Prehospital Treatment of the Acutely Agitated Patient: Ketamine in the Spotlight

Mental and behavioral health emergencies represent a large proportion of both pre-hospital and emergency department volumes with estimates ranging anywhere from 5-15% of Emergency Medical Services (EMS) call volume1 and up to 10% of emergency department (ED) visits each year.2 The term “EDP” or “emotionally disturbed person” has become popular amongst emergency services personnel and the term is used to encompass acute psychiatric conditions, intoxication with mind altering substances and for patients acting strangely due to significant medical decompensation. When an EDP call is dispatched, it is not uncommon for police to be the first on scene to ensure scene safety for EMS personnel, bystanders and the patients themselves. It is at this intersection of police, EMS, and EDPs that we have unfortunately identified a pattern of unnecessary patient deaths which have been more and more often found in the national spotlight. Cases of death in EMS or police custody as of late can often be found in the national news, with high profile lawsuits, payouts, and recently, with criminal charges to EMS and police involved.

There is one other significant factor that has been found to be interwoven with so many of these unfortunate encounters: the use of ketamine. Ketamine, a dissociative anesthetic, has had a meteoric rise in popularity over the past few decades in the emergency medicine (EM) and EMS worlds. It is a versatile medication, with indications ranging from procedural sedation, induction for intubation, pain control and in cases of EDPs, as a fast-acting chemical restraint.³ However, amidst the rising scrutiny against this medicine by the general public and the media demonizing it for its purported role in patient deaths, the question remains: is this medication safe?

Yes. Ketamine is overwhelmingly safe. For the remainder of this article, I would like to discuss the efficacy and safety of ketamine, the historical use of terms including Excited Delirium, and the interplay between ketamine and restraint in so many of these highly publicized deaths.

Ketamine is a competitive antagonist of glutamate at the N-methyl-D-aspartate (NMDA) receptor, with hepatic breakdown and renal excretion. When given intramuscularly (IM), it takes effect within 3-5 minutes, when given intravenously (IV), within 15-30 seconds, and with effects lasting 5-30 minutes, in a dose dependent manner.⁴ At low doses, it provides a marked anesthetic effect. At higher doses, it also creates a dissociative amnesia, making it a powerful tool to facilitate procedures or render a patient into a non-combative state, after which additional medical aid can be administered. However, no drug is without side effects, and ketamine is no exception. It can, rarely, be associated with laryngospasm, hypersalivation, emesis, emergence reaction (recovery agitation) and when administered too quickly, transient apnea.^4,5 Once thought to increase intracranial pressure and potentiate neurologic injury, especially in trauma patients, recent studies have largely disproven these effects. Some concerns also exist in regards to giving ketamine to known psychiatric patients, as NMDA receptor antagonism was thought to potentiate acute psychiatric illness; however, ketamine use was not found to increase the need for inpatient psychiatric admission.⁶ Even in quantities far exceeding the typical recommended maximums (2mg/kg IV and 6mg/kg IM), patients do not lose their respiratory drive in a dose dependent manner⁷ or develop hemodynamic instability when controlled for comorbid conditions and other concurrent medication and drug use. Rather, the duration of their dissociative period is just prolonged.⁸ All of this literature is to say, ketamine is remarkably safe.

Ketamine is not the only medication at the disposal of our prehospital practitioners to assist with agitated patients. Traditionally, benzodiazepines and antipsychotics have also been employed with relative success. In comparison with benzodiazepines, such as midazolam and lorazepam, ketamine is not associated with a decrease in blood pressure and has been found to act much faster.⁹ While all of these sedative medications have some associated need for intubation for airway protection post administration, rates following ketamine administration appear much lower than once thought;¹⁰some studies suggesting higher rates may be due to individual physician practice variation.¹¹ Compared to antipsychotics such as haloperidol and olanzapine, ketamine is much faster in onset and requires fewer repeat administrations to maintain appropriate levels of sedation.¹²

To shift gears for a moment, the terminology we associate with these patients should also be discussed. Historically, the term “Excited Delirium Syndrome” (EDS) or “Agitated Delirium” (AD) were used as a blanket diagnosis for any patient presenting with significant agitation. It did not matter whether these patients were in the midst of an acute medical condition, drug intoxication, or psychiatric emergency, they received a generalized diagnosis, which was then often met with a singular response: immediate physical and chemical restraint. The unfortunate end result is that this term began to be disproportionately applied to African American males and those with underlying psychiatric disorders, which led to an increase in perceived danger, which primed a greater use of physical and chemical restraint in the prehospital setting.¹³ The consequences were deadly. The term Excited Delirium Syndrome soon became co-opted by police literature, followed by another term “Death in Custody Syndrome;” these terms were often found interwoven. The development of these terms and their widespread adoption into medical and police literature created the illusion of a unique standalone pathology that was responsible for these patient’s deaths. The term EDS even began to show up on death certificates, without the underlying causes being identified or evaluated further.

Fortunately, this terminology is losing favor. As of now, the majority of medical institutions have disavowed EDS. Many groups including the American Medical Association,¹⁴ the American Psychological Association,¹⁵the American Academy of Emergency Medicine,¹⁶ and the American College of Medical Toxicology¹⁷ have put out position statements refuting the term, in favor of identifying a specific condition, or describing symptoms instead if no readily available diagnosis exists.

The American College of Emergency Physicians has also rejected EDS in favor of “Hyperactive Delirium with Severe Agitation,” or just “Hyperactive Delirium.” This term will be utilized for the remainder of this article. Their position statement also calls for additional research into the underlying causes and also includes a clause that suggests the decision to chemically sedate should be at the directive of the medical team, and no one else.¹⁸

Hyperactive Delirium and its underlying causes inherently carry a mortality risk. Hyperthermia, arrythmia, electrolyte imbalances, transient cardiomyopathy, rhabdomyolysis and seizures can all occur if not treated in a time sensitive manner, and cardiac arrest may occur spontaneously if there is not rapid intervention.¹⁹ This is in addition to the trauma that can occur with altered mental status in regards to accidental trauma by means of falls, traffic and direct violence. Hyperactive Delirium is a high lethality situation, and aborting it in a timely fashion with quick acting medications is the best way to save lives. Unfortunately, some of these patients will die due to their underlying pathologies despite receiving appropriate chemical sedation. This is one of the confounding factors that I would like to propose in relation to purported ketamine related deaths. A retrospective analysis on prehospital ketamine use and mortality evaluated ¹¹,291 patients administered ketamine which included 128 deaths, but were able to effectively disregard ketamine as a primary contributor in all but 8 cases; this represents only 0.07% of patients who received ketamine.²⁰

The compounding factors in the lethality of Hyperactive Delirium occur during and immediately after the administration of ketamine or other sedative agents: physical restraint, patient positioning, and monitoring. Physical restraint, though often necessary to facilitate safe patient contact initially, has been strongly linked with these deaths. A 2020 metanalysis investigating Excited and Agitated Delirium deaths found that 90% of Hyperactive Delirium patient deaths occurred in settings where physical restraint was employed. Digging even deeper into this study, only 2% of deaths specifically did not involve physical restraint (and 8% did not indicate clearly if physical restraint was used or not).²¹ Restraint in a prone position, in a classic hog tie, or in cases involving pressure, such as knee’s, to the chest or back can all significantly impede adequate chest excursion during respiration. Combine physical restraint (appropriately employed or not) to an agitated patient with elevated metabolic demand, possible impairment with additional substances, and a chemical sedative like ketamine, and positional asphyxia will ensue. In cases of improper monitoring, this will be deadly.

The bottom line is this. Some patients with Hyperactive Delirium will require chemical and physical restraints to be treated and ketamine is a reliable and low risk option to employ. However, all medications and procedures carry risk; I will argue that sedating and restraining these patients is safer than not. Chemically sedating a patient should be treated with the same attention any other involved procedure is given and only performed after less invasive alternatives like verbal de-escalation have been exhausted. Positioning and monitoring are the ultimate keys to safety. As soon as it is safe to do so, physical restraint should be minimized or removed, monitoring tools initiated, back up airway equipment should be readily available and these patients should be brought expeditiously to the emergency department where they can receive the remainder of their care. The solution to preventing these unnecessary deaths is not in restricting ketamine or limiting sedation protocols in the prehospital setting, it is just to maintain good patient care.

I wish to end with two additional sources of information which can further shed light on this issue and provide guidance on best practices. First, please direct your attention to emupdates.com, where you can find extensive educational materials provided by Dr. Reuben Strayer on agitation and chemical sedation with step-by-step pathways and treatments for mild, moderate and severely agitated patients in the emergency department environment.²² I also wish to provide a referral to the website thehardwork.org, created by Paramedic and Attorney Eric Jaeger. Mr. Jaeger is uniquely experienced in both the medical and legal sides of prehospital sedation and has been able to provide expert guidance to many EMS agencies across the country.²³

Take Home Points:

-Hyperactive Delirium is a highly lethal condition which requires rapid intervention.

-Only proceed with chemical restraint if you, the medical provide, feel it is warranted.

-Physical restraint and prone positioning can be lethal, even before sedative medications.

-Proper patient positioning and monitoring are key to reducing unnecessary patient deaths.

-Ketamine is a remarkably safe medication when used correctly.

References

• Ding ML, Gerberi DJ, McCoy RG. Engaging emergency medical services to improve post-acute management of behavioral health emergency calls: a protocol of a scoping literature review. BMJ Open. 2023;13(3):e067272. Published 2023 Mar 13. doi:10.1136/bmjopen-2022-067272
• Rezaie, Salim, “The Evolution of Ketamine for Severe Agitation”, REBEL EM blog, July 1, 2019. Available at: https://rebelem.com/the-evolution-of-ketamine-for-severe-agitation/
• Villas-Boas S, Kaplan S, White JS, Hsia RY. Patterns of US Mental Health–Related Emergency Department Visits During the COVID-19 Pandemic. JAMA Netw Open. 2023;6(7):e2322720. doi:10.1001/jamanetworkopen .2023.22720
• Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent Refindings). CNS Neurosci Ther. 2013;19(6):370-380. doi:10.1111/cns.12099
• Friedman MS, Saloum D, Haaland A, Drapkin J, Likourezos A, Strayer RJ. Description of Adverse Events in a Cohort of Dance Festival Attendees with Stimulant-Induced Severe Agitation Treated with Dissociative-Dose Ketamine. Prehosp Emerg Care. 2021 Nov-Dec;25(6):761-767. doi: 10.1080/10903127.2020.1837311. Epub 2020 Nov 11
• Lebin JA, Akhavan AR, Hippe DS, Gittinger MH, Pasic J, McCoy AM, Vrablik MC. Psychiatric Outcomes of Patients With Severe Agitation Following Administration of Prehospital Ketamine. Acad Emerg Med. 2019 Aug;26(8):889-896. doi: 10.1111/acem.13725. Epub 2019 Apr 3
• Parks DJ, Alter SM, Shih RD, Solano JJ, Hughes PG, Clayton LM. Rescue intubation in the emergency department after prehospital ketamine administration for agitation. Prehosp Disaster Med. 2020;00(00):1-5 doi:10.1017/S1049023X20001168
• Paulina B. Sergot, Loren B. Mead, Elizabeth B. Jones, Remle P. Crowe & Ryan M. Huebinger (2023): Association of Ketamine Dosing with Intubation and Other Adverse Events in Patients with Behavioral Emergencies, Prehospital Emergency Care, DOI:10.1080/10903127.2023.2234491
• Barbic D, Andolfatto G, Grunau B, Scheuermeyer FX, Macewan B, Qian H, Wong H, Barbic SP, Honer WG. Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial. Ann Emerg Med. 2021 Dec;78(6):788-795. doi: 10.1016/j. annemergmed.2021.05.023. Epub 2021 Aug 2
• Coffey SK, Vakkalanka JP, Egan H, Wallace K, Harland KK, Mohr NM, Ahmed A. Outcomes Associated with Lower Doses of Ketamine by Emergency Medical Services for Profound Agitation. West J Emerg Med. 2021 Aug 30;22(5):1183-1189. doi: 10.5811/westjem.2021.5.50845
• Cole JB, Klein LR, Nystrom PC, Moore JC, Driver BE, Fryza BJ, Harrington J, Ho JD. A prospective study of ketamine as primary therapy for prehospital profound agitation. Am J Emerg Med. 2018 May;36(5):789-796. doi: 10.1016/j.ajem.2017.10.022. Epub 2017 Oct 7
• Cole JB, Moore JC, Nystrom PC, Orozco BS, Stellpflug SJ, Kornas RL, Fryza BJ, Steinberg LW, O’Brien-Lambert A, Bache-Wiig P, Engebretsen KM, Ho JD. A prospective study of ketamine versus haloperidol for severe prehospital agitation. Clin Toxicol (Phila). 2016 Aug;54(7):556-62. doi: 10.1080/15563650.2016.1177652. Epub 2016 Apr 22
• Fiscella K, Pinals DA, Shields CG. “Excited delirium,” erroneous concepts, dehumanizing language, false narratives, and threat to Black lives. Acad Emerg Med. 2022 Jul;29(7):911-913. doi: 10.1111/acem.14483. Epub 2022 Apr 5
• American Medical Association, Pharmacological Intervention for Agitated Individuals in the Out-of-Hospital Setting H-130.932, last modified 2021, retrieved March 25, 2024 from https://policysearch.ama-assn.org/policyfinder/detail/H-130.932?uri=%2FAMADoc%2FHOD.xml-H-130.932.xml
• American Psychiatric Association, Position Statement on Concerns About Use of the Term “Excited Delirium” and Appropriate Medical Management in Out-of-Hospital Contexts, Approved by the Board of Trustees December 2020, retrieved March 25, 2024 from https://www.psychiatry.org/getattachment/7769e617-ee6a-4a89-829f-4fc71d831ce0/Position-Use-of-Term-Excited-Delirium.pdf
• American Academy of Emergency Medicine, AAEM Revised Excited Delirium Statement, updated September 21, 2022, retrieved March 25, 2024 from https://www.aaem.org/statements/
• American College of Medical Toxicology, Ketamine Sedation and Law Enforcement, September 28, 2020, retrieved March 25, 2024 from https://www.acmt.net/news/ketamine-sedation-and-law-enforcement/
• American College of Emergency Physicians Hyperactive Delirium Task Force. ACEP Task Force Report on Hyperactive Delirium with Severe Agitation in Emergency Settings. Approved by the ACEP Board of Directors, June 23, 2021. Retrieved March 25, 2024 from https://www.acep.org/news/acep-newsroom-articles/aceps-position-on-hyperactive-delirium
• Stratton SJ, Rogers C, Brickett K, Gruzinski G. Factors associated with sudden death of individuals requiring restraint for excited delirium. Am J Emerg Med. 2001 May;19(3):187-91. doi: 10.1053/ajem.2001.22665
• Fernandez AR, Bourn SS, Crowe RP, Bronsky ES, Scheppke KA, Antevy P, Myers JB. Out-of-Hospital Ketamine: Indications for Use, Patient Outcomes, and Associated Mortality. Ann Emerg Med. 2021 Jul;78(1):123-131. doi: 10.1016/j.annemergmed.2021.02.020. Epub 2021 Jun 7
• Strömmer, E.M.F., Leith, W., Zeegers, M.P. et al. The role of restraint in fatal excited delirium: a research synthesis and pooled analysis. Forensic Sci Med Pathol 16, 680–692 (2020). https://doi.org/10.1007/s12024-020-00291-8
• Strayer, Reuben, Category: Agitation, Retrieved April 2, 2024 from https://emupdates.com/category/agitation/https://emupdates.com/category/agitation/
• Jaeger, Eric, Overview: Death in Custody, Retrieved March 25, 2024 from https://www.thehardwork.org/dic-overview