Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial

Abstract

We hypothesized that the use of intramuscular ketamine would result in a clinically relevant shorter time to target sedation.Methods: We conducted a randomized clinical trial comparing the rapidity of onset, level of sedation, and adverse effect profile of ketamine compared to a combination of midazolam and haloperidol for behavioral control of emergency department patients with severe psychomotor agitation. We included patients with severe psychomotor agitation measured by a Richmond Agitation Score (RASS) þ3. Patients in the ketamine group were treated with a 5 mg/kg intramuscular injection. Patients in the midazolam and haloperidol group were treated with a single intramuscular injection of 5 mg midazolam and 5 mg haloperidol. The primary outcome was the time, in minutes, from study medication administration to adequate sedation, defined as RASS -1. Secondary outcomes included the need for rescue medications and serious adverse events.Results: Between June 30, 2018, and March 13, 2020, we screened 308 patients and enrolled 80. The median time to sedation was 14.7 minutes for midazolam and haloperidol versus 5.8 minutes for ketamine (difference 8.8 minutes [95% confidence interval (CI) 3.0 to 14.5]). Adjusted Cox proportional model analysis favored the ketamine arm (hazard ratio 2.43, 95% CI 1.43 to 4.12). Five (12.5%) patients in the ketamine arm and 2 (5.0%) patients in the midazolam and haloperidol arm experienced serious adverse events (difference 7.5% [95% CI -4.8% to 19.8%]). Conclusion:In ED patients with severe agitation, intramuscular ketamine provided significantly shorter time to adequate sedation than a combination of intramuscular midazolam and haloperidol. [

A Comparative Analysis Between Ketamine Versus Combination of Midazolam and Haloperidol for Rapid Safe Control of Agitated Patients in Emergency Department: A Systematic Review

“…We included three studies in our manuscript [12][13][14]. O'Connor et al was a retrospective cohort study that evaluated the effect of ketamine, a combination of haloperidol and benzodiazepine, and physical strain on agitated patients who came to ED [12].…”

Promises and Pitfalls of NMDA Receptor Antagonists in Treating Violent Aggression

“…They possess a quicker onset of action and fewer observed side effects than current alternatives. NMDARs also have great potential as a long-lasting treatment option due to their effects on synaptic plasticity (Roberts and Geeting, 2001 ; Cummings et al, 2008 ; Hopper et al, 2015 ; Cole et al, 2016 ; Riddell et al, 2017 ; Barbic et al, 2021 ), where these drugs can induce persistent changes in synaptic function, neural firing, and animal behavior, in some cases, even after a single dose (Wilcock et al, 2008 ; Moda-Sava et al, 2019 ; Tran and Mierzwinski-Urban, 2019 ; Nordman et al, 2022 ).…”

“…Ketamine gained popularity as a party drug in the 1980s, with sub-anesthetic doses sending users into the colloquially named “K-hole”—a dissociative state commonly accompanied by out-of-body experiences, a sensation of weightlessness, and distortions of time (Dillon et al, 2003 ). The FDA has approved ketamine for the induction and maintenance of general anesthesia, but there are also many off-label uses of ketamine, including as a local anesthetic, in procedural sedation, pain management, asthma, and depression (Papolos et al, 2013 ; Burger et al, 2016 ; Dwyer et al, 2017 ; Cullen et al, 2018 ; Tran and Mierzwinski-Urban, 2019 ; Zarrinnegar et al, 2019 ; Barbic et al, 2021 ; Kim et al, 2021 ; Solano et al, 2021 ).…”

“…Many studies support the use of ketamine to treat violent aggression, agitation, psychosis, self-harm, and suicidal ideation (Burger et al, 2016 ; Dwyer et al, 2017 ; Cullen et al, 2018 ; Zarrinnegar et al, 2019 ). In the majority of these cases, clinicians take advantage of ketamine’s sedative properties to control aggressive outbursts in hospital and pre-hospital settings (Roberts and Geeting, 2001 ; Melamed et al, 2007 ; Le Cong et al, 2012 ; Scheppke et al, 2014 ; Riddell et al, 2017 ; Barbic et al, 2021 ; Kent et al, 2022 ). Sedative doses of ketamine fall in the 1–2 mg/kg range if given intravenously, and 3–5 mg/kg if given intramuscularly.…”

“…We propose in this review that NMDAR antagonists are favorable in treating aggression over traditional methods due to their quicker onset of action, fewer observed side effects, and potential as a long-lasting treatment option due to their effects on synaptic plasticity (Roberts and Geeting, 2001 ; Cummings et al, 2008 ; Wilcock et al, 2008 ; Hopper et al, 2015 ; Cole et al, 2016 ; Riddell et al, 2017 ; Tran and Mierzwinski-Urban, 2019 ; Barbic et al, 2021 ; Nordman et al, 2022 ). Though there are multiple clinically available NMDAR antagonists, such as the non-competitive antagonists dextromethorphan and amantadine (Hewitt, 2000 ) and the non-selective, NMDAR-binding opioids methadone, dextropropoxyphene, and ketobemidone (Sang, 2000 ), we will focus on the non-competitive antagonists ketamine and memantine, as they are the most widely used and successful NMDAR antagonists on the market.…”