Background: Acutely agitated and aggressive patients have become an unfortunate commonality in emergency departments throughout the world.  They are often the most difficult patient encounters during a shift. Initially, when these patients’ present, medical providers are trying to figure out the underlying etiology including organic, psychiatric, or drug related illness.  Coaxing agitated patients out of an aggressive and often altered state with verbal and environmental modification is often fruitless.  When verbal de-escalation does not work, the next options are physical and/or chemical sedation.
Finding an ideal combination of medications for chemical sedation is critically important and the most ideal medication(s) need to work quickly and have a good safety profile. Over the last few years there is increasing literature evaluating different agents of chemical sedation, looking mainly at antipyschotic agents and benzodiazepines, in isolation and combination.

What Article are we Reviewing:

• Kroczak S et al. Chemical Agents for the Sedation of Agitated Patient in the ED: A Systematic Review. Am Journal of Emerg Med 2016. (34); 2426-2431. PMID: 27707527

What Clinical Questions Were Trying to Be Answered:

• Are antipsychotics, benzodiazepines or a combination of the 2 agents more effective at:

1. Sedating patients within 15-20 minutes
2. Causing less adverse events
3. Requiring repeat sedation

What Type of Study is This:

• Systematic review and Meta-analysis of studies comparing ≥2 chemical agents for sedation of agitated patients in the ED
• Only studies comparing 2 or more drugs were included in this search

Intervention: Single dose of antipsychotic agent (Droperidol, Haloperidol, Olanzapine, or Ziprasidone), benzodiazepine (Lorazepam or Midazolam) or a combination of an antipyschotic agent + benzodiazepine (Lorazepam and Haloperidol, Droperidol and Midazolam, Olanzapine and Midazolam)

Control: No Control Group

Outcomes:

• Proportion of patients sedated at 15-20 minutes
• Proportion of patients experiencing adverse effects
• Proportion of patients requiring repeat sedation

Excluded:

• Patients aged < 16 years
• Studies prior to 1995
• Review articles
• Studies not taking place in an ED setting
• Studies with <10 cases
• Studies not comparing a minimum of 2 chemical agents
• Studies not reporting on safety or effectiveness of medications

Primary Results:

• Search resulted in 1055 possible articles
• 7 studies (1135 patients) ultimately included

Proportion Sedated at 15-20 Minutes:

• RR = Risk Ratio
• No difference between antipyschotics and benzodiazepines individually [RR=0.88 CI (0.7-1.1) p = .25]
• Combination therapy (Antipsychotic + Benzodiazepine) outperformed benzodiazepines alone [RR=1.31 CI (1.15-1.49) p= <.0001]

Repeat Sedation

• Antipsychotics needed less repeat sedation than benzodiazepines [RR=0.49 CI (0.36-0.67) p= .<.0001]
• Combination therapy required less repeat sedation than benzodiazepines [RR=0.64 CI (0.48-85) p= .002]

Adverse Events:

• Antipsychotics had slightly less adverse events than benzodiazepines [RR=0.85 CI (0.59-1.23) p= .38]
  • Respiratory adverse events were the most common in the benzodiazepine alone group
• Combination therapy had less adverse events than benzodiazepines alone [RR = 0.63 CI (0.42 – 0.97); p = 0.03]
• There was no difference in adverse events between antipsychotics and combination therapy [RR=1.12 CI (0.61-2.04) p= .71]

Strengths:

• Used PRISMA guidelines
• Used multiple databases for their search and included a gray literature search as well as including studies in all languages
• Searched the most recent literature from 1995 onwards to try and reflect current clinical practices
• Divided adverse events into respiratory (affecting airway, ventilation, or oxygenation) events, cardiovascular (affecting cardiac rhythm or blood pressure) events, and “other” (seizures or extrapyramidal symptoms) events
• Used the Jadad Score to assess the quality of trials included

Limitations:

• Only 7 trials were eligible for inclusion
• Large heterogeneity in data reported in articles, with different outcome measures being reported
• Large variability in doses of medications and routes of administration between the studies
• Only 1 study compared antipsychotics to combination therapy and so no analysis or conclusions could be made.
• Studies not including antipsychotic medications and benzodiazepines were not included in this review (i.e. diphenhydramine, ketamine, etc…)
• Not clear how 15 – 20 minutes until sedation is considered ideal in the ED setting

Discussion:

• This article quotes shockingly high numbers of assault and abuse. 90% of ED nursing staff have experienced assault or physical intimidation during their career and almost all ED staff report verbal abuse
• Unfortunately, in the US, droperidol use is infrequent due to an FDA black box warning of prolonged QT interval and potential ventricular arrhythmias
• Confounders such as alcohol intoxication and coexistent drug overdoses could have impacted the number and types of adverse events, and not have been reported in studies
• The definition of the most “efficacious” drug regimen for chemical sedation is variable. In general, most would agree an efficacious chemical sedation regimen should have rapid onset of action. Duration can be more contentious; usually we want short acting medications so we can reassess the patient once they’ve recovered from their agitated state and form an appropriate disposition. Sometimes, we want something longer acting, like for an aggressive and violently decompensated psychiatric patient. The bottom line here is chemical sedation can be variable and no one single aspect should be a marker of clinical efficacy.

Author’s Conclusions:

“Combination therapy sedated a greater proportion of patients at 15 – 20 minutes than benzodiazepines alone. Antipsychotics and combination therapy were more effective, requiring less repeat doses for sedation than benzodiazepines. The risk of any adverse event was higher with benzodiazepines.”

Our Conclusions:

This was a good attempt at a meta analysis of a subject of prime importance, chemical sedation of agitated patients. There seems to be a lot of heterogeneity in the literature (time to sedation, medication regimens, etc). Given the difficulty of studying agitated patients, who do not have capacity and are unable to give consent, it’s not surprising there is a paucity of articles and standardization. Clearly in chemical sedation, one shoe does not fit all. However, this article supports the use of combination therapy over lone benzodiazepine use.

Potential Impact to Current Practice:

Giving patients isolated doses of benzodiazepines is often regarded as a prudent and cautious route for sedation. This study supports a better safety profile for combination therapy, both in the number of adverse events seen in patients, as well as for the safety of staff and other patients in the emergency department. Further research comparing the ideal benzodiazepine (the more rapid onset of action and shorter half life of midazolam seems ideal) for sedation, as well as comparing the ideal antipsychotic (including classical antipsychotics vs atypical antipsychotics) for sedation are needed.

Clinical Bottom Line:

Chemical sedation will never have a “one shoe fits all” strategy. Combination therapy with benzodiazepines and antipsychotics appears to help sedate a larger proportion of patients at 10 – 15 minutes, and has a significantly improved safety profile than chemical sedation with a benzodiazepine alone.

Guest Post By:

Bradford Schwartz
Clinical Instructor-University Of Maryland
Prince George Hospital Center
Cheverly, MD
No twitter as of yet

References:

1. Kroczak S et al. Chemical Agents for the Sedation of Agitated Patient in the ED: A Systematic Review. Am Journal of Emerg Med 2016. (34); 2426-2431. PMID: 27707527
2. Bieniek SA, Ownby RL, Penalver A, et al. A Double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy 1998. 18:57–62. PMID: 9469682
3. Wilson MP et al. The Psychopharmacology of Agitation: Consensus Statement of the American Association for Emergency Psychiatry Project BETA Psychopharmacology Workgroup. Western Journal of Emergency Medicine 2012. 12 (1):26-34. PMCID: PMC3298219

For More on This Topic Checkout:

• Rob Orman on ERCast: Art of the Chemical Takedown
• John McKean at Taming the SRU: The Agitated Patient
• Scott Weingart at EMCrit: On Human Bondage and the Art of the Chemical Takedown
• Reuben Strayer at Emergency Medicine Updates: Emergency Management of the Agitated Patient

This Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie) and Anand Swaminathan (Twitter: @EMSwami)