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Date: May 12th, 2018

Reference: Gonin P et al. Excited Delirium: A Systematic Review. AEM May 2018.

Guest Skeptic: Dr. Chris Bond is an emergency physician and clinical lecturer at the University of Calgary. He is currently the host of CAEP Casts, which highlights educational innovations from emergency medicine residency programs across Canada. Chris also has his own #FOAMed blog called Standing on the Corner Minding My Own Business (SOCMOB).

Case: A 24-year-old male is brought into the emergency department by police. He was running around wearing a Batman suit, jumping on cars and screaming he is Batman. He is brought to the emergency department extremely agitated and despite being held down by two police and three security guards he is still trying to bite the staff. You cannot obtain any vital signs and this patient is a danger to himself and staff. How will you manage this patient?

Background: Cases of extreme agitation have been described since the 19thcentury, with Luther Bell’s eponymous “Bell’s mania” being published in the American Journal of Insanity (now American Journal of Psychiatry) in October, 1849 [1]. Bell distinguished these cases of extreme agitation from delirium tremens, diseases of the meninges and advanced typhoid based on a list of clinical criteria, as well as autopsy results from the brains and intestines of the patients.

American Journal of Insanity

Bell’s case mortality rate for this condition was approximately 75%, though this was by no means rigorous data analysis. Interestingly, physicians of the day did not think these cases of extreme agitation would benefit from venesection (blood-letting) but did recommend this for the differential diagnoses.

We have covered Alexander Hamilton’s blood-letting experiment from 1816 on camp fever with Dr. Rob Leeper on SGEM#200. The number needed to harm (death) with blood-letting for soldiers with camp fever was four (NNH 4) and therefore we could not recommend blood-letting as a treatment modality for camp fever.

The term excited delirium syndrome (ExDS) was coined in the 1980s, after a flurry of deaths of individuals in custody or during arrests following extremeagitation [2]. ExDS usually involved men in their 30s after cocaine, methamphetamine, or ecstacy abuse [3-5].

These cases were not limited to patients in custody, however, and fatal cases of ExDS appeared in the hospital without any trauma, physical restraint or police intervention [5]. Given the significant morbidity and mortality rate of 8-10%, this syndrome remains of great importance to the emergency provider [6,7].

Over 150 years since it was first described, there is still no standardized definition of ExDS and diagnostic criteria have not been universally recognized. While the American Psychiatric Association and World Health Organization do not recognize this syndrome as a distinct clinical entity, the American College of Emergency Physicians (ACEP) has recognized it since 2009 [7].

The ACEP definition of ExDS includes “acute delirium (not linked to dementia or preexisting pathologies) associated with extreme physical and psychomotor agitation”.The criteria for this diagnosis are inspired by a Canadian police census report [8] and other case descriptions [2, 7, 9]

Clinical Question: What is the definition, epidemiology, pathophysiology and evidence-based management and treatment of excited delirium?

Reference: Gonin P et al. Excited Delirium: A Systematic Review. AEM May 2018.

  • Population: Patients with excited delirium
  • Intervention: N/A
  • Comparison: N/A
  • Outcome: The review outcome was to clarify and answer four questions:
    1. What are the definition or diagnostic criteria of ExDS?
    2. What are the epidemiological characteristics of ExDS (prevalence, incidence, and case characteristics)?
    3. What are the hypotheses and evidence about the pathophysiologic mechanisms underlying ExDS?
    4. What are the evidence-based medicine management and treatment recommendations of ExDS?

Dr. Gonin

This is an SGEMHOP episode. Dr. Gonin provided written responses to our questions.  Here is what he said got him interested in researching ExDS.

This is an highly acute problematic, requiring a multidisciplinary response, with the coordination of policemen, paramedics, in-hospital nurses, emergency doctors, psychiatrics and event law enforcement specialist.  

Another point is that it’s a subject relatively frequently described in media, because witnessed people who see patients in excited delirium are frequently frightened by the agitation, the medical and police responses, and because of the potentially dramatic ending of the mediated cases. This syndrome is relatively ill-defined but clearly present in our “daily business” and we were therefore interested to investigate in the literature the evidence about causes, mechanism and management.

Authors’ Conclusions: “The overall quality of studies was poor. A universally recognized definition is lacking, remaining mostly syndromic and based on clinical subjective criteria. High mortality rate may be due to definition inconsistency and reporting bias. Our results suggest that ExDS is a real clinical entity that still kills people and that has probably specific mechanisms and risk factors. No comparative study has been performed to conclude whether one treatment approach is preferable to another in the case of ExDS.”

Quality Checklistfor Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable. Yes/Unsure
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. No
  4. The methodological quality of primary studies were assessed for bias. Yes
  5. The assessment of studies were reproducible. Yes
  6. The outcomes were clinically relevant. Yes
  7. There was low heterogeneity for estimates of sensitivity or specificity. N/A
  8. There was low statistical heterogeneity for the primary outcomes. N/A
  9. The treatment effect was large enough and precise enough to be clinically significant. N/A

Key Results:This review was an attempt to clarify and answer four questions about excited delirium syndrome.

  1. Definition/Diagnostic Criteria for ExDS: Three retrospective studies totaling 108 patients proposed a definition for ExDS. There was no universally accepted definition of ExDS, and a large variety of criteria were used with the only pre-requisite being “delirium associated with excited behavior or agitation”. 
  2. Epidemiology of ExDS: There were 23 articles related to epidemiology of ExDS. These studies came from ExDS patients in the context of police interventions, prehospital emergency services, the forensic setting and in hospital. Overall, ExDS patients were middle aged men:
    • 14-71 years old (mean 33.3 and median 30.0) with 83-95% male
  3. Pathophysiology of ExDS: There were 38 articles were related to pathophysiology or risk factors with ExDS mortality. A number of hypotheses were described:
    • Twelve articles hypothesized catecholamine surge, either exogenous (drugs) or endogenous (stress or physical exertion related) or a combination of the two (eg. exertion + cocaine)
    • Nine articles proposed dopamine transporter pathway activation.
    • Six articles proposed individual variation/genetic susceptibility related to chronic stimulant induced abnormalities or dopamine receptor variations.
    • Less frequently proposed mechanisms included cocaine induced neurotoxicity from reactive oxygen species in the CNS, and variations in alpha-synuclein protein or opioid receptors.

Drug abuse is the largest risk factor for ExDS and was associated with ExDS in 15 articles, cocaine being the most frequently associated drug.

Odds ratios of specific risk factors for fatal ExDS from all cocaine related deaths in Dade Country, Florida from 1969-1990 [4].

  • Male gender (OR = 9.3)
  • Young age (OR = 1.1)
  • Afro-American origin (OR=3.5)
  • Overweight (OR=2.7) – BMI quartiles 2-4
    • Note: We would have liked to see 95% confidence intervals around these point estimates, also what did they mean by “young”? That is a moving target and goes up with every birthday.
  1. Evidence Based Management and Treatment of ExDS: They identified 27 articles on the management and treatment of ExDS. Some of the key points included:
    • Restraint Position – Do not restrain in a prone position. It is recommended to move patients to a side lying or seated position.
    • Chemical Sedation – Benzodiazepines (6 articles), neuroleptics (2 articles), benzodiazepines + neuroleptics (1 article) and ketamine (14 articles).
    • Hyperthermia – This was not mentioned in the article although treatment is usually just sedation, intubation and external cooling.

It’s time to talk nerdy. We normally have the lead author on the podcast to answer our nerdy questions. As mentioned earlier, there were some language barriers that I totally understand. I would not want to discuss the nuances of my research in another language.

Hopefully we will soon have a universal translator like on Star Trek that works over skype. Until then Dr. Gonin has agreed to respond in writing to our nerdy question that will be posted to the SGEM blog.

  1. Limits of Evidence Based Medicine: You did an exhaustive search but there is just not much high-quality literature on the topic of ExDS. This can be a limitation of evidence-based medicine. What question using a PICO format would Dr. Gonin propose to study ExDS?
    • First, an “objective” definition is lacking. I think a definition based on objective criteria should be proposed and then used to identify all the cases presented as “Excited delirium”. This would better identify and describe the study-Population.
    • The Intervention to be investigated could be the use of a “rapid sedation protocol”, with clinical quality indicators, such as the reduction of a validated agitation score obtained in a specified time-lapse.
    • As Comparison, we could have different groups, with different sedation protocols and different substances
    • Outcome – Mortality, according to the sedation protocols, the aetiologies of ExDs and the characteristics of the patient. Interestingly, for the patients who survive, we have no information about potential sequelae or recurrence risk of ExDs.
  2. Definition of ExDS: There is no accepted definition for ExDS and this makes it hard to study. ACEP has recognized this condition back in 2009. What would your definition of ExDS be? Is there any progress toward a universal definition at this time? How useful is establishing a definition clinically, these patients are often so agitated that it’s more of an act now and consider the diagnosis later scenario.
    • We didn’t find any progress toward a universal definition, especially to an objective definition. The definition proposed by ACEP has partly subjective criteria. This definition has been used by some investigators, but hasn’t always had the same number of criteria included.
    • I think the objective part of the ACEP definition should be kept: delirium and an agitatied state. We should then think about the accompanying criteria, which should also be objective and minimal in number. As criteria, we could think about body temperature or tachypnea for example, and eventually add some in-hospital criteria that could be optionally used (eg. carbon dioxide in blood gas analysis, acidosis, pH, etc.)
    • It’s clear that it is an “act now situation”, and this also makes it interesting. By acting without a definitive diagnosis, you are just treating symptoms. But you don’t know if you are treating them correctly, or in an evidence-based fashion. In order to know if you are using the best treatment option, you have to investigate the ExDS, and for this you need a universally validated definition. After this you will know, we hope, which treatment option is the best to use first line when you encounter a highly agitated patient.
  3. Social Determinants of Health: The risk factors associated with ExDS seem to point towards a social problem (young, male, African-American, substance abuse). What strategies do you think could help address the social determinants of health, so these individuals do not end up presenting to the police and then to the emergency department (education, jobs, food security, access to mental health, affordable housing, drug treatment programs, etc.)
    • This question is difficult to answer for me. I’m wondering if those strategies are not different in different parts of the world; it is likely substance abuse is an essential issue, and we should see which factors are implicated in this problem. The other important population in this context present with psychiatric comorbidities. An issue could be to see if the stress-inducing situations have different impact on these groups and if the stress should be mitigated more aggressively in some sub-groups, with different sedation protocols or different physical coercive measures. 
  4. Police/Law Enforcement: Great emergency care starts in the pre-hospital setting and goes all the way to follow-up after discharge from hospital and everything in-between. Much of the literature found was from non-traditional emergency medicine sources. Police are a very important part of the health care system, are there any specific management recommendations from the police studies?
    • The most important point is that police forces should be aware of this syndrome and should collaborate with the Emergency Medical Services. The aim is to minimize the time the patient is physically exerted, and to initiate sedation at the same time as the physical measures.
  5. Pharmacological Management: A variety of treatments have been used for ExDS. Clinician’s first choice may identify when they trained (B52, type of benzodiazepam, type of anti-psychotic). Ketamine is becoming a treatment for everything (procedural sedation, rapid sequence intubation, depression, pain control). What are your thoughts on the best medication and what agent do you routinely use first? Can you be specific about drugs/doses as table 6 shows very big ranges? What could someone take from this podcast and use on their next shift? As an aside, to give 400 mg ketamine IM, give it as two separate vastus lateralis injections on each side. What about the management of hyperthermia in these cases?
    • That’s right, many different sedation protocols have been used and none of them were prospectively validated. The ideal drug should be short-acting, have no secondary effect or complication, and ideally have an antidote available. It would be even better if the drug could be administered to the patient without direct physical contact.
    • Clearly, this ideal drug does not exist.
    • Most of the recent publications are related to benzodiazepines, presenting some of the aforementioned characteristics. The doses are highly variable, probably in the absence of an universal standardization of the sedation protocol, but also because of the huge heterogeneity of the patients. The main point is probably the rapid titration of the same drug, for example with midazolam 5 mg.
    • Ketamine is an interesting option, but also with limited evidence (most of the cases are case reports or limited case series). The difficulty is to manage ketamine adequately, with the risk of increased agitation with small doses and the anesthetic effect with high doses. But clearly an alternative in extreme agitation! Finally, cocktails should probably be avoided, to prevent secondary effect or complication.    

Is there anything else you would like the SGEMers to know about your research on ExDS?

“It was a great opportunity for me to do this review and I thank all the co-authors, without whom this work wouldn’t have been possible. It shows that there is still a long way until we have answers to all the questions about this topic. From a clinical view, evidence-based, validated sedation protocols would be of great interest for EMS and in-hospital emergency teams”

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors conclusion.

SGEM Bottom Line: The excited delirium syndrome remains a poorly defined disease and is difficult to study because of its inconsistent definition. However, it is a dangerous, high morbidity and mortality condition that requires aggressive management in the emergency department.

Case Resolution: After attempting to calm the patient verbally, you give him several doses of midazolam and his agitation subsides. His vital signs normalize and after a few hours he is more lucid and no longer thinks he is Batman. He admits to using methamphetamine earlier and you have a discussion about the dangers of drug use and offer support for drug cessation.

Clinical Application: Excited delirium is a life threatening medical condition and must be acted on quickly and aggressively in order to treat the patient and protect staff.

Dr. Chris Bond

What Do I Tell My Patient? You are extremely agitated because of a serious medical condition and/or drugs you have taken. We need to give you medication to calm you down as this is life threatening and you are both a danger to yourself and others in if we do not.

Keener Kontest: Last weeks’ winner was Peter Trachy. He knew Bane was the super villain who broke Batman’s back, leaving him crippled and wheelchair-bound? This is a back-to-back win for Peter and I will be sending him a special cool skeptical prize.

Listen to the SGEM podcast on iTunes to hear this weeks’ question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed Resources:

  • EM Cases: Excited Delirium
  • ALiEM: Ketamine for Excited Delirium Syndrome
  • RCEM Learning: Anecdote-based Emergency Medicine #1: excited delirium
  • EMCrit:On Human Bondage and the Art of the Chemical Takedown

SGEMHOP: Now it is your turn SGEMers. What do you think of this episode on ExDS? Tweet your comments using #SGEMHOP. What questions do you have for Dr. Gonin and his team? Ask them on the SGEM blog. The best social media feedback will be published in AEM.

Also, don’t forget those of you who are subscribers to Academic Emergency Medicine can head over to the AEM home page to get CME credit for this podcast and article. We will put the process on the SGEM blog:

  • Go to the Wiley Health Learning web-site
  • Register and create a log in
  • Search for Academic Emergency Medicine – “May”
  • Complete the five questions and submit your answers
  • Please email Corey (coreyheitzmd@gmail.com) with any questions or difficulties.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’Guide to Emergency Medicine.

References:

  1. Bell LV. On a form of disease resembling some advanced stages of mania and fever, but so contradistinguished from any ordinary observed or described combination of symptoms as to render it probable that it may be overlooked and hitherto unrecorded malady. Am J Insanity 1849;6.
  2. Wetli CV, Fishbain DA. Cocaine-induced psychosis and sudden death in recreational cocaine users. J Forensic Sci 1985;30:873–80.
  3. 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;19:187–91.
  4. Ruttenber AJ, Lawler-Heavner J, Yin M, Wetli CV, Hearn WL, Mash DC. Fatal excited delirium following cocaine use: epidemiologic findings provide new evidence for mechanisms of cocaine toxicity. J Forensic Sci 1997;42:25–31.
  5. O’Halloran RL, Lewman LV. Restraint asphyxiation in excited delirium. Am J Forensic Med Pathol 1993;14:289–95.
  6. Vilke GM, DeBard ML, Chan TC, et al. Excited delirium syndrome (ExDS): defining based on a review of the literature. J Emerg Med 2012;43:897–905.
  7. DeBard ML, Adler J, Bozeman W, Chan T. White Paper Report on Excited Delirium Syndrome. 2009. Available at: http://www.fmhac.net/Assets/Documents/2012/Presentations/KrelsteinExcitedDelirium.pdf. Accessed Feb 10, 2016.
  8. Hall C, Butler C, Kader A, et al. Police use of force, injuries and death: prospective evaluation of outcomes for all police use of force/restraint including conducted energy weapons in a large Canadian city. Acad Emerg Med 2009;16:198–9.
  9. Strote J, Walsh M, Auerbach D, Burns T, Maher P. Medical conditions and restraint in patients experiencing excited delirium. J Emerg Med 2014;32:1093–6.