

MDZ 4 mg IM

39

Negative

Inpatient admission (cellulitis)

HAL + LZP

DRO 5 mg + MDZ 5 mg IM

15

Negative

Discharge

HAL + LZP

MDZ 2 mg IM

21

N/A

Discharge

HAL + LZP

LZP 2 mg IM

29

N/A

Discharge AMA

HAL + LZP

DRO 5 mg IM

17

N/A

Discharge

AMA: against medical advice. DRO: droperidol. MDZ: midazolam. HAL: haloperidol. LZP: lorazepam.

* Time from study medication administration to rescue sedation administration.

Table 5

Dispositions.

Droperidol 5 mg + Midazolam 5 mg

Haloperidol 5 mg + Lorazepam 2 mg

(n = 43)

(n = 43)

Discharge

33 (76.7)

31 (72.1)

Admit to Inpatient

4 (9.3)

8 (18.6)

Admit to Psychiatry

6 (14)

4 (9.3)

this study aimed to directly compare combination agents for acute un- differentiated agitation.

In the setting of acute agitation requiring security assistance, the difference in time to sedation in this study has many potential effects on patient safety regarding rates of restraint-injuries, hyperthermia, ac- idosis, and rhabdomyolysis as well as staff safety. Baseline characteris- tics including sex, age, and BMI were similar between the two arms. Longer drug half-lives have been associated with longer ED length of stay [29]. Since the half-lives of haloperidol/lorazepam (20 h and 15.5 h, respectively) are significantly longer than droperidol/midazolam (2.3 h and 4.2 h, respectively), one could anticipate increased ED LOS when utilizing haloperidol/lorazepam for acute agitation management [3-6]. However, groups in this study had no difference in LOS (7.0 h hal- operidol/lorazepam vs 6.7 h droperidol/midazolam). Additionally, more patients in the haloperidol/lorazepam arm experienced treatment fail- ure and required additional rescue sedation. Despite similar length of stay between the two arms, patients receiving haloperidol/lorazepam may be more resource intensive during their stay than those receiving droperidol/midazolam.

More patients in the droperidol/midazolam arm required oxygen supplementation through nasal cannula compared to the haloperidol/ lorazepam arm. One patient in the haloperidol/lorazepam group re- quired an airway intervention (nasopharyngeal airway), likely related to the administration of additional rescue sedation with IM ketamine. No subjects in either group had extrapyramidal symptoms, arrhyth- mias, or respiratory compromise requiring intubation.

    1. Limitations

There are several limitations in this prospective, observational study. Though patient characteristics were similar in both groups, patients were not truly randomized. Providers and patients were unblinded to study medication selection, which could introduce subjectivity in the recorded ED SAT score. Study authors, both pharmacists and physicians, were often working in the emergency department during patient en- rollment. While study investigators facilitated patient enrollment in ac- cordance with the departmental protocol, only nurses caring for the patient were performing the SAT scoring. The department staff utilized SAT scores prior to this study, and nursing familiarity with the score helps to mitigate potential bias in the evaluation of these patients. The requirement of oxygen supplementation was also subject to the discre- tion of the nurse taking care of the patient. While more patients achieved a SAT score of -2 in the droperidol/midazolam arm, many pa- tients were placed on nasal cannula due to the depth of sedation and not due to decreased oxygen saturations. Due to lack of documentation of oxygen saturations, it is difficult to discern if the difference in oxygen re- quirements was a result of patient hypoxemia or nurse discretion. Over- all, only 1 patient required the bag-valve mask ventilation, likely due to ketamine rescue sedation, and the remaining patients were on nasal cannula at low flow rates.

  1. Conclusion

Intramuscular droperidol/midazolam was superior to intramuscular haloperidol/lorazepam in achieving adequate sedation at all measured timepoints in this study. Patients in the droperidol/midazolam arm

may be more likely to receive oxygen supplementation than those in the haloperidol/lorazepam arm. However, the shorter onset of action for droperidol/midazolam and less need for rescue medications seem to indicate superiority for safe management of Emergency Department acutely agitated patients.

Financial support

None.

Credit authorship contribution statement

Pauline Thiemann: Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. David Roy: Writing – review & editing, Supervision, Methodology, Investigation, Conceptual- ization. Martin Huecker: Writing – review & editing, Supervision, Methodology, Investigation. Joshua Senn: Writing – review & editing, Methodology, Conceptualization. Jessica Javed: Writing – original draft, Methodology, Investigation. Alyssa Thomas: Project administra- tion, Conceptualization. Jacob Shreffler: Writing – review & editing, Visualization, Validation, Formal analysis, Conceptualization. Isaac Shaw: Writing – review & editing, Supervision, Methodology, Investiga- tion, Conceptualization.

Declaration of Competing Interest

No conflicts of interest to report.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2022.02.042.

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